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1
Misch, Monica, and Prasanth Puthanveetil. "The Head-to-Toe Hormone: Leptin as an Extensive Modulator of Physiologic Systems." International Journal of Molecular Sciences 23, no. 10 (May 13, 2022): 5439. http://dx.doi.org/10.3390/ijms23105439.
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Leptin is a well-known hunger-sensing peptide hormone. The role of leptin in weight gain and metabolic homeostasis has been explored for the past two decades. In this review, we have tried to shed light upon the impact of leptin signaling on health and diseases. At low or moderate levels, this peptide hormone supports physiological roles, but at chronically higher doses exhibits detrimental effects on various systems. The untoward effects we observe with chronically higher levels of leptin are due to their receptor-mediated effect or due to leptin resistance and are not well studied. This review will help us in understanding the non-anorexic roles of leptin, including their contribution to the metabolism of various systems and inflammation. We will be able to get an alternative perspective regarding the physiological and pathological roles of this mysterious peptide hormone.
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Flatow, Elizabeth A., Evilin N. Komegae, Monique T. Fonseca, Camila F. Brito, Florin M. Musteata, José Antunes-Rodrigues, and Alexandre A. Steiner. "Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, no. 5 (November 1, 2017): R572—R582. http://dx.doi.org/10.1152/ajpregu.00171.2017.
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To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0–20 μg·kg−1·h−1) or intracerebroventricularly (0–1 μg·kg−1·h−1). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in vitro experiments to investigate whether an action of leptin on macrophages could parallel our in vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a proinflammatory effect but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted.
3
Wisse, Brent E., Kayoko Ogimoto, Gregory J. Morton, Charles W. Wilkinson, R. Scott Frayo, David E. Cummings, and Michael W. Schwartz. "Physiological regulation of hypothalamic IL-1β gene expression by leptin and glucocorticoids: implications for energy homeostasis." American Journal of Physiology-Endocrinology and Metabolism 287, no. 6 (December 2004): E1107—E1113. http://dx.doi.org/10.1152/ajpendo.00038.2004.
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Interleukin-1β (IL-1β) is synthesized in a variety of tissues, including the hypothalamus, where it is implicated in the control of food intake. The current studies were undertaken to investigate whether hypothalamic IL-1β gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1β mRNA levels twofold, measured by real-time PCR ( P < 0.05 vs. sham-operated controls), and this effect was blocked by subcutaneous infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1β mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity caused by leptin receptor mutation ( P = 0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1β mRNA levels in fa/fa rats ( P = 0.02) is similar to that seen in normal animals. Moreover, fasting for 48 h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1β mRNA levels by 30% ( P = 0.02), and this decrease was fully reversed by refeeding for 12 h. Thus leptin and GCs exert opposing effects on hypothalamic IL-1β gene expression, and corticosterone plays a physiological role to limit expression of this cytokine in both the presence and absence of intact leptin signaling. Consistent with this hypothesis, systemic leptin administration to normal rats (2 mg/kg ip) increased hypothalamic IL-1β mRNA levels twofold ( P < 0.05 vs. vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1β is subject to opposing physiological regulation by corticosterone and leptin.
4
Powis, Jeff E., Jaideep S. Bains, and Alastair V. Ferguson. "Leptin depolarizes rat hypothalamic paraventricular nucleus neurons." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 274, no. 5 (May 1, 1998): R1468—R1472. http://dx.doi.org/10.1152/ajpregu.1998.274.5.r1468.
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Leptin, the protein product of the ob/ obgene, is thought to have a central site of action, presumably within the hypothalamus, through which it regulates feeding behavior. The paraventricular nucleus (PVN) is one structure that has been implicated in regulating feeding behavior. Using patch-clamp recording techniques, this study examines the direct membrane effects of leptin on neurons in a coronal PVN slice. Bath application of the physiologically active leptin fragment (amino acids 22–56) elicited dose-related depolarizations in 82% of the type I cells tested ( n = 17) and 67% of the type II cells tested ( n = 9). By contrast, the physiologically inactive leptin fragment (amino acids 57–92) had no discernible effect on membrane potential ( n = 7). The effects of this peptide were unaffected following synaptic isolation of the cells by bath application of the sodium channel blocker tetrodotoxin ( n = 5). Voltage clamp recordings in six cells demonstrated that leptin increased a nonspecific cation conductance with a reversal potential near −30 mV. These findings suggest that neurons in PVN may play an important role in the central neuronal circuitry involved in the physiological response to leptin.
5
Linnemann, K., A. Malek, H. Schneider, and C. Fusch. "Physiological and pathological regulation of feto/placento/maternal leptin expression." Biochemical Society Transactions 29, no. 2 (May 1, 2001): 86–90. http://dx.doi.org/10.1042/bst0290086.
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There is clear evidence of placental leptin production, as shown recently in trophoblast cultures and by dual in vitro placenta perfusion (median production of 225 pg/min per g of tissue; 98.4% released into the maternal and 1.6% into the fetal circulation). However, the physiological impact for the mother and the fetus is unclear. The classical role of leptin is to provide information about energy stores to the central nervous system, and to reduce appetite if the energy stores are full. In pregnancy, maternal plasma leptin concentrations are elevated, and lack the well established correlation with body fat energy stores that is observed in non-pregnant women, indicating an alternative function for leptin during pregnancy and fetal development. Maternal and fetal plasma leptin levels are dysregulated in pathological conditions such as gestational diabetes, pre-eclampsia and intra-uterine growth retardation, representing an effect or a cause of disturbances in the feto/placento/maternal unit.
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Ghizzoni, Lucia, George Mastorakos, Mariangela Ziveri, Mariangela Furlini, Angela Solazzi, Alessandra Vottero, and Sergio Bernasconi. "Interactions of Leptin and Thyrotropin 24-Hour Secretory Profiles in Short Normal Children." Journal of Clinical Endocrinology & Metabolism 86, no. 5 (May 1, 2001): 2065–72. http://dx.doi.org/10.1210/jcem.86.5.7452.
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Thyroid hormones and leptin have effects on similar aspects of body homeostasis, such as energy expenditure, thermogenesis, and metabolic efficiency. Thus, the cross-talk between the thyrostat and the lipostat might play a crucial role in the maintenance of body homeostasis. To investigate the relationship between the hypothalamic-pituitary-thyroid (HPT) axis and leptin under physiological conditions, we evaluated the pulsatility and circadian rhythmicity and time-cross-correlated the 24-h secretory patterns of leptin and TSH in 12 short normal prepubertal children (6 girls and 6 boys). In both male and female subjects, leptin was secreted in a pulsatile and circadian fashion, with a nocturnal leptin surge that was more pronounced in males than in females. Mean 24-h leptin levels and total area under the curve were significantly higher in girls than in boys. This was mainly due to the nighttime mean leptin levels and total area under the curve, which were higher than those in boys. The cross-correlated 24-h leptin and TSH levels revealed significant positive and negative correlations. The positive one, of leptin over TSH, suggests a positive feedback regulation by leptin on the HPT axis, which might play an important role in triggering the neuroendocrine response to starvation, including decreased thyroid hormone levels. The negative correlation, of TSH over leptin, could explain the compensatory changes in adipocyte metabolism, and indirectly in circulating leptin levels, in response to alterations in thyroid status. In conclusion, we suggest that under baseline physiological conditions, the HPT axis has a prevailing inhibitory effect on leptin secretion, whereas leptin has a prevailing positive effect on the HPT axis. The sexual dimorphism in leptin levels does not seem to influence in a major way the interactions between the HPT axis and leptin.
7
Shebl, M. M. "Effect of leptin on LH and FSH release in ovariectomized rats." Eastern Mediterranean Health Journal 08, no. 01 (March 15, 2002): 105–13. http://dx.doi.org/10.26719/2002.8.1.105.
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We compared the estradiol/progesterone-induced luteinizing hormone [LH] and follicle-stimulating hormone [FSH] release between normally fed and leptin-supplemented starved ovariectomized female rats and studied also the effect of hyper-leptinaemia on the steroid-induced hormonal release in normally fed ovariectomized rats. Three days’ starvation completely abolished steroid-induced LH and FSH release. Significant recovery of the hormonal release was shown in the leptin-supplemented starved group. The magnitudes of LH and FSH release in the normally fed animals with a higher dose of leptin were statistically the same as those in the normally fed group without leptin. These observations indicate that physiological concentrations of circulating leptin exert a stimulatory effect on steroid-induced LH and FSH release.
8
Jethwa, Preeti H., Caroline J. Small, Kirsty L. Smith, Asha Seth, Sarah J. Darch, Caroline R. Abbott, Kevin G. Murphy, Jeannie F. Todd, Mohammad A. Ghatei, and Stephen R. Bloom. "Neuromedin U has a physiological role in the regulation of food intake and partially mediates the effects of leptin." American Journal of Physiology-Endocrinology and Metabolism 289, no. 2 (August 2005): E301—E305. http://dx.doi.org/10.1152/ajpendo.00404.2004.
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Intracerebroventricular (ICV) administration of Neuromedin U (NMU), a hypothalamic neuropeptide, or leptin, an adipostat hormone released from adipose tissue, reduces food intake and increases energy expenditure. Leptin stimulates the release of NMU in vitro, and NMU expression is reduced in models of low or absent leptin. We investigated the role of NMU in mediating leptin-induced satiety. ICV administration of anti-NMU immunoglobulin G (IgG) (5 nmol) to satiated rats significantly increased food intake 4 h after injection, an effect seen for ≤8 h after injection. ICV administration of NMU (1 nmol) to fasted rats reduced food intake 1 h after injection compared with control, an effect attenuated by pretreatment with anti-NMU IgG. ICV administration of leptin (0.625 nmol) reduced 24-h food intake. This was partially attenuated by the administration of anti-NMU IgG [24 h after onset of dark phase: vehicle, 22.5 ± 2.0 g; leptin, 13.7 ± 2.3 g ( P < 0.005 vs. vehicle), leptin/NMU IgG, 19.4 ± 1.3 g ( P < 0.05 vs. leptin)]. Intraperitoneal administration of leptin (1.1 mg/kg body wt) reduced 24-h food intake. This was partially attenuated by ICV administration of anti-NMU IgG [24 h after onset of dark phase: vehicle, 31.4 ± 4.9 g; leptin, 20.8 ± 2.6 g ( P < 0.01 vs. vehicle); leptin/NMU IgG, 28.7 ± 1.1 g ( P < 0.01 vs. leptin)]. These results suggest that NMU plays a physiological role in the regulation of appetite and partially mediates the leptin-induced satiety.
