Статті в журналах: "AgRP neuron"

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Oh, Youjin, Eun-Seon Yoo, Sang Hyeon Ju, Eunha Kim, Seulgi Lee, Seyun Kim, Kevin Wickman, and Jong-Woo Sohn. "GIRK2 potassium channels expressed by the AgRP neurons decrease adiposity and body weight in mice." PLOS Biology 21, no. 8 (August 18, 2023): e3002252. http://dx.doi.org/10.1371/journal.pbio.3002252.

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It is well known that the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase appetite and decrease thermogenesis. Previous studies demonstrated that optogenetic and/or chemogenetic manipulations of NPY/AgRP neuronal activity alter food intake and/or energy expenditure (EE). However, little is known about intrinsic molecules regulating NPY/AgRP neuronal excitability to affect long-term metabolic function. Here, we found that the G protein-gated inwardly rectifying K+ (GIRK) channels are key to stabilize NPY/AgRP neurons and that NPY/AgRP neuron-selective deletion of the GIRK2 subunit results in a persistently increased excitability of the NPY/AgRP neurons. Interestingly, increased body weight and adiposity observed in the NPY/AgRP neuron-selective GIRK2 knockout mice were due to decreased sympathetic activity and EE, while food intake remained unchanged. The conditional knockout mice also showed compromised adaptation to coldness. In summary, our study identified GIRK2 as a key determinant of NPY/AgRP neuronal excitability and driver of EE in physiological and stress conditions.

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Klima, Michelle, Amber Alhadeff, Kayla Kruger, Santiago Pulido, Aaron McKnight, and J. Nicholas Betley. "A Neural Circuit for the Suppression of Peripheral Inflammation by Hunger." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 228.23. http://dx.doi.org/10.4049/jimmunol.204.supp.228.23.

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Abstract Hunger is a primal biological drive that can initiate behavioral changes. Intuitively, hunger can inhibit behaviors such as sleep while simultaneously promoting foraging. Because pain can prevent an animal from seeking food we questioned if hunger could suppress pain. We found that food deprived mice reduce their response to inflammatory nociceptive stimuli. This reduction in nocifensive behavior during hunger is specific to inflammatory pain as the response to acute thermal and mechanical nociceptive stimuli remains intact. During hunger, agouti-related protein expressing (AgRP) neurons in the hypothalamus become active. AgRP neuron activation is both necessary and sufficient for feeding behavior and is thus a way to model hunger without the peripheral complications. Importantly, activating AgRP neurons recapitulates the analgesic effects of hunger. Because food deprivation reduces inflammatory pain responses, we next explored the influence of hunger and AgRP neuron activity on peripheral inflammation. To address this question, we measured paws after an injection of Complete Freund’s Adjuvant (CFA) in food deprived mice. We found that food deprivation was able to reduce CFA-induced paw inflammation compared to ad libitum fed controls. To assess the role of the AgRP circuit on inflammation, we measured CFA injected paws during optogenetic stimulation of AgRP neurons. Optogenetic activation of AgRP neurons rapidly reduces paw inflammation. This rapid and robust reduction in peripheral inflammation following activity in a CNS circuit suggests that AgRP neuron activity interacts with the immune system. Current experiments are aimed to determine the CNS à immune pathway that quickly reduces peripheral inflammation.

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Lin, Chiu-Ya, Kun-Yun Yeh, Hsin-Hung Lai, and Guor Mour Her. "AgRP Neuron-Specific Ablation Represses Appetite, Energy Intake, and Somatic Growth in Larval Zebrafish." Biomedicines 11, no. 2 (February 9, 2023): 499. http://dx.doi.org/10.3390/biomedicines11020499.