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Agarwal, Sanjay K., Klara Vogel, Stacy R. Weitsman, and Denis A. Magoffin. "Leptin Antagonizes the Insulin-Like Growth Factor-I Augmentation of Steroidogenesis in Granulosa and Theca Cells of the Human Ovary1." Journal of Clinical Endocrinology & Metabolism 84, no. 3 (March 1, 1999): 1072–76. http://dx.doi.org/10.1210/jcem.84.3.5543.
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There is increasing evidence that leptin is a physiological link between obesity and infertility. Although leptin receptors have been demonstrated in human ovaries, there is no information regarding the effects of leptin on cells from developing ovarian follicles. To test the direct effects of leptin on human ovarian cells, granulosa cells (GC) and theca cells were isolated from the ovaries of regularly cycling women. Serum was obtained at the time of surgery, and follicular fluid was aspirated from the follicles before isolation of the ovarian cells. Leptin concentrations were similar in follicular fluid and serum. RT-PCR analysis demonstrated that the long, signaling form of the leptin receptor was expressed in both theca and GC. In cultured GC, leptin had no effect on estradiol production, alone or in the presence of FSH, but caused a concentration-related inhibition of the insulin-like growth factor I (IGF-I) augmentation of FSH-stimulated estradiol production. The effect of leptin was specific, because there was no effect on progesterone production. In cultured theca cells, leptin did not alter androstenedione production, alone or in the presence of LH. Leptin caused a concentration-related inhibition of the IGF-I augmentation of LH-stimulated androstenedione production. These data demonstrate that leptin can directly inhibit IGF-I action in ovarian theca and GC at concentrations commonly present in obese women.
10
Deem, Jennifer D., Kenjiro Muta, Kayoko Ogimoto, Jarrell T. Nelson, Kevin R. Velasco, Karl J. Kaiyala, and Gregory J. Morton. "Leptin regulation of core body temperature involves mechanisms independent of the thyroid axis." American Journal of Physiology-Endocrinology and Metabolism 315, no. 4 (October 1, 2018): E552—E564. http://dx.doi.org/10.1152/ajpendo.00462.2017.
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The ability to maintain core temperature within a narrow range despite rapid and dramatic changes in environmental temperature is essential for the survival of free-living mammals, and growing evidence implicates an important role for the hormone leptin. Given that thyroid hormone plays a major role in thermogenesis and that circulating thyroid hormone levels are reduced in leptin-deficient states (an effect partially restored by leptin replacement), we sought to determine the extent to which leptin’s role in thermogenesis is mediated by raising thyroid hormone levels. To this end, we 1) quantified the effect of physiological leptin replacement on circulating levels of thyroid hormone in leptin-deficient ob/ob mice, and 2) determined if the effect of leptin to prevent the fall in core temperature in these animals during cold exposure is mimicked by administration of a physiological replacement dose of triiodothyronine (T3). We report that, as with leptin, normalization of circulating T3 levels is sufficient both to increase energy expenditure, respiratory quotient, and ambulatory activity and to reduce torpor in ob/ob mice. Yet, unlike leptin, infusing T3 at a dose that normalizes plasma T3 levels fails to prevent the fall of core temperature during mild cold exposure. Because thermal conductance (e.g., heat loss to the environment) was reduced by administration of leptin but not T3, leptin regulation of heat dissipation is implicated as playing a uniquely important role in thermoregulation. Together, these findings identify a key role in thermoregulation for leptin-mediated suppression of thermal conduction via a mechanism that is independent of the thyroid axis.
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Zouhar, Petr, Günaj Rakipovski, Muhammad Hamza Bokhari, Oliver Busby, Johan F. Paulsson, Kilian W. Conde-Frieboes, Johannes J. Fels, et al. "UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia." American Journal of Physiology-Endocrinology and Metabolism 318, no. 1 (January 1, 2020): E72—E86. http://dx.doi.org/10.1152/ajpendo.00253.2019.
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The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity — and thus also leptin levels — in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
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Herrid, Muren, Yin Xia, Tim O'Shea, and James R. McFarlane. "Leptin inhibits basal but not gonadotrophin-stimulated testosterone production in the immature mouse and sheep testis." Reproduction, Fertility and Development 20, no. 4 (2008): 519. http://dx.doi.org/10.1071/rd07062.
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The mechanisms whereby leptin regulates testosterone secretion are complex and are likely to involve actions at different levels of the hypothalamus–pituitary–gonadal axis. In the present study, the effect of leptin on testicular steroidogenesis at different developmental stages in mice and sheep was investigated. Testosterone data from testicular slice and Leydig cells of immature and adult mice testes demonstrated that the action of leptin in the regulation of steroidogenesis appears to be dependent on the developmental stage of the testis. Leptin biphasically modulates basal testosterone production in immature testicular slice cultures: at relatively low concentrations (6.25–12.5 ng mL–1) leptin exerts a significant inhibitory effect, but has less of an effect at very low (1.25 ng mL–1) or high concentrations (25 ng mL–1). However, leptin failed to modulate basal testosterone levels in Leydig cell preparations. In contrast with immature testes, leptin was unable to regulate either basal or human chorionic gonadotrophin (10 IU mL–1)-stimulated testosterone production in adult testicular slices or Leydig cell cultures. The age- and concentration-dependent regulation pattern was confirmed using sheep testicular slice culture. Leptin (1.56–25 ng mL–1) significantly inhibited basal testosterone production in the testis from birth to Day 21, but had no effect on Day 27 or older testes. However, the plasma and testicular concentrations of leptin and testosterone data in the ram indicate that such a regulatory effect of leptin on testis steroidogenesis in vitro is unable to efficiently influence testosterone concentrations in vivo. This does not exclude the possibility of a non-competitive mechanism of interaction between leptin and luteinising hormone to regulate testosterone production. Thus, we hypothesise that leptin is not an important independent regulator of testosterone concentration in the normal physiological state. The physiological significance and mechanism of leptin regulation of basal testosterone production are not known; further studies are required to elucidate these important issues.
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Mistry, Anahita M., Andrew Swick, and Dale R. Romsos. "Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 277, no. 3 (September 1, 1999): R742—R747. http://dx.doi.org/10.1152/ajpregu.1999.277.3.r742.
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Leptin inhibits food intake and increases metabolic rates in adult mice. Neonatal mice need to maximize food intake and also maintain high thermoregulatory metabolic rates to optimize survival, suggesting that leptin may function differentially in neonatal versus adult animals. The efficacy of exogenous leptin to alter these two physiological functions during development was thus examined in C57BL/6J lean (+/+ or ob/+) and ob/ ob(leptin-deficient) mice. Intraperitoneal leptin administration (1 mg/kg body wt) to lean and ob/ obpups from 7 to 10 days of age did not affect milk intake, oxygen consumption, body weight, or epididymal fat pad weights. Intracerebroventricular injection of 1 μg leptin to 9-day-old pups also failed to influence milk intake or oxygen consumption. Because neither lean nor ob/ obpups responded to exogenous leptin, high endogenous plasma leptin concentrations per se in these lean mice do not explain their resistance to leptin. Leptin administered intracerebroventricularly also failed to alter milk/food intakes of 17-day-old pups but markedly increased oxygen consumption of these older mice. By 28 days of age, intracerebroventricular leptin inhibited food intake. The well-defined actions of leptin to reduce food intake and enhance metabolic rates do not develop synchronously. The ability of leptin to accelerate metabolic rates is acquired early in life and independent of its anorectic action, which may promote survival of neonates.
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Ortiga-Carvalho, TM, KJ Oliveira, BA Soares, and CC Pazos-Moura. "The role of leptin in the regulation of TSH secretion in the fed state: in vivo and in vitro studies." Journal of Endocrinology 174, no. 1 (July 1, 2002): 121–25. http://dx.doi.org/10.1677/joe.0.1740121.
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Leptin has been shown to stimulate the hypothalamus-pituitary-thyroid axis in fasting rodents; however, its role in thyroid axis regulation under physiological conditions is still under investigation. Here it was investigated in freely fed rats whether leptin modulates thyrotroph function in vivo and whether leptin has direct pituitary effects on TSH release. Since leptin is produced in the pituitary, the possibility was also investigated that leptin may be a local regulator of TSH release. TSH was measured by specific RIA. Freely fed adult rats 2 h after being injected with a single s.c. injection of 8 microg leptin/100 g body weight showed a 2-fold increase in serum TSH (P<0.05). Hemi-pituitary explants incubated with 10(-9) and 10(-7) M leptin for 2 h showed a reduced TSH release of 40 and 50% respectively (P<0.05). Conversely, incubation of hemi-pituitary explants with antiserum against leptin, aiming to block the action of locally produced leptin, resulted in higher TSH release (45%, P<0.05). In conclusion, also in the fed state, leptin has an acute stimulatory effect on TSH release in vivo, acting probably at the hypothalamus. However, the direct pituitary effect of leptin is inhibitory and data also provide evidence that in the rat pituitary leptin may act as an autocrine/paracrine inhibitor of TSH release.
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Kendall, N. R., C. G. Gutierrez, R. J. Scaramuzzi, D. T. Baird, R. Webb, and B. K. Campbell. "Direct in vivo effects of leptin on ovarian steroidogenesis in sheep." Reproduction 128, no. 6 (December 2004): 757–65. http://dx.doi.org/10.1530/rep.1.00256.
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Leptin, the metabolic fat hormone, has been shown to have effects on reproduction in mice and to modulate steroid production by cultured ovarian somatic cells in a number of species. However, a direct role of leptin on normal ovarian function in vivo has not been shown. In this paper the effect of passive immunisation against leptin (experiment 1; 20 ml antiserum or non-immune plasma i.v.; n = 6/treatment) and direct ovarian infusion of leptin (experiment 2; 0, 2 or 20 μg recombinant ovine leptin; n = 4/treatment) during the early follicular phase was investigated in sheep with ovarian autotransplants, which allow recovery of ovarian venous blood and regular non-invasive scanning of the ovary. Passive immunisation against leptin resulted in an acute increase (P < 0.05) in ovarian oestradiol secretion but had no effect on gonadotrophin concentrations, ovulation or subsequent luteal function. Conversely, direct ovarian arterial infusion of the low dose of leptin resulted in an acute decline (P < 0.05) in ovarian oestradiol secretion whereas the high dose, which resulted in supra-physiological leptin concentrations, had no effect on oestradiol production compared with the controls. Neither dose of leptin had any effect on gonadotrophin concentrations or ovulation but both doses resulted in an increase (P < 0.05) in progesterone concentrations over the subsequent luteal phase. In conclusion, together these data provide strong in vivo evidence that leptin can modulate ovarian steroidogenesis directly and acutely in ruminants and suggest that leptin is an alternate regulatory system whereby nutritional status can regulate reproductive activity.
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Breslow, Michael J., Kyoung Min-Lee, Daniel R. Brown, V. P. Chacko, David Palmer, and Dan E. Berkowitz. "Effect of leptin deficiency on metabolic rate inob/obmice." American Journal of Physiology-Endocrinology and Metabolism 276, no. 3 (March 1, 1999): E443—E449. http://dx.doi.org/10.1152/ajpendo.1999.276.3.e443.
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Reduced metabolic rate may contribute to weight gain in leptin-deficient ( ob/ob) mice; however, available studies have been criticized for referencing O2 consumption (V˙o 2) to estimated rather than true lean body mass. To evaluate whether leptin deficiency reduces energy expenditure, four separate experiments were performed: 1) NMR spectroscopy was used to measure fat and nonfat mass, permittingV˙o 2 to be referenced to true nonfat mass; 2) dietary manipulation was used in an attempt to eliminate differences in body weight and composition between ob/ob and C57BL/6J mice; 3) short-term effects of exogenous leptin (0.3 mg ⋅ kg−1 ⋅ day−1) on V˙o 2 were examined; and 4) body weight and composition were compared in leptin-repleted and pair-fed ob/ob animals. ob/ob animals had greater mass, less lean body mass, and a 10% higher metabolic rate whenV˙o 2 was referenced to lean mass. Dietary manipulation achieved identical body weight in ob/ob and C57BL/6J animals; however, despite weight gain in C57BL/6J animals, percent fat mass remained higher in ob/ob animals (55 vs. 30%). Exogenous leptin increasedV˙o 2 in ob/ob but not control animals. Weight loss in leptin-repleted ob/ob mice was greater than in pair-fed animals (45 vs. 17%). We conclude, on the basis of the observed increase inV˙o 2 and accelerated weight loss seen with leptin repletion, that leptin deficiency causes a reduction in metabolic rate in ob/obmice. In contrast, these physiological studies suggest that comparison of V˙o 2 in obese and lean animals does not produce useful information on the contribution of leptin to metabolism.
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Heintges, U., M. Hennies, A. Gertler, and H. Sauerwein. "Leptin and its effect on glucose and insulin metabolism in pregnant and lactating goats." Proceedings of the British Society of Animal Science 2002 (2002): 96. http://dx.doi.org/10.1017/s1752756200007523.
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Pregnancy and lactation are phases during which major adaptations in maternal metabolism are necessary to meet the requirements of foetal growth and of lactation. Leptin, an adipocyte derived hormone, involved in regulation of energy metabolism, has been implicated in the coordination of these adaptive processes. Similar to monogastric species, increased leptin blood concentrations are reported for sheep at mid-pregnancy when compared to prebreeding, late pregnancy or early lactation (Ehrhardt et al., 2001). In sheep, the changes of leptin concentrations showed no obvious relation with the ability of insulin to promote glucose utilisation (Ehrhardt et al., 2001). With the study presented herein, we aimed to elucidate whether exogenous leptin modulates insulin responsiveness and whether the responsiveness is dependent of the physiological status of the animal. Using specific clamp techniques i.e. glucose infusion studies to quantify insulin secretion and resistance, we compared the effect of leptin application on glucose metabolism in pregnant versus lactating goats.
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Leury, Brian J., Lance H. Baumgard, Stephanie S. Block, Nthabisheng Segoale, Richard A. Ehrhardt, Robert P. Rhoads, Dale E. Bauman, Alan W. Bell, and Yves R. Boisclair. "Effect of insulin and growth hormone on plasma leptin in periparturient dairy cows." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 5 (November 2003): R1107—R1115. http://dx.doi.org/10.1152/ajpregu.00320.2003.
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After parturition, dairy cows suffer from an intense energy deficit caused by the onset of copious milk secretion and an inadequate increase in voluntary food intake. We previously showed that this energy deficit contributes to a decline in plasma leptin. This decline mirrors that of plasma insulin but is reciprocal to the profile of plasma growth hormone (GH), suggesting that both hormones may regulate plasma leptin in periparturient dairy cows. To study the role of insulin, hyperinsulinemic-euglycemic clamps were performed on six dairy cows in late pregnancy (LP, 31 days prepartum) and early lactation (EL, 7 days postpartum). Infusion of insulin (1 μg·kg body wt-1·h-1) caused a progressive rise in the plasma concentration of leptin that reached maximum levels at 24 h during both physiological states. At steady states, the absolute increase in plasma leptin was greater in LP than in EL cows (2.4 vs. 0.4 ng/ml). Insulin infusion increased leptin mRNA in adipose tissue during LP but not during EL. During lactation, mammary epithelial cells expressed leptin mRNA but insulin did not increase milk leptin output. In contrast, a 3-day period of GH administration had no effect on plasma leptin during LP or EL. Therefore, insulin increases plasma leptin in LP by stimulating adipose tissue synthesis but has only marginal effects in EL, when cows are in negative energy balance. Other factors, such as increased response of adipose tissue to β-adrenergic signals, probably contribute to the reduction of plasma leptin in early lactating dairy cows.
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Rosenbaum, Michael, and Rudolph L. Leibel. "20 YEARS OF LEPTIN: Role of leptin in energy homeostasis in humans." Journal of Endocrinology 223, no. 1 (July 25, 2014): T83—T96. http://dx.doi.org/10.1530/joe-14-0358.
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The hyperphagia, low sympathetic nervous system tone, and decreased circulating concentrations of bioactive thyroid hormones that are common to states of congenital leptin deficiency and hypoleptinemia following and during weight loss suggest that the major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. In weight-reduced humans, these phenotypes together with pronounced hypometabolism and increased parasympathetic nervous system tone create the optimal circumstance for weight regain. Based on the weight loss induced by leptin administration in states of leptin deficiency (obese) and observed similarity of phenotypes in states of congenital and dietary-induced states of hypoleptinemia (reduced obese), it has been suggested that exogenous leptin could potentially be useful in initiating, promoting, and sustaining weight reduction. However, the responses of human beings to exogenous leptin administration are dependent not only on extant energy stores but also on energy balance. Leptin administration to humans at usual weight has little, if any, effect on body weight while leptin administration during weight loss mitigates hunger, especially if given in supraphysiological doses during severe caloric restriction. Leptin repletion is most effective following weight loss by dietary restriction. In this state of weight stability but reduced energy stores, leptin at least partially reverses many of the metabolic, autonomic, neuroendocrine, and behavioral adaptations that favor weight regain. The major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. Leptin, and pharmacotherapies affecting leptin signaling pathways, is likely to be most useful in sustaining weight loss.
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Yang, Meng-Jie, Fang Wang, Jiang-Hua Wang, Wen-Ning Wu, Zhuang-Li Hu, Jin Cheng, Dan-Fang Yu, et al. "PI3K integrates the effects of insulin and leptin on large-conductance Ca2+-activated K+ channels in neuropeptide Y neurons of the hypothalamic arcuate nucleus." American Journal of Physiology-Endocrinology and Metabolism 298, no. 2 (February 2010): E193—E201. http://dx.doi.org/10.1152/ajpendo.00155.2009.
Full textAbstract:
The adipocyte-derived hormone leptin and the pancreatic β-cell-derived hormone insulin function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. They act in hypothalamic centers to modulate the function of specific neuronal subtypes, such as neuropeptide Y (NPY) neurons, by modifying neuronal electrical activity. To investigate the intrinsic activity of these neurons and their responses to insulin and leptin, we used a combination of morphological features and immunocytochemical technique to identify the NPY neurons of hypothalamic arcuate nucleus (ARC) and record whole cell large-conductance Ca2+-activated potassium (BK) currents on them. We found that both of the hormones increase the peak amplitude of BK currents, shifting the steady-state activation curve to the left. The effect of both insulin and leptin can be prevented by pretreatment with inhibitors of tyrosine kinase and phosphatidylinositol 3-kinase (PI3K) but not MAPK. These data indicate that PI3K-mediated signals are the common regulators of BK channels by insulin and leptin and mediated the two hormones' identical activatory effects on ARC NPY neurons. The effect of insulin and leptin together was similar to that of insulin or leptin alone, and leptin or insulin pretreatment did not lead to insulin- or leptin-sensitizing effects, respectively. These intracellular signaling mechanisms may play key roles in regulating ARC NPY neuron activity and physiological processes such as the control of food intake and body weight, which are under the combined control of insulin and leptin.
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Morton, Gregory J., Karl J. Kaiyala, Jonathan D. Fisher, Kayoko Ogimoto, Michael W. Schwartz, and Brent E. Wisse. "Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice." American Journal of Physiology-Endocrinology and Metabolism 300, no. 2 (February 2011): E392—E401. http://dx.doi.org/10.1152/ajpendo.00546.2010.
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Mechanisms regulating spontaneous physical activity remain poorly characterized despite evidence of influential genetic and acquired factors. We evaluated ambulatory activity and wheel running in leptin-deficient ob/ob mice and in wild-type mice rendered hypoleptinemic by fasting in both the presence and absence of subcutaneous leptin administration. In ob/ob mice, leptin treatment to plasma levels characteristic of wild-type mice acutely increased both ambulatory activity (by 4,000 ± 200 beam breaks/dark cycle, P < 0.05) and total energy expenditure (TEE; by 0.11 ± 0.01 kcal/h during the dark cycle, P < 0.05) in a dose-dependent manner and acutely increased wheel running (+350%, P < 0.05). Fasting potently increased ambulatory activity and wheel running in wild-type mice (AA: +25%, P < 0.05; wheel running: +80%, P < 0.05), and the effect of fasting was more pronounced in ob/ob mice (AA: +400%, P < 0.05; wheel running: +1,600%, P < 0.05). However, unlike what occurred in ad libitum-fed ob/ob mice, physiological leptin replacement attenuated or prevented fasting-induced increases of ambulatory activity and wheel running in both wild-type and ob/ob mice. Thus, plasma leptin is a physiological regulator of spontaneous physical activity, but the nature of leptin's effect on activity is dependent on food availability.