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Neuronal circuits regulating appetite are dominated by arcuate nucleus neurons, which include appetite-promoting and -suppressing neurons that release the orexigenic neuropeptide agouti-related protein (AgRP) and anorexigenic neuropeptide pro-opiomelanocortin, respectively, to compete for melanocortin receptors to modulate feeding behavior. In this study, we expressed novel agrp promoters, including different lengths of the 5’ flanking regions of the agrp gene (4749 bp) in the zebrafish genome. We used the agrp promoter to derive the enhanced green fluorescent protein (EGFP)-nitroreductase (NTR) fusion protein, allowing expression of the green fluorescence signal in the AgRP neurons. Then, we treated the transgenic zebrafish AgRP4.7NTR (Tg [agrp-EGFP-NTR]) with metronidazole to ablate the AgRP neurons in the larvae stage and observed a decline in their appetite and growth. The expression of most orexigenic and growth hormone/insulin-like growth factor axis genes decreased, whereas that of several anorexigenic genes increased. Our findings demonstrate that AgRP is a critical regulator of neuronal signaling for zebrafish appetite and energy intake control. Thus, AgRP4.7NTR can be used as a drug-screening platform for therapeutic targets to treat human appetite disorders, including obesity. Furthermore, the unique agrp promoter we identified can be a powerful tool for research on AgRP neurons, especially AgRP neuron-mediated pathways in the hypothalamus, and appetite.

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4

van de Wall, Esther, Rebecca Leshan, Allison W. Xu, Nina Balthasar, Roberto Coppari, Shun Mei Liu, Young Hwan Jo, et al. "Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion." Endocrinology 149, no. 4 (December 27, 2007): 1773–85. http://dx.doi.org/10.1210/en.2007-1132.

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Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

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Padilla, Stephanie L., Jian Qiu, Casey C. Nestor, Chunguang Zhang, Arik W. Smith, Benjamin B. Whiddon, Oline K. Rønnekleiv, Martin J. Kelly, and Richard D. Palmiter. "AgRP to Kiss1 neuron signaling links nutritional state and fertility." Proceedings of the National Academy of Sciences 114, no. 9 (February 14, 2017): 2413–18. http://dx.doi.org/10.1073/pnas.1621065114.

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Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.

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Na, Junewoo, Byong Seo Park, Doohyeong Jang, Donggue Kim, Thai Hien Tu, Youngjae Ryu, Chang Man Ha, et al. "Distinct Firing Activities of the Hypothalamic Arcuate Nucleus Neurons to Appetite Hormones." International Journal of Molecular Sciences 23, no. 5 (February 26, 2022): 2609. http://dx.doi.org/10.3390/ijms23052609.

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The hypothalamic arcuate nucleus (Arc) is a central unit that controls the appetite through the integration of metabolic, hormonal, and neuronal afferent inputs. Agouti-related protein (AgRP), proopiomelanocortin (POMC), and dopaminergic neurons in the Arc differentially regulate feeding behaviors in response to hunger, satiety, and appetite, respectively. At the time of writing, the anatomical and electrophysiological characterization of these three neurons has not yet been intensively explored. Here, we interrogated the overall characterization of AgRP, POMC, and dopaminergic neurons using genetic mouse models, immunohistochemistry, and whole-cell patch recordings. We identified the distinct geographical location and intrinsic properties of each neuron in the Arc with the transgenic lines labelled with cell-specific reporter proteins. Moreover, AgRP, POMC, and dopaminergic neurons had different firing activities to ghrelin and leptin treatments. Ghrelin led to the increased firing rate of dopaminergic and AgRP neurons, and the decreased firing rate of POMC. In sharp contrast, leptin resulted in the decreased firing rate of AgRP neurons and the increased firing rate of POMC neurons, while it did not change the firing rate of dopaminergic neurons in Arc. These findings demonstrate the anatomical and physiological uniqueness of three hypothalamic Arc neurons to appetite control.

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Fang, Xing, Shujun Jiang, Jiangong Wang, Yu Bai, Chung Sub Kim, David Blake, Neal L. Weintraub, Yun Lei, and Xin-Yun Lu. "Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity." Molecular Psychiatry 26, no. 6 (January 11, 2021): 2299–315. http://dx.doi.org/10.1038/s41380-020-01004-x.

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AbstractPrevious studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.

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Huang, Hu, Seung Hwan Lee, Chianping Ye, Ines S. Lima, Byung-Chul Oh, Bradford B. Lowell, Janice M. Zabolotny, and Young-Bum Kim. "ROCK1 in AgRP Neurons Regulates Energy Expenditure and Locomotor Activity in Male Mice." Endocrinology 154, no. 10 (October 1, 2013): 3660–70. http://dx.doi.org/10.1210/en.2013-1343.