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Mostyn, A., D. H. Keisler, R. Webb, T. Stephenson, and M. E. Symonds. "The role of leptin in the transition from fetus to neonate." Proceedings of the Nutrition Society 60, no. 2 (May 2001): 187–94. http://dx.doi.org/10.1079/pns200086.
Full textAbstract:
Leptin is a 16 kDa hormone which has been shown to have a major physiological role in the control of energy balance. Leptin is produced primarily in white adipose tissue, although there is evidence for its production in brown adipose tissue (BAT) and the placenta. BAT is critically important for the initiation of non-shivering thermogenesis in the newborn through the BAT-specific uncoupling protein (UCP), UCP1. This factor is particularly important in lambs in which levels of UCP1 peak at birth, concomitant with a rapid decline in plasma leptin levels. Our studies have examined the effect of acute and chronic administration of leptin to neonatal lambs, investigating effects on colonic temperature, UCP1 and thermogenic potential of BAT. Administration of leptin in sequential physiological doses of 10, 100 and 100 µg to neonatal lambs caused a modest increase in colonic temperature which was not observed in weight-matched vehicle-treated controls. This increase in colonic temperature was not mediated by an increase in either abundance or thermogenic potential of UCP1, as previously shown in adult rodents. UCP1 mRNA levels were 30 % lower in leptin-treated lambs, which is also contradictory to findings in adult rodents. Leptin treatment resulted in a dose-dependent rise in plasma leptin, with levels at the end of the study being almost twenty times greater in leptin-treated animals. To determine whether these findings in neonatal lambs were transient due to the complex milieu of hormones present after birth, we examined the effect of chronic leptin treatment over 6 d. Pairs of lambs were treated daily, from the second to seventh day of life with 100 µg leptin or vehicle. Colonic temperatures of leptin- and vehicle-treated animals remained similar throughout the study. UCP1 abundance was significantly lower in the leptin-treated animals, suggesting that the drop in UCP1 mRNA seen in the previous study had been translated to protein levels. In conclusion, the decline in plasma leptin levels at birth may be a signal to initiate enteral feeding. In lambs, the rapid loss of UCP1 mRNA, which occurs within the first few days of life, appears to be accelerated by leptin administration, possibly stimulating the development of white adipose tissue and generation of body heat through mechanisms other than non-shivering thermogenesis by UCP1 in BAT.
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McAlister, Edward D., and Dean A. Van Vugt. "Effect of leptin administration versus re-feeding on hypothalamic neuropeptide gene expression in fasted male rats." Canadian Journal of Physiology and Pharmacology 82, no. 12 (December 1, 2004): 1128–34. http://dx.doi.org/10.1139/y04-122.
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Adipocytes are the primary source of circulating leptin. Leptin inhibits eating, increases metabolism, and stimulates the reproductive axis. Numerous hypothalamic neuropeptides have been implicated in leptin's behavioral and neuroendocrine effects, including neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART). The aim of this study was to investigate the physiological relevance of leptin's signaling of nutritional status by comparing the effects of leptin with the effects of re-feeding on fasting-induced changes in the expression of the long form of the leptin receptor (Ob-Rb), NPY, and CART. Adult male rats were fasted for 48 h and treated with either intra cere broventricular (i.c.v.) or subcutaneous (s.c.) leptin throughout the fast, or fed ad libitum for 24 h after terminating the fast. Expression of NPY, Ob-Rb, and CART mRNA in the arcuate nucleus (ARC) was determined by in situ hybridization histochemistry and compared with vehicle-treated fed or fasted controls. Fasting increased NPY and Ob-Rb expression and decreased CART expression in the ARC. Leptin (regardless of route) and re-feeding were equally effective in normalizing CART mRNA expression. A similar trend was observed with Ob-Rb expression. In contrast, neither re-feeding nor s.c. leptin reversed the increased expression of NPY that was induced by fasting. Only i.c.v. leptin was effective in this regard. Our results indicate leptin and re-feeding are equally effective in normalizing fasting-induced changes in CART and Ob-Rb expression, but less effective in normalizing NPY expression. These results suggest that leptin is the primary nutritional signal regulating CART and Ob-Rb expression in the ARC, and highlight potential differences between CART and NPY neuron sensitivity to leptin signaling.Key words: CART, leptin receptor, NPY, neuropeptide gene expression, fasting, refeeding, hypothalamus.
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Balland, Eglantine, Weiyi Chen, Tony Tiganis, and Michael A. Cowley. "Persistent Leptin Signaling in the Arcuate Nucleus Impairs Hypothalamic Insulin Signaling and Glucose Homeostasis in Obese Mice." Neuroendocrinology 109, no. 4 (2019): 374–90. http://dx.doi.org/10.1159/000500201.
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Background: Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance. Objectives: Here, we demonstrate that contrary to expectations, leptin signaling not only remains functional but also is constantly activated in the arcuate nucleus of the hypothalamus (ARH) neurons of obese mice. This state of persistent response to endogenous leptin underpins the lack of response to exogenous leptin. Methods and Results: The study of combined leptin and insulin signaling demonstrates that there is a common pool of ARH neurons responding to both hormones. More importantly, we show that the constant activation of leptin receptor neurons in the ARH prevents insulin signaling in these neurons, leading to impaired glucose tolerance. Accordingly, antagonising leptin signaling in diet-induced obese (DIO) mice restores insulin signaling in the ARH and improves glucose homeostasis. Direct inhibition of PTP1B in the CNS restores arcuate insulin signaling similarly to leptin inhibition; this effect is likely to be mediated by AgRP neurons since PTP1B deletion specifically in AgRP neurons restores glucose and insulin tolerance in DIO mice. Conclusions: Finally, our results suggest that the constant activation of arcuate leptin signaling in DIO mice increases PTP1B expression, which exerts an inhibitory effect on insulin signaling leading to impaired glucose homeostasis.
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Wilsey, Jared, Michael K. Matheny, and Philip J. Scarpace. "Oral Vanadium Enhances the Catabolic Effects of Central Leptin in Young Adult Rats." Endocrinology 147, no. 1 (January 1, 2006): 493–501. http://dx.doi.org/10.1210/en.2004-1358.
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Recently, vanadium has been shown to enhance leptin signal transduction in vitro. We hypothesized that chronic oral administration of an organic vanadium complex would enhance both leptin signaling and physiological responsiveness in vivo. Three-month-old F344 × Brown Norway male rats were provided a solution containing escalating doses of vanadyl acetoacetonate (V), peaking at 60 mg/liter elemental vanadium in drinking water on the 11th d of V treatment. Although V treatment tended to suppress weight gain, absolute body weights did not significantly differ between groups after 62 d of treatment. At this point, a permanent cannula was placed into the left lateral ventricle of all animals. The cannula was connected to a sc minipump providing either 5 μg/d leptin or artificial cerebral spinal fluid (ACSF) control solution. This yielded four groups: C-ACSF, C-leptin, V-ACSF, and V-leptin. During the ensuing 26 d, weight gain was similar in C-ACSF and V-ACSF. As expected, leptin caused dramatic weight loss in C-leptin, but leptin-induced weight loss was 43% greater in V-leptin. V enhanced leptin-induced signal transducer and activator of transcription-3 phosphorylation in the hypothalamus, whereas V alone had no effect. V also augmented the leptin-induced increase in brown adipose tissue uncoupling protein-1. The effects of vanadium on responsiveness to a submaximal dose of leptin (0.25 μg/d) were also evaluated, yielding qualitatively similar results. These data demonstrate, for the first time, that chronic V administration enhances the weight-reducing effects of centrally administered leptin in young adult animals, and the mechanism appears to involve enhanced leptin signal transduction.
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Arvaniti, Konstantinia, Denis Richard, Frédéric Picard, and Yves Deshaies. "Lipid deposition in rats centrally infused with leptin in the presence or absence of corticosterone." American Journal of Physiology-Endocrinology and Metabolism 281, no. 4 (October 1, 2001): E809—E816. http://dx.doi.org/10.1152/ajpendo.2001.281.4.e809.
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The aim of the present study was to assess whether the glucocorticoid corticosterone (Cort) modulates the effects of leptin on food intake and lipid deposition. Rats were subjected to a 6-day intracerebroventricular infusion of leptin and were either sham-adrenalectomized (Sham-ADX) or ADX and supplemented with 0 (C0), 40 (C40), or 80 mg (C80) of Cort. Investigation of potential peripheral sites of interaction of leptin and Cort included liver and plasma triglyceride (TG) content and lipoprotein lipase (LPL) activity in adipose and muscle tissues. The study confirmed the respective anorectic and orexigenic effects of leptin and Cort and revealed that the leptin-induced reduction in food intake was dampened by the high dose of Cort replacement. Such an interaction did not, however, extend to body and adipose tissue weights, which were lowered by leptin infusion independently of the Cort status. Leptin and ADX significantly reduced liver TG content and triglyceridemia, whereas Cort replacement significantly increased these variables. Central infusion of leptin also lowered plasma insulin levels, accompanied by a reduction in LPL activity of storage tissues (inguinal and epididymal white adipose tissue, 2- and 3-fold, respectively). In contrast, leptin infusion increased LPL activity in oxidative tissues (soleus and vastus lateralis muscles, 3- and 4-fold, respectively). Cort replacement prevented the ADX-induced fall in epididymal LPL activity but failed to do so in leptin-infused rats. The study demonstrates that, whereas the anorectic effect of leptin is dampened by high but physiological plasma levels of corticosterone, leptin can produce its effects on body weight, lipid transport and accumulation, and adipose and muscle LPL activity in the absence or presence of an intact hypothalamic-pituitary-adrenal axis.
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Dawson, R., M. A. Pelleymounter, W. J. Millard, S. Liu, and B. Eppler. "Attenuation of leptin-mediated effects by monosodium glutamate-induced arcuate nucleus damage." American Journal of Physiology-Endocrinology and Metabolism 273, no. 1 (July 1, 1997): E202—E206. http://dx.doi.org/10.1152/ajpendo.1997.273.1.e202.
Full textAbstract:
Leptin is a protein secreted by adipocytes that is important in regulating appetite and adiposity. Recent studies have suggested the presence of leptin receptors in the arcuate nucleus of the hypothalamus (ANH). Neonatal administration of monosodium glutamate (MSG) damages the ANH, resulting in obesity and neuroendocrine dysfunction. Neonatal administration of MSG was utilized to test the hypothesis that the anatomic site for many of leptin's actions is the ANH. Female control (n = 6) and MSG-treated rats (n = 7) were implanted for 14 days with osmotic minipumps containing phosphate-buffered saline or leptin (1 mg.kg-1.day-1). Leptin suppressed (P < 0.05) body weight gain in controls but did not suppress weight gain in MSG-treated rats. Leptin decreased (P < 0.05) fat depots in controls but had no effect in MSG-treated rats. Night feeding was suppressed (P < 0.05) in leptin-treated control rats. MSG-treated rats showed a suppression in food intake that was of a smaller magnitude and appeared later in the course of leptin treatment. These findings suggest that leptin mediates some physiological actions related to fat mobilization via receptors located in the ANH.
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Fan, WuQiang, Toshihiko Yanase, Yoshihiro Nishi, Seiichi Chiba, Taijiro Okabe, Masatoshi Nomura, Hironobu Yoshimatsu, Shigeaki Kato, Ryoichi Takayanagi, and Hajime Nawata. "Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor." Endocrinology 149, no. 12 (August 14, 2008): 6028–36. http://dx.doi.org/10.1210/en.2008-0431.
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Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice.
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Maymó, Julieta L., Antonio Pérez Pérez, José L. Dueñas, Juan Carlos Calvo, Víctor Sánchez-Margalet, and Cecilia L. Varone. "Regulation of Placental Leptin Expression by Cyclic Adenosine 5′-Monophosphate Involves Cross Talk between Protein Kinase A and Mitogen-Activated Protein Kinase Signaling Pathways." Endocrinology 151, no. 8 (May 19, 2010): 3738–51. http://dx.doi.org/10.1210/en.2010-0064.
Full textAbstract:
Leptin, a 16-kDa protein mainly produced by adipose tissue, has been involved in the control of energy balance through its hypothalamic receptor. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in placenta, where it was found to be expressed. In the current study, we examined the effect of cAMP in the regulation of leptin expression in trophoblastic cells. We found that dibutyryl cAMP [(Bu)2cAMP], a cAMP analog, showed an inducing effect on endogenous leptin expression in BeWo and JEG-3 cell lines when analyzed by Western blot analysis and quantitative RT-PCR. Maximal effect was achieved at 100 μM. Leptin promoter activity was also stimulated, evaluated by transient transfection with a reporter plasmid construction. Similar results were obtained with human term placental explants, thus indicating physiological relevance. Because cAMP usually exerts its actions through activation of protein kinase A (PKA) signaling, this pathway was analyzed. We found that cAMP response element-binding protein (CREB) phosphorylation was significantly increased with (Bu)2cAMP treatment. Furthermore, cotransfection with the catalytic subunit of PKA and/or the transcription factor CREB caused a significant stimulation on leptin promoter activity. On the other hand, the cotransfection with a dominant negative mutant of the regulatory subunit of PKA inhibited leptin promoter activity. We determined that cAMP effect could be blocked by pharmacologic inhibition of PKA or adenylyl ciclase in BeWo cells and in human placental explants. Thereafter, we decided to investigate the involvement of the MAPK/ERK signaling pathway in the cAMP effect on leptin induction. We found that 50 μm PD98059, a MAPK kinase inhibitor, partially blocked leptin induction by cAMP, measured both by Western blot analysis and reporter transient transfection assay. Moreover, ERK 1/2 phosphorylation was significantly increased with (Bu)2cAMP treatment, and this effect was dose dependent. Finally, we observed that 50 μm PD98059 inhibited cAMP-dependent phosphorylation of CREB in placental explants. In summary, we provide some evidence suggesting that cAMP induces leptin expression in placental cells and that this effect seems to be mediated by a cross talk between PKA and MAPK signaling pathways.
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Irani, Boman G., Christelle Le Foll, Ambrose Dunn-Meynell, and Barry E. Levin. "Effects of Leptin on Rat Ventromedial Hypothalamic Neurons." Endocrinology 149, no. 10 (June 12, 2008): 5146–54. http://dx.doi.org/10.1210/en.2008-0357.
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Neurons in the ventromedial and arcuate hypothalamic nuclei (VMN and ARC, respectively) mediate many of leptin’s effects on energy homeostasis. Some are also glucosensing, whereby they use glucose as a signaling molecule to regulate their firing rate. We used fura-2 calcium (Ca2+) imaging to determine the interactions between these two important mediators of peripheral metabolism on individual VMN neurons and the mechanisms by which leptin regulates neuronal activity in vitro. Leptin excited 24%, inhibited 20%, and had a biphasic response in 10% of VMN neurons. Excitation occurred with a EC50 of 5.2 fmol/liter and inhibition with a IC50 of 4.2 fmol/liter. These effects were independent of the ambient glucose levels, and both glucosensing and non-glucosensing neurons were affected by leptin. In contrast, the ARC showed a very different distribution of leptin-responsive neurons, with 40% leptin excited, 10% leptin inhibited, and 2% having a biphasic response (χ2 = 60.2; P < 0.0001). Using pharmacological manipulations we found that leptin inhibits VMN neurons via activation of phosphoinositol-3 kinase and activation of the ATP-sensitive K+ channel. In addition, leptin inhibition was antagonized by 5′-AMP-activated protein kinase activation in 39% of neurons but was unaffected by 5′-AMP-activated protein kinase inhibition. No mechanism was delineated for leptin-induced excitation. Thus, within the physiological range of brain glucose levels, leptin has a differential effect on VMN vs. ARC neurons, and acts on both glucosensing and non-glucosensing VMN neurons in a glucose-independent fashion with inhibition primarily dependent upon activation of the ATP-sensitive K+ channel.
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Hernández Morante, Juan José, Inmaculada Díaz Soler, Joaquín S. Galindo Muñoz, Horacio Pérez Sánchez, Mª del Carmen Barberá Ortega, Carlos Manuel Martínez, and Juana Mª Morillas Ruiz. "Moderate Weight Loss Modifies Leptin and Ghrelin Synthesis Rhythms but Not the Subjective Sensations of Appetite in Obesity Patients." Nutrients 12, no. 4 (March 27, 2020): 916. http://dx.doi.org/10.3390/nu12040916.
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Obesity is characterized by a resistance to appetite-regulating hormones, leading to a misalignment between the physiological signals and the perceived hunger/satiety signal. A disruption of the synthesis rhythm may explain this situation. The aim of this study was to evaluate the effect of dietary-induced weight loss on the daily rhythms of leptin and ghrelin and its influence on the daily variability of the appetite sensations of patients with obesity. Twenty subjects with obesity underwent a hypocaloric dietary intervention for 12 weeks. Plasma leptin and ghrelin were analyzed at baseline and at the end of the intervention and in 13 normal-weight controls. Appetite ratings were analyzed. Weight loss decreased leptin synthesis (pauc < 0.001) but not the rhythm characteristics, except the mean variability value (pmesor = 0.020). By contrast, the mean ghrelin level increased after weight loss. The rhythm characteristics were also modified until a rhythm similar to the normal-weight subjects was reached. The amount of variability of leptin and ghrelin was correlated with the effectiveness of the dietary intervention (p < 0.020 and p < 0.001, respectively). Losing weight partially restores the daily rhythms of leptin and modifies the ghrelin rhythms, but appetite sensations are barely modified, thus confirming that these hormones cannot exercise their physiological function properly.
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Kata, Faris, Saad W. Alsulaitti, and Muneera M. Adlan. "Leptin and Vascular Cell Adhesion Protein 1 as Physiological Biomarkers in Serum of Women Suffering from Rheumatoid Arthritis." Open Access Macedonian Journal of Medical Sciences 10, A (January 19, 2022): 164–69. http://dx.doi.org/10.3889/oamjms.2022.8208.
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BACKGROUND: Rheumatoid arthritis is defining as a common chronic and inflammatory disorder of systematic autoimmune disease. Leptin is a small peptide hormone involved in the inflammatory and immunomodulators processes of several diseases. AIM: The study aimed at evaluating the level of leptin and Vascular Cell Adhesion Protein 1 (VCAM-1) and proves that they act as vital markers in the serum of rheumatoid arthritis. MATERIALS AND METHODS: In this study, 80 serum samples from women were obtains (56 serum samples were distributing for women with rheumatoid arthritis and 24 serum samples for uninfected women who were considered a healthy group). RESULTS: There are no significant difference in the concentration of the leptin hormone in the serum of both patients and healthy women, and that age, period, and severity of the disease had no effect on the level of leptin hormone. However, the results confirmed that at the probability level p < 0.05 the VCAM-1 concentration increased significantly in patients’ serum when compared with the healthy group, and demonstrated that age groups only affected the VCAM-1 biomarker level. CONCLUSIONS: Our current study concludes that leptin levels in the serum were not impacts by the inflammatory state in patients with rheumatism, whereas VCAM-1 level in rheumatic patients may be associate with inflammatory reactions.
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Wójcik, Maciej, Andrzej Przemysław Herman, Dorota Anna Zieba, and Agata Krawczyńska. "The Impact of Photoperiod on the Leptin Sensitivity and Course of Inflammation in the Anterior Pituitary." International Journal of Molecular Sciences 21, no. 11 (June 10, 2020): 4153. http://dx.doi.org/10.3390/ijms21114153.
Full textAbstract:
Leptin has a modulatory impact on the course of inflammation, affecting the expression of proinflammatory cytokines and their receptors. Pathophysiological leptin resistance identified in humans occurs typically in sheep during the long-day photoperiod. This study aimed to determine the effect of the photoperiod with relation to the leptin-modulating action on the expression of the proinflammatory cytokines and their receptors in the anterior pituitary under physiological or acute inflammation. Two in vivo experiments were conducted on 24 blackface sheep per experiment in different photoperiods. The real-time PCR analysis for the expression of the genes IL1B, IL1R1, IL1R2, IL6, IL6R, IL6ST, TNF, TNFR1, and TNFR2 was performed. Expression of all examined genes, except IL1β and IL1R2, was higher during short days. The leptin injection increased the expression of all examined genes during short days. In short days the synergistic effect of lipopolysaccharide and leptin increased the expression of IL1B, IL1R1, IL1R2, IL6, TNF, and TNFR2, and decreased expression of IL6ST. This mechanism was inhibited during long days for the expression of IL1R1, IL6, IL6ST, and TNFR1. The obtained results suggest the occurrence of leptin resistance during long days and suggest that leptin modulates the course of inflammation in a photoperiod-dependent manner in the anterior pituitary.