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Normal leptin signaling is essential for the maintenance of body weight homeostasis. Proopiomelanocortin- and agouti-related peptide (AgRP)-producing neurons play critical roles in regulating energy metabolism. Our recent work demonstrates that deletion of Rho-kinase 1 (ROCK1) in the AgRP neurons of mice increased body weight and adiposity. Here, we report that selective loss of ROCK1 in AgRP neurons caused a significant decrease in energy expenditure and locomotor activity of mice. These effects were independent of any change in food intake. Furthermore, AgRP neuron-specific ROCK1-deficient mice displayed central leptin resistance, as evidenced by impaired Signal Transducer and Activator of Transcription 3 activation in response to leptin administration. Leptin's ability to hyperpolarize and decrease firing rate of AgRP neurons was also abolished in the absence of ROCK1. Moreover, diet-induced and genetic forms of obesity resulted in reduced ROCK1 activity in murine arcuate nucleus. Of note, high-fat diet also impaired leptin-stimulated ROCK1 activity in arcuate nucleus, suggesting that a defect in hypothalamic ROCK1 activity may contribute to the pathogenesis of central leptin resistance in obesity. Together, these data demonstrate that ROCK1 activation in hypothalamic AgRP neurons is required for the homeostatic regulation of energy expenditure and adiposity. These results further support previous work identifying ROCK1 as a key regulator of energy balance and suggest that targeting ROCK1 in the hypothalamus may lead to development of antiobesity therapeutics.

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9

Liu, Yang, Ying Huang, Tiemin Liu, Hua Wu, Huxing Cui, and Laurent Gautron. "Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice." Endocrinology 157, no. 6 (April 25, 2016): 2380–92. http://dx.doi.org/10.1210/en.2015-2081.

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Although Agouti-related peptide (AgRP) neurons play a key role in the regulation of food intake, their contribution to the anorexia caused by proinflammatory insults has yet to be identified. Using a combination of neuroanatomical and pharmacogenetics experiments, this study sought to investigate the importance of AgRP neurons and downstream targets in the anorexia caused by the peripheral administration of a moderate dose of lipopolysaccharide (LPS) (100 μg/kg, ip). First, in the C57/Bl6 mouse, we demonstrated that LPS induced c-fos in select AgRP-innervated brain sites involved in feeding but not in any arcuate proopiomelanocortin neurons. Double immunohistochemistry further showed that LPS selectively induced c-Fos in a large subset of melanocortin 4 receptor-expressing neurons in the lateral parabrachial nucleus. Secondly, we used pharmacogenetics to stimulate the activity of AgRP neurons during the course of LPS-induced anorexia. In AgRP-Cre mice expressing the designer receptor hM3Dq-Gq only in AgRP neurons, the administration of the designer drug clozapine-N-oxide (CNO) induced robust food intake. Strikingly, CNO-mediated food intake was rapidly and completely blunted by the coadministration of LPS. Neuroanatomical experiments further indicated that LPS did not interfere with the ability of CNO to stimulate c-Fos in AgRP neurons. In summary, our findings combined together support the view that the stimulation of select AgRP-innervated brain sites and target neurons, rather than the inhibition of AgRP neurons themselves, is likely to contribute to the rapid suppression of food intake observed during acute bacterial endotoxemia.

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Coutinho, Eulalia A., Melanie Prescott, Sabine Hessler, Christopher J. Marshall, Allan E. Herbison, and Rebecca E. Campbell. "Activation of a Classic Hunger Circuit Slows Luteinizing Hormone Pulsatility." Neuroendocrinology 110, no. 7-8 (October 21, 2019): 671–87. http://dx.doi.org/10.1159/000504225.