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Xiao, Ennian, Linna Xia-Zhang, Nicolas R. Vulliémoz, Michel Ferin, and Sharon L. Wardlaw. "Leptin Modulates Inflammatory Cytokine and Neuroendocrine Responses to Endotoxin in the Primate." Endocrinology 144, no. 10 (October 1, 2003): 4350–53. http://dx.doi.org/10.1210/en.2003-0532.
Full textAbstract:
Leptin, which plays a crucial role in regulating energy balance, can also modulate the inflammatory response. Although leptin-deficient rodents are more sensitive to the toxic effects of bacterial endotoxin, it is unknown if leptin can modulate inflammatory cytokine or neuroendocrine responses to inflammation in a primate model. We have therefore studied the effects of leptin on plasma cytokine and hypothalamic-pituitary-adrenal responses to endotoxin (5 μg iv) in nine ovariectomized rhesus monkeys. Human leptin (50 μg/h) or saline was infused iv for 16 h before and 4 h after endotoxin injection; mean plasma leptin increased from 3.6 ± 1.0 ng/ml to 18 ± 1.7 ng/ml (P < 0.001). Leptin infusion had no effect on baseline plasma cytokine and hormone levels before endotoxin injection. As expected, endotoxin stimulated TNF-α, IL-6, IL-1 receptor antagonist (IL-1ra), ACTH, and cortisol in the saline-infused animals (P < 0.001). There was a significant attenuation of the IL-6 (P < 0.005) and cortisol (P < 0.001) responses (repeated measures ANOVA) to endotoxin in the leptin-infused animals. There was a significant reduction (by paired analysis) in the responses of the leptin compared with saline-treated animals: 47% for TNF-α, 48% for IL-6, 30% for IL1ra, 42% for ACTH, and 22% for cortisol (P < 0.05). We conclude that an increase in circulating leptin, within the physiological range of our monkey colony, can blunt the inflammatory cytokine and hypothalamic-pituitary-adrenal responses to an inflammatory challenge. These results, coupled with our recent finding that endotoxin stimulates leptin release in the monkey, demonstrate that leptin can be both released in response to inflammatory cytokines and act to attenuate the responses to these cytokines.
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Glasow, A., W. Kiess, U. Anderegg, A. Berthold, A. Bottner, and J. Kratzsch. "Expression of Leptin (Ob) and Leptin Receptor (Ob-R) in Human Fibroblasts: Regulation of Leptin Secretion by Insulin." Journal of Clinical Endocrinology & Metabolism 86, no. 9 (September 1, 2001): 4472–79. http://dx.doi.org/10.1210/jcem.86.9.7792.
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Leptin, a hormone of the cytokine family, is mainly synthesized by white adipocytes. As fibroblasts and adipocytes share a common stem cell origin, we hypothesized that connective tissue may be another candidate for leptin synthesis. We demonstrated leptin receptors, inclusive of all isoforms, on cultured fibroblasts (n = 13) by RT-PCR and immunohistochemistry. In contrast to its receptor, basal leptin mRNA expression and protein secretion were found in 8 of 13 cultures, reaching 1.4 ng/350,000 cells·24 h. Incubation with physiological insulin concentrations (1 nmol/liter) increased leptin secretion in fibroblast culture supernatants to 152% of basal levels. A maximal stimulation of the basal level up to 192% was found with 10 nmol/liter insulin after 24 h. Actinomycin D and cycloheximide abolished this effect, providing evidence that active RNA and protein synthesis are involved in insulin’s action. Completing these in vitro results, we could show protein expression for leptin and leptin receptors in fibroblasts by immunostaining of human skin biopsies in situ. In conclusion, we provide evidence of leptin synthesis and secretion by human fibroblasts that are regulated by insulin. Leptin produced by fibroblasts may thus exert important local autocrine and paracrine actions and contribute to the total plasma pool. Hence it might in part account for variations in body mass index-dependent reference ranges of leptin as well as disruptions in the relationship between fat content and leptin.
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Rooks, Cherie R., Dawn M. Penn, Emily Kelso, Robert R. Bowers, Timothy J. Bartness, and Ruth B. S. Harris. "Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 289, no. 1 (July 2005): R92—R102. http://dx.doi.org/10.1152/ajpregu.00858.2004.
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Leptin increases sympathetic nervous system (SNS) activity in brown adipose tissue and renal nerves. Experiments described here tested whether SNS innervation is required for peripheral, physiological concentrations of leptin to reduce body fat. In experiment 1, one epididymal (EPI) fat pad was sympathectomized by local injection of 6-hydroxydopamine (6OHDA) in C57BL/6 mice that were then infused for 13 days with PBS or 10 μg leptin/day from an intraperitoneal miniosmotic pump. Surprisingly, EPI denervation increased total body fat of PBS-infused mice but leptin decreased the size of both injected and noninjected EPI pads in 6OHDA mice. Experiment 2 was identical except for the use of male Sprague-Dawley rats that were infused with 50 μg leptin/day. Leptin had little effect on EPI weight or norepinephrine (NE) content, but denervation of one EPI pad decreased the effect of leptin on intact EPI, inguinal and retroperitoneal (RP) fat and increased the size of the mesenteric fat pad. Experiment 3 included groups in which either one EPI or one RP pad was denervated. RP denervation reduced RP NE content but did not prevent a leptin-induced reduction in fat pad mass. Therefore, the SNS is not required for low doses of leptin to reduce body fat. EPI denervation significantly increased adipocyte number in contralateral EPI and RP fat pads and this was prevented by leptin. These changes in intact pads of rats with one denervated fat pad imply communication between fat depots and suggest that both leptin and the SNS regulate the size of individual depots.
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Ngai, Ying Fai, Whitney L. Quong, Melissa B. Glier, Maria M. Glavas, Sandra L. Babich, Sheila M. Innis, Timothy J. Kieffer, and William T. Gibson. "Ldlr−/− Mice Display Decreased Susceptibility to Western-Type Diet-Induced Obesity Due to Increased Thermogenesis." Endocrinology 151, no. 11 (September 29, 2010): 5226–36. http://dx.doi.org/10.1210/en.2010-0496.
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The low-density lipoprotein receptor (Ldlr) is a key molecule involved with lipid clearance. The Ldlr−/− mouse has been used extensively as a model for studying atherosclerosis. This study sought to characterize the energy balance phenotype of Ldlr−/− mice with respect to weight gain, body composition, energy expenditure (EE), glucose homeostasis, and leptin sensitivity. Adult Ldlr−/− mice and Ldlr+/+ controls on a C57Bl/6J background were fed either a chow or a high-fat, high-sucrose Western-type diet (WTD) for eight wk. Physiological studies of food intake, EE, activity, insulin sensitivity, and leptin responsiveness were performed. The effect of these diet interventions on circulating leptin and on leptin gene expression was also examined. On the chow diet, Ldlr−/− mice had lower EE and higher activity levels relative to controls. On the WTD, Ldlr−/− mice gained less weight relative to Ldlr+/+ mice, specifically gaining less fat mass. Increased thermogenesis in Ldlr−/− mice fed the WTD was detected. Additionally, leptin responsiveness was blunted in chow-fed Ldlr−/− mice, suggesting a novel role for the Ldlr pathway that extends to leptin’s regulation of energy balance. In addition to its known role in lipid transport, these results demonstrate the importance of the Ldlr in energy homeostasis and suggest a direct physiological link between altered lipid transport and energy balance.
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Zhang, Yiying, Kai-Ying Guo, Patricia A. Diaz, Moonseong Heo, and Rudolph L. Leibel. "Determinants of leptin gene expression in fat depots of lean mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 1 (January 1, 2002): R226—R234. http://dx.doi.org/10.1152/ajpregu.00392.2001.
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The relationship of leptin gene expression to adipocyte volume was investigated in lean 10-wk-old male C57BL/6J mice. mRNA levels for leptin, insulin receptor, glucocorticoid receptor, and tumor necrosis factor (TNF)-α in inguinal, epididymal, and retroperitoneal adipose tissues were quantified and related to adipocyte volume. Leptin mRNA levels were highly correlated with adipocyte volume within each fat depot. Multiple regression analysis of pooled data from the three depots showed that leptin mRNA levels were strongly correlated with adipocyte volumes (β = 0.84, P < 0.001) and, to a smaller degree, with glucocorticoid receptor mRNA levels (β = 0.36, P < 0.001). Depot of origin had no effect ( P > 0.9). Rates of leptin secretion in vitro were strongly correlated with leptin mRNA levels ( r = 0.89, P < 0.001). mRNA levels for TNF-α, insulin receptor, and glucocorticoid receptor showed no significant correlation with adipocyte volume. These results demonstrate that depot-specific differences in leptin gene expression are mainly related to the volumes of the constituent adipocytes. The strong correlation between leptin gene expression and adipocyte volume supports leptin's physiological role as a humoral signal of fat mass.
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Maymó, Julieta L., Antonio Pérez Pérez, Víctor Sánchez-Margalet, José L. Dueñas, Juan Carlos Calvo, and Cecilia L. Varone. "Up-Regulation of Placental Leptin by Human Chorionic Gonadotropin." Endocrinology 150, no. 1 (September 11, 2008): 304–13. http://dx.doi.org/10.1210/en.2008-0522.
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Leptin, the 16,000 molecular weight protein product of the obese gene, was originally considered as an adipocyte-derived signaling molecule for the central control of metabolism. However, leptin has been suggested to be involved in other functions during pregnancy, particularly in placenta, in which it was found to be expressed. In the present work, we have found that recombinant human chorionic gonadotropin (hCG) added to BeWo choriocarcinoma cell line showed a stimulatory effect on endogenous leptin expression, when analyzed by Western blot. This effect was time and dose dependent. Maximal effect was achieved at hCG 100 IU/ml. Moreover, hCG treatment enhanced leptin promoter activity up to 12.9 times, evaluated by transient transfection with a plasmid construction containing different promoter regions and the reporter gene luciferase. This effect was dose dependent and evidenced with all the promoter regions analyzed, regardless of length. Similar results were obtained with placental explants, thus indicating physiological relevance. Because hCG signal transduction usually involves cAMP signaling, this pathway was analyzed. Contrarily, we found that dibutyryl cAMP counteracted hCG effect on leptin expression. Furthermore, cotransfection with the catalytic subunit of PKA and/or the transcription factor cAMP response element binding protein repressed leptin expression. Thereafter we determined that hCG effect could be partially blocked by pharmacologic inhibition of MAPK pathway with 50 μM PD98059 but not by the inhibition of the phosphatidylinositol 3-kinase pathway with 0.1 μm wortmannin. Moreover, hCG treatment promoted MAPK kinase and ERK1/ERK2 phosphorylation in placental cells. Finally, cotransfection with a dominant-negative mutant of MAPK blocked the hCG-mediated activation of leptin expression. In conclusion, we provide some evidence suggesting that hCG induces leptin expression in trophoblastic cells probably involving the MAPK signal transduction pathway. Human chorionic gonadotropin induces leptin expression in trophoblastic BeWo cells and placental explants analyzed by western-blot and reporter gene strategy. This effect involves the MAPK signal transduction pathway.