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Introduction: The central regulation of fertility is carefully coordinated with energy homeostasis, and infertility is frequently the outcome of energy imbalance. Neurons in the hypothalamus expressing neuropeptide Y and agouti-related peptide (NPY/AgRP neurons) are strongly implicated in linking metabolic cues with fertility regulation. Objective: We aimed here to determine the impact of selectively activating NPY/AgRP neurons, critical regulators of metabolism, on the activity of luteinizing hormone (LH) pulse generation. Methods: We employed a suite of in vivo optogenetic and chemogenetic approaches with serial measurements of LH to determine the impact of selectively activating NPY/AgRP neurons on dynamic LH secretion. In addition, electrophysiological studies in ex vivo brain slices were employed to ascertain the functional impact of activating NPY/AgRP neurons on gonadotropin-releasing hormone (GnRH) neurons. Results: Selective activation of NPY/AgRP neurons significantly decreased post-castration LH secretion. This was observed in males and females, as well as in prenatally androgenized females that recapitulate the persistently elevated LH pulse frequency characteristic of polycystic ovary syndrome (PCOS). Reduced LH pulse frequency was also observed when optogenetic stimulation was restricted to NPY/AgRP fiber projections surrounding GnRH neuron cell bodies in the rostral preoptic area. However, electrophysiological studies in ex vivo brain slices indicated these effects were likely to be indirect. Conclusions: These data demonstrate the ability of NPY/AgRP neuronal signaling to modulate and, specifically, reduce GnRH/LH pulse generation. The findings suggest a mechanism by which increased activity of this hunger circuit, in response to negative energy balance, mediates impaired fertility in otherwise reproductively fit states, and highlight a potential mechanism to slow LH pulsatility in female infertility disorders, such as PCOS, that are associated with hyperactive LH secretion.

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11

Morton, GJ, and MW Schwartz. "The NPY/AgRP neuron and energy homeostasis." International Journal of Obesity 25, S5 (December 2001): S56—S62. http://dx.doi.org/10.1038/sj.ijo.0801915.

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Landry, Taylor, Daniel Shookster, Alec Chaves, Katrina Free, Tony Nguyen, and Hu Huang. "Exercise increases NPY/AgRP and TH neuron activity in the hypothalamus of female mice." Journal of Endocrinology 252, no. 3 (March 1, 2022): 167–77. http://dx.doi.org/10.1530/joe-21-0250.

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Recent evidence identifies a potent role for aerobic exercise to modulate the activity of hypothalamic neurons related to appetite; however, these studies have been primarily performed in male rodents. Since females have markedly different neuronal mechanisms regulating food intake, the current study aimed to determine the effects of acute treadmill exercise on hypothalamic neuron populations involved in regulating appetite in female mice. Mature, untrained female mice were exposed to acute sedentary, low- (10 m/min), moderate- (14 m/min), and high (18 m/min)-intensity treadmill exercise in a randomized crossover design. Mice were fasted 10 h before exercise, and food intake was monitored for 48 h after bouts. Immunohistochemical detection of cFOS was performed 3 h post-exercise to determine the changes in hypothalamic neuropeptide Y (NPY)/agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), tyrosine hydroxylase (TH), and SIM1-expressing neuron activity concurrent with the changes in food intake. Additionally, stains for pSTAT3tyr705 and pERKthr202/tyr204 were performed to detect exercise-mediated changes in intracellular signaling. Briefly, moderate- and high-intensity exercises increased 24-h food intake by 5.9 and 19%, respectively, while low-intensity exercise had no effects. Furthermore, increases in NPY/AgRPARC, SIM1PVN, and TH neuron activity were observed 3 h after high-intensity exercise, with no effects on POMCARC neurons. While no effects of exercise on pERKthr202/tyr204 were observed, pSTAT3tyr705 was elevated specifically in NPY/AgRP neurons 3 h post-exercise. Overall, aerobic exercise increased the activity of several appetite-stimulating neuron populations in the hypothalamus of female mice, which may provide insight into previously reported sexual dimorphisms in post-exercise feeding.

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Jones, Edward S., Nicolas Nunn, Adam P. Chambers, Søren Østergaard, Birgitte S. Wulff, and Simon M. Luckman. "Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice." Endocrinology 160, no. 11 (May 10, 2019): 2737–47. http://dx.doi.org/10.1210/en.2019-00100.