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Mehebik, Nadia, Anne-Marie Jaubert, Dominique Sabourault, Yves Giudicelli, and Catherine Ribière. "Leptin-induced nitric oxide production in white adipocytes is mediated through PKA and MAP kinase activation." American Journal of Physiology-Cell Physiology 289, no. 2 (August 2005): C379—C387. http://dx.doi.org/10.1152/ajpcell.00320.2004.
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Leptin injection increases plasma levels of nitrites and/or nitrates, an index of nitric oxide (NO) production. Because plasma levels of NO are correlated with fat mass and because adipose tissue is the main source of leptin, it seems that adipose tissue plays a major role in NO release induced by leptin. Adipocytes express both leptin receptors and nitric oxide synthase (NOS; including the endothelial isoform, NOS III, and the inducible isoform, NOS II). In this study, we have demonstrated that physiological concentrations of leptin stimulate NOS activity in adipocytes. This effect of leptin is abolished by 1) AG490, an inhibitor of Janus tyrosine kinase 2/signal transducer and activator of transcription 3; 2) U0126, an inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (p42/p44 MAPK); and 3) N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89) or Rp diastereomer of adenosine 3′,5′-cyclic phosphorothioate, two inhibitors of protein kinase A, but not by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. Immunoblotting studies have shown that leptin fails to activate Akt but increases p42/p44 MAPK phosphorylation, an effect that is prevented by U0126 but not by H-89. Furthermore, leptin induces NOS III phosphorylation at Ser1179and Thr497, but not when adipocytes are pretreated with H-89 or U0126. Finally, stimulation of adipocyte NOS activity by leptin is either unaltered when protein phosphatase 2A is inhibited by 1 nM okadaic acid or completely abolished when protein phosphatase 1 (PP1) activity is inhibited by 3 nM tautomycin, which supports a crucial role for PP1 in mediating this effect of leptin. On the whole, these experiments demonstrate that NOS activity is a novel target for leptin in adipocytes and that the leptin-induced NOS activity is at least in part the result of NOS III phosphorylations via both protein kinase A and p42/p44 MAPK activation. More generally, this study also leads to the hypothesis of NO as a potentially important factor for leptin signaling in adipocytes.
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Penn, Dawn M., Lisa C. Jordan, Emily W. Kelso, Jessica E. Davenport, and Ruth B. S. Harris. "Effects of central or peripheral leptin administration on norepinephrine turnover in defined fat depots." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 6 (December 2006): R1613—R1621. http://dx.doi.org/10.1152/ajpregu.00368.2006.
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Leptin preserves lean tissue but decreases adipose tissue by increasing lipolysis and/or inhibiting lipogenesis. The sympathetic nervous system (SNS) is a primary regulator of lipolysis, but it is not known if leptin increases norepinephrine turnover (NETO) in white adipose tissue. In this study, we examined the effect of leptin administered either as a chronic physiological dose (40 μg/day for 4 days from ip miniosmotic pumps) or as an acute injection in the third ventricle (1.5 μg injected two times daily for 2 days) on NETO and the size of brown and white fat depots in male Sprague Dawley rats. NETO was determined from the decline in tissue norepinephrine (NE) during 4 h following administration of the NE synthesis inhibitor α-methyl-para-tryrosine. The centrally injected leptin-treated animals demonstrated more dramatic reductions in food intake, body weight, and fat pad size and an increase in NETO compared with the peripherally infused animals. Neither route of leptin administration caused a uniform increase in NETO across all fat pads tested, and in both treatment conditions leptin decreased the size of certain fat pads independent of an increase in NETO. Similar discrepancies in white fat NETO were found for rats pair fed to leptin-treated animals. These results demonstrate that leptin acting either centrally or peripherally selectively increases sympathetic outflow to white fat depots and that a leptin-induced change in fat pad weight does not require an increase in NETO.
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Xu, Jing, Melissa A. Kirigiti, Kevin L. Grove, and M. Susan Smith. "Regulation of Food Intake and Gonadotropin-Releasing Hormone/Luteinizing Hormone during Lactation: Role of Insulin and Leptin." Endocrinology 150, no. 9 (May 21, 2009): 4231–40. http://dx.doi.org/10.1210/en.2009-0190.
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Abstract Negative energy balance during lactation is reflected by low levels of insulin and leptin and is associated with chronic hyperphagia and suppressed GnRH/LH activity. We studied whether restoration of insulin and/or leptin to physiological levels would reverse the lactation-associated hyperphagia, changes in hypothalamic neuropeptide expression [increased neuropeptide Y (NPY) and agouti-related protein (AGRP) and decreased proopiomelanocortin (POMC), kisspeptin (Kiss1), and neurokinin B (NKB)] and suppression of LH. Ovariectomized lactating rats (eight pups) were treated for 48 h with sc minipumps containing saline, human insulin, or rat leptin. The arcuate nucleus (ARH) was analyzed for NPY, AGRP, POMC, Kiss1, and NKB mRNA expression; the dorsal medial hypothalamus (DMH) was analyzed for NPY mRNA. Insulin replacement reversed the increase in ARH NPY/AGRP mRNAs, partially recovered POMC, but had no effect on recovering Kiss1/NKB. Leptin replacement only affected POMC, which was fully recovered. Insulin/leptin dual replacement had similar effects as insulin replacement alone but with a slight increase in Kiss1/NKB. The lactation-induced increase in DMH NPY was unchanged after treatments. Restoration of insulin and/or leptin had no effect on food intake, body weight, serum glucose or serum LH. These results suggest that the negative energy balance of lactation is not required for the hyperphagic drive, although it is involved in the orexigenic changes in the ARH. The chronic hyperphagia of lactation is most likely sustained by the induction of NPY in the DMH. The negative energy balance also does not appear to be a necessary prerequisite for the suppression of GnRH/LH activity.
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Roy, A. F., Y. Benomar, V. Bailleux, C. M. Vacher, A. Aubourg, A. Gertler, J. Djiane, and M. Taouis. "Lack of cross-desensitization between leptin and prolactin signaling pathways despite the induction of suppressor of cytokine signaling 3 and PTP-1B." Journal of Endocrinology 195, no. 2 (November 2007): 341–50. http://dx.doi.org/10.1677/joe-07-0321.
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Hyperprolactinemia and hyperleptinemia occur during gestation and lactation with marked hyperphagia associated with leptin resistance. Prolactin (PRL) induces the expression of orexigenic neuropeptide Y (NPY) through the activation of JAK-2/STAT-3 signaling pathway in hypothalamic paraventricular nucleus (PVN) leading to hyperphagia. PRL may also act through the inhibition of anorexigenic effect of leptin via induction of suppressor of cytokine signaling 3 (SOCS-3). This paper aimed to co-localize PRL (PRL-R) and leptin (ObRb) receptors in the hypothalamus of female rats and investigate the possible cross-desensitization between PRL-R and ObRb. We showed that: 1) PRL-R and ObRb are expressed in the PVN and co-localized in the same neurons; 2) in lactating females leptin failed to activate JAK-2/STAT-3 signaling pathway; 3) in Chinese Hamster Ovary (CHO) stably co-expressing PRL-R and ObRb, overexposure to PRL did not affect leptin signaling but totally abolished PRL-dependent STAT-5 phosphorylation. The overexposure to leptin produces similar results with strong alteration of leptin-dependent STAT-3 phosphorylation, whereas PRL-dependent STAT-5 was not affected; and 4) CHO-ObRb/PRL-R cells overexposure to leptin or PRL induces the expression of negative regulators SOCS-3 and PTP-1B. Thus, we conclude that these negative regulators affect specifically the inducer signaling pathway; for instance, SOCS-3 induced by PRL will affect PRL-R signaling but not ObRb signaling and vice versa. Finally, the lack of cross-desensitization between PURL-R and ObRb suggests that hyperphagia observed during gestation and lactation may be attributed to a direct effect of PRL on NPYexpression, and is most likely exacerbated by the physiological leptin resistance state.
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Fanjul, Carmen, Jaione Barrenetxe, Lorena De Pablo-Maiso, and María Pilar Lostao. "In vivo regulation of intestinal absorption of amino acids by leptin." Journal of Endocrinology 224, no. 1 (October 27, 2014): 17–23. http://dx.doi.org/10.1530/joe-14-0453.
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Leptin is secreted by the gastric mucosa and is able to reach the intestinal lumen and bind to its receptors located in the apical membranes of enterocytes. We have previously demonstrated that apical leptin inhibits uptake of amino acids in rat intestine in vitro and in Caco-2 cells. The aim of the present work was to investigate the effect of leptin on absorption of amino acids using in vivo techniques, which generate situations closer to physiological conditions. In vivo intestinal absorption of amino acids in rats was measured by isolating a jejunal loop and using the single-pass perfusion system. Disappearance of glutamine (Gln), proline (Pro), and β-alanine (β-Ala) from the perfusate, in the absence or presence of leptin, was measured using a radioactivity method. Luminal leptin (25 nM) inhibited the absorption of 2 mM Pro, 5 mM β-Ala, and 5 mM Gln by approximately 45% after 5–15 min; the effect remained constant until the end of the experiment (80 min) and was rapidly and completely reversed when leptin was removed from the perfusion medium. Moreover, leptin was able to regulate the absorption of galactose and Gln in the same animal, indicating a direct action of the hormone on the specific transporters implicated in the uptake of each nutrient. The results of the present work indicate that luminal leptin decreases absorption of amino acids in vivo in a short-term manner and in a reversible way. These results, together with our previous findings, make it evident that leptin can be considered as a hormone which provides the intestine with a control mechanism to handle absorption of nutrients.
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Roh, Cecilia, Galini Thoidis, Stephen R. Farmer, and Konstantin V. Kandror. "Identification and characterization of leptin-containing intracellular compartment in rat adipose cells." American Journal of Physiology-Endocrinology and Metabolism 279, no. 4 (October 1, 2000): E893—E899. http://dx.doi.org/10.1152/ajpendo.2000.279.4.e893.
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The major leptin-containing membrane compartment was identified and characterized in rat adipose cells by means of equilibrium density and velocity sucrose gradient centrifugation. This compartment appears to be different from peptide-containing secretory granules present in neuronal, endocrine, and exocrine cells, as well as from insulin-sensitive GLUT-4-containing vesicles abundant in adipocytes. Exocytosis of both leptin- and GLUT-4-containing vesicles can be induced by insulin; however, only leptin secretion is responsive to serum stimulation. This latter effect is resistant to cycloheximide, suggesting that serum triggers the release of a stored pool of presynthesized leptin molecules. We conclude that regulated secretion of leptin and insulin-dependent translocation of GLUT-4 represent different pathways of membrane trafficking in rat adipose cells. NIH 3T3 cells ectopically expressing CAAT box enhancer binding protein-α and Swiss 3T3 cells expressing peroxisome proliferator-activated receptor-γ undergo differentiation in vitro and acquire adipocyte morphology and insulin-responsive glucose uptake. Only the former cell line, however, is capable of leptin secretion. Thus different transcriptional mechanisms control the developmental onset of these two major and independent physiological functions in adipose cells.
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Torday, J. S., and V. K. Rehan. "Stretch-stimulated surfactant synthesis is coordinated by the paracrine actions of PTHrP and leptin." American Journal of Physiology-Lung Cellular and Molecular Physiology 283, no. 1 (July 1, 2002): L130—L135. http://dx.doi.org/10.1152/ajplung.00380.2001.
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Intrauterine lung development, culminating in physiological pulmonary surfactant production by epithelial type II (TII) cells, is driven by fluid distension through unknown mechanisms. Differentiation of alveolar epithelial and mesenchymal cells is mediated by soluble factors like parathyroid hormone-related protein (PTHrP), a stretch-sensitive TII cell product. PTHrP stimulates pulmonary surfactant production by a paracrine feedback loop mediated by leptin, a soluble product of the mature lipofibroblast (LF). When LFs and TIIs are stretched in coculture, there is a fivefold increase in surfactant phospholipid synthesis that can be “neutralized” by inhibitors of PTHrP or leptin, implicating a paracrine feedback loop in this mechanism. Stretching LFs stimulates PTHrP binding (2.5-fold) and downstream stimulation of triglyceride uptake quantitatively (15–25%) due to upregulation of adipose differentiation-related protein expression. Stretching TII cells increases leptin stimulation of their surfactant phospholipid synthesis threefold, suggesting that retrograde signaling by leptin to TII cells is also stretch sensitive. We conclude that the effect of stretch on alveolar LF and TII differentiation is coordinated by PTHrP, leptin, and their receptors.
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Viengchareun, S., H. Bouzinba-Segard, J.-P. Laigneau, M.-C. Zennaro, P. A. Kelly, A. Bado, M. Lombès, and N. Binart. "Prolactin potentiates insulin-stimulated leptin expression and release from differentiated brown adipocytes." Journal of Molecular Endocrinology 33, no. 3 (December 2004): 679–91. http://dx.doi.org/10.1677/jme.1.01563.
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The pituitary hormone prolactin (PRL) exerts pleiotropic effects, which are mediated by a membrane receptor (PRLR) present in numerous cell types including adipocytes. Brown adipose tissue (BAT) expresses uncoupling proteins (UCPs), involved in thermogenesis, but also secretes leptin, a key hormone involved in the control of body weight. To investigate PRL effects on BAT, we used the T37i brown adipose cell line, and demonstrated that PRLRs are expressed as a function of cell differentiation. Addition of PRL leads to activation of the JAK/STAT and MAP kinase signaling pathways, demonstrating that PRLRs are functional in these cells. Basal and catecholamine-induced UCP1 expression were not affected by PRL. However, PRL combined with insulin significantly increases leptin expression and release, indicating that PRL potentiates the stimulatory effect of insulin as revealed by the recruitment of insulin receptor substrates and the activation of phosphatidylinositol 3-kinase. To explore the in vivo physiological relevance of PRL action in BAT, we showed that leptin content was significantly increased in BAT of PRLR-null mice compared with wild-type mice, highlighting the involvement of PRL in the leptin secretion process. This study provides the first evidence for a functional link between PRL and energy balance via a cross-talk between insulin and PRL signaling pathways in brown adipocytes.
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Morton, Gregory J., Kevin D. Niswender, Christopher J. Rhodes, Martin G. Myers, James E. Blevins, Denis G. Baskin, and Michael W. Schwartz. "Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats." Endocrinology 144, no. 5 (May 1, 2003): 2016–24. http://dx.doi.org/10.1210/en.2002-0115.
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Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, leprb, in the ARC of leptin receptor-deficient Koletsky (fak/fak) rats. Successful expression of adenovirus containing leprb (Ad-leprb) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-leprb into the ARC restored low hypothalamic levels of leprb mRNA to values approximating those of wild-type (Fak/Fak) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fak/fak rats injected with a control adenovirus (Ad-lacZ) (P < 0.05 for each comparison). In contrast, Ad-leprb delivery to either the lateral hypothalamic area of fak/fak rats or to the ARC of wild-type Fak/Fak rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.
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Zimmermann-Belsing, T., G. Brabant, JJ Holst, and U. Feldt-Rasmussen. "Circulating leptin and thyroid dysfunction." European Journal of Endocrinology 149, no. 4 (October 1, 2003): 257–71. http://dx.doi.org/10.1530/eje.0.1490257.
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The identification and sequencing of the ob gene and its product, leptin, in 1994 opened new insights in the study of the mechanisms controlling body weight and led to a surge of research activity. Since its discovery, leptin has been the subject of an enormous amount of work especially within the fields of nutrition, metabolism and endocrinology. Leptin is accepted as an adipose signal, and even though the underlying mechanisms are not fully clarified, leptin, in addition to the thyroid hormones, is believed to be involved in regulation during the switch from the fed to the starved state. It is not clear whether leptin and the melanocortin pathways interact with the thyroid axis under physiological conditions other than during starvation or in response to severe illness, both states in which the hypothalamo-pituitary-thyroid axis may be severely suppressed. In addition to the suggested central relationship between leptin and thyroid hormones, there might also be a peripheral relationship although this effect is not clear. Both thyroid hormones and leptin might be involved in the adaptive thermogenesis through mitochondrial uncoupling proteins and heat production because both thyroxine and triiodothyronine are involved in the starvation-induced decrease in thermogenesis. Both rodent and human studies of leptin have failed to show any consistent relationship between thyroid function and serum leptin concentrations. However, leptin might have an important role in thyroid pathophysiology due to thyroid hormone involvement in thermogenesis and regulation of uncoupling proteins. In this review, we have focused on leptin in relation to thyroid pathophysiology.
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Arias-Alvarez, M., R. M. Garcia-Garcia, L. Revuelta, P. G. Rebollar, and P. L. Lorenzo. "238 EFFECTS OF LEPTIN SUPPLEMENTATION ON NUCLEAR AND CYTOPLASMIC IN VITRO MATURATION OF RABBIT OOCYTES." Reproduction, Fertility and Development 20, no. 1 (2008): 198. http://dx.doi.org/10.1071/rdv20n1ab238.
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Reproductive function is affected substantially by nutritional status. Leptin is a peptide secreted mainly by adipocytes that reflects the amount of body fat and acts as a modulator of oocyte quality. The aim of this study was to analyze, for the first time in the rabbit, the influence of leptin on meiotic and cytoplasmic maturation (cortical granule (CG) migration) of rabbit oocytes in vitro (IVM). Cumulus–oocyte complexes (COCs) were collected from 25 young New Zealand white female rabbits (<3 parturitions) in 3 replicates. COCs were aspirated from ovarian follicles >1 mm in size and were matured in TCM-199 medium, containing sodium pyruvate, sodium bicarbonate, BSA, and 10 ng mL–1 epidermal growth factor (EGF), and supplemented with 0, 10, or 100 ng mL–1 leptin. A total of 163 COCs were treated progressively with hyaluronidase (2 mm), 0.5% pronase, 4% paraformaldehyde, 0.02% Triton X-100, and 7.5% BSA after the maturation period. Oocytes were incubated with 100 mg mL–1 fluorescein isothiocyanate (FITC)-conjugated Lens culinaris agglutinin (LCA) for CG staining and with 4′,6-diamino-2-phenylindole (DAPI) for nuclear staining, and observed under a confocal laser-scanning microscope. In addition, 17 ovulated oocytes recovered from oviducts at 20 h post- GnRH were used as in vivo-maturated controls for CG distribution. Most of the ovulated oocytes at metaphase II (MII, 100%) presented CGs located in the cortex beneath the plasma membrane (61.1 ± 11.8%). Addition of 10 ng mL–1 leptin to IVM medium significantly increased the rate of oocytes reaching MII, compared to the 0 and 100 ng mL–1 leptin concentrations (P < 0.05). The percentage of oocytes showing CG migration to the cortex was significantly increased in the 10 ng mL–1 leptin treatment group (Table 1) compared to that in the 100 ng mL–1 leptin group (P < 0.05) and tended to be higher than that in the 0 ng mL–1 leptin group (P < 0.08). The rest of the oocytes showed homogeneous CG distribution, as they were not cytoplasmic maturated. Moreover, both in vivo- and in vitro-matured oocytes had a GC-free domain overlying the MII spindle. In conclusion, addition of leptin to IVM medium at physiological dose (10 ng mL–1) improves both meiotic and cytoplasmic maturation of rabbit oocytes, whereas an excessive leptin concentration does not exert a beneficial effect. These findings suggest a physiological role for leptin in the relationship between nutritional status and regulation of oocyte maturation. Table 1. Nuclear maturation and CG distribution of oocytes after IVM This research was supported by AGL05-196 and UCM-CM research program (920249). MAA received a grant from CM and FSE. RMGG was supported by the Juan de la Cierva-MEC Program.