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Abstract To study the effects of an analog of the gut-produced hormone peptide YY (PYY3-36), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity. NNC0165-1273, a modified form of the peptide hormone PYY3-36 with potent selectivity at Y2 receptor (>5000-fold over Y1, 1250-fold over Y4, and 650-fold over Y5 receptor), was tested in vivo and in vitro in mouse models. NNC0165-1273 has fivefold lower relative affinity for Y2 compared with PYY3-36, but >250-, 192-, and 400-fold higher selectivity, respectively, for the Y1, Y4, and Y5 receptors. NNC0165-1273 produced a reduction in nighttime feeding at a dose at which PYY3-36 loses efficacy. The normal behavioral satiety sequence observed suggests that NNC0165-1273 is not nauseating and, instead, reduces food intake by producing early satiety. Additionally, NNC0165-1273 blocked ghrelin-induced cFos expression in NPY/AgRP neurons. In vitro electrophysiological recordings showed that, opposite to ghrelin, NNC0165-1273 hyperpolarized NPY/AgRP neurons and reduced action potential frequency. Administration of NNC0165-1273 via subcutaneous osmotic minipump caused a dose-dependent decrease in body weight and fat mass in an obese mouse model. Finally, NNC0165-1273 attenuated the feeding response when NPY/AgRP neurons were activated using ghrelin or more selectively with designer receptors. NNC0165-1273 is nonnauseating and stimulates a satiety response through, at least in part, a direct action on hypothalamic NPY/AgRP neurons. Modification of PYY3-36 to produce compounds with increased affinity to Y2 receptors may be useful as antiobesity therapies in humans.

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KNIGHT, ZACHARY. "314-OR: Mechanisms of AgRP Neuron-Induced Hunger." Diabetes 68, Supplement 1 (June 2019): 314—OR. http://dx.doi.org/10.2337/db19-314-or.

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15

Shiuchi, Tetsuya, Airi Otsuka, Noriyuki Shimizu, Sachiko Chikahisa, and Hiroyoshi Séi. "Feeding Rhythm-Induced Hypothalamic Agouti-Related Protein Elevation via Glucocorticoids Leads to Insulin Resistance in Skeletal Muscle." International Journal of Molecular Sciences 22, no. 19 (October 7, 2021): 10831. http://dx.doi.org/10.3390/ijms221910831.

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Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance.

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Oliveira, Vanessa, Anne E. Kwitek, Curt D. Sigmund, Lisa L. Morselli, and Justin L. Grobe. "Recent Advances in Hypertension." Hypertension 77, no. 4 (April 2021): 1061–68. http://dx.doi.org/10.1161/hypertensionaha.120.14513.

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Obesity represents the single greatest ongoing roadblock to improving cardiovascular health. Prolonged obesity is associated with fundamental changes in the integrative control of energy balance, including the development of selective leptin resistance, which is thought to contribute to obesity-associated hypertension, and adaptation of resting metabolic rate (RMR) when excess weight is reduced. Leptin and the melanocortin system within the hypothalamus contribute to the control of both energy balance and blood pressure. While the development of drugs to stimulate RMR and thereby reverse obesity through activation of the melanocortin system has been pursued, most of the resulting compounds simultaneously cause hypertension. Evidence supports the concept that although feeding behaviors, RMR, and blood pressure are controlled through mechanisms that utilize similar molecular mediators, these mechanisms exist in anatomically dissociable networks. New evidence supports a major change in molecular signaling within AgRP (Agouti-related peptide) neurons of the arcuate nucleus of the hypothalamus during prolonged obesity and the existence of multiple distinct subtypes of AgRP neurons that individually contribute to control of feeding, RMR, or blood pressure. Finally, ongoing work by our laboratory and others support a unique role for AT 1 (angiotensin II type 1 receptor) within one specific subtype of AgRP neuron for the control of RMR. We propose that understanding the unique biology of the AT 1 -expressing, RMR-controlling subtype of AgRP neurons will help to resolve the selective dysfunctions in RMR control that develop during prolonged obesity and potentially point toward novel druggable antiobesity targets that will not simultaneously cause hypertension.

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Smith, Mark A., Agharul I. Choudhury, Justyna A. Glegola, Paulius Viskaitis, Elaine E. Irvine, Pedro Caldas Custodio de Campos Silva, Sanjay Khadayate, Hanns Ulrich Zeilhofer, and Dominic J. Withers. "Extrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behavior." Journal of Clinical Investigation 130, no. 1 (November 18, 2019): 126–42. http://dx.doi.org/10.1172/jci130340.

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DEEM, JENNIFER D., KAYOKO OGIMOTO, JARRELL NELSON, BAO ANH N. PHAN, KEVIN R. VELASCO, VINCENT DAMIAN, MICHAEL W. SCHWARTZ, and GREGORY J. MORTON. "98-OR: Cold-Induced Hyperphagia Requires AgRP Neuron Activation." Diabetes 68, Supplement 1 (June 2019): 98—OR. http://dx.doi.org/10.2337/db19-98-or.

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Alhadeff, Amber L., Onyoo Park, Elen Hernandez, and J. Nicholas Betley. "Inhibition of Itch by Hunger and AgRP Neuron Activity." Neuroscience 450 (December 2020): 126–34. http://dx.doi.org/10.1016/j.neuroscience.2020.06.005.

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Lee, Jong Han, Bingzhong Xue, Zheng Chen, and Yuxiang Sun. "Neuronal GHS-R Differentially Modulates Feeding Patterns under Normal and Obesogenic Conditions." Biomolecules 12, no. 2 (February 11, 2022): 293. http://dx.doi.org/10.3390/biom12020293.

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The orexigenic hormone ghrelin increases food intake and promotes obesity through its receptor, growth hormone secretagogue receptor (GHS-R). We previously reported two neuron-specific GHS-R knockout mouse lines, namely pan-neuronal deletion by Syn1-cre and hypothalamic deletion by AgRP-cre, exhibiting differential diet-dependent effects on body weight. GHS-R deficiency in neurons elicited less pronounced metabolic effects under regular diet (RD) than high fat diet (HFD). While there was no difference in total food intake of HFD in either mouse line, Syn1-cre; Ghsrf/f mice showed much greater anti-obesity effect than that of AgRP-cre; Ghsrf/f mice. Meal feeding pattern is known to have a major impact on energy homeostasis and obesity development. Here, we investigated the feeding behaviors of these two neuron-specific GHS-R knockout mice under RD and HFD feeding, by assessing meal number, meal size, meal duration, and feeding frequency. Under the normal diet, RD-fed Syn1-cre; Ghsrf/f mice showed a decreased meal size in dark phase, while RD-fed AgRP-cre; Ghsrf/f mice showed an increased meal duration in dark phase. Under the obesogenic diet, HFD-fed Syn1-cre; Ghsrf/f mice displayed reduced meal numbers in light phase and increased feeding in both light and dark phases, whereas HFD-fed AgRP-cre; Ghsrf/f mice showed a decreased meal duration in the light phase only. Consistently, the expression of neuropeptides (Neuropeptide Y and Orexin) was increased in the hypothalamus of RD-fed Syn1-cre; Ghsrf/f mice, whereas the expression of cannabinoid receptor type 1 (CB1) was increased in the hypothalamus of HFD fed Syn1-cre; Ghsrf/f mice. Overall, feeding pattern changes were more pronounced in Syn1-cre; Ghsrf/f mice than that in AgRP-cre; Ghsrf/f mice, and HFD elicited greater alteration than RD. While AgRP-cre; Ghsrf/f mice consumed HFD meals faster during the day (showing shorter meal duration), Syn1-cre; Ghsrf/f mice ate few HFD meals during the light phase and ate slowly throughout the day (showing longer meal duration in both phases). Our findings reveal that neuronal GHS-R regulates energy homeostasis by altering feeding patterns, and differentially modulates feeding patterns in a site- and diet-dependent manner. The distinctive data in these two mouse lines also suggest that eating slowly during the optimal feeding period (dark phase for mice) may be beneficial in combating obesity.

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Johnson, Miranda D., Sebastien G. Bouret, Ambrose A. Dunn-Meynell, Christina N. Boyle, Thomas A. Lutz, and Barry E. Levin. "Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 311, no. 6 (December 1, 2016): R1032—R1044. http://dx.doi.org/10.1152/ajpregu.00326.2016.

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Selectively bred diet-induced obese (DIO) rats become obese on a high-fat diet and are leptin resistant before becoming obese. Compared with diet-resistant (DR) neonates, DIO neonates have impaired leptin-dependent arcuate (ARC) neuropeptide Y/agouti-related peptide (NPY/AgRP) and α-melanocyte-stimulating hormone (α-MSH; from proopiomelanocortin (POMC) neurons) axon outgrowth to the paraventricular nucleus (PVN). Using phosphorylation of STAT3 (pSTAT3) as a surrogate, we show that reduced DIO ARC leptin signaling develops by postnatal day 7 (P7) and is reduced within POMC but not NPY/AgRP neurons. Since amylin increases leptin signaling in adult rats, we treated DIO neonates with amylin during postnatal hypothalamic development and assessed leptin signaling, leptin-dependent ARC-PVN pathway development, and metabolic changes. DIO neonates treated with amylin from P0–6 and from P0–16 increased ARC leptin signaling and both AgRP and α-MSH ARC-PVN pathway development, but increased only POMC neuron number. Despite ARC-PVN pathway correction, P0–16 amylin-induced reductions in body weight did not persist beyond treatment cessation. Since amylin enhances adult DIO ARC signaling via an IL-6-dependent mechanism, we assessed ARC-PVN pathway competency in IL-6 knockout mice and found that the AgRP, but not the α-MSH, ARC-PVN pathway was reduced. These results suggest that both leptin and amylin are important neurotrophic factors for the postnatal development of the ARC-PVN pathway. Amylin might act as a direct neurotrophic factor in DIO rats to enhance both the number of POMC neurons and their α-MSH ARC-PVN pathway development. This suggests important and selective roles for amylin during ARC hypothalamic development.

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Smith, A. W., M. A. Bosch, E. J. Wagner, O. K. Rønnekleiv та M. J. Kelly. "The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol". American Journal of Physiology-Endocrinology and Metabolism 305, № 5 (1 вересня 2013): E632—E640. http://dx.doi.org/10.1152/ajpendo.00281.2013.

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Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (Gq-mER) ligand STX rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB receptors to G protein-coupled inwardly rectifying K+ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110β subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the estrogen receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.

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Porniece Kumar, Marta, Anna Lena Cremer, Paul Klemm, Lukas Steuernagel, Sivaraj Sundaram, Alexander Jais, A. Christine Hausen, et al. "Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity." Nature Metabolism 3, no. 12 (December 2021): 1662–79. http://dx.doi.org/10.1038/s42255-021-00499-0.

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AbstractInsulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

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Deng, Guorui, Lisa L. Morselli, Valerie A. Wagner, Kirthikaa Balapattabi, Sarah A. Sapouckey, Kevin L. Knudtson, Kamal Rahmouni, et al. "Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity." Hypertension 76, no. 2 (August 2020): 589–97. http://dx.doi.org/10.1161/hypertensionaha.120.15137.

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Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide ( Agrp ) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in Agrp neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in Agrp neuron biology, possibly secondary to altered CREB signaling.

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Wu, Q., M. P. Howell, M. A. Cowley, and R. D. Palmiter. "Starvation after AgRP neuron ablation is independent of melanocortin signaling." Proceedings of the National Academy of Sciences 105, no. 7 (February 13, 2008): 2687–92. http://dx.doi.org/10.1073/pnas.0712062105.

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Krashes, Michael J., Bhavik P. Shah, Shuichi Koda, and Bradford B. Lowell. "Rapid versus Delayed Stimulation of Feeding by the Endogenously Released AgRP Neuron Mediators GABA, NPY, and AgRP." Cell Metabolism 18, no. 4 (October 2013): 588–95. http://dx.doi.org/10.1016/j.cmet.2013.09.009.

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Teaney, Nicole A., and Nicole E. Cyr. "Sirtuin 1 Regulates Synapsin 1 in POMC-Producing N43-5 Neurons via FOXO1." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A56—A57. http://dx.doi.org/10.1210/jendso/bvab048.114.

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Abstract The nutrient-sensor protein Sirtuin 1 (Sirt1; silent mating type information regulation 2 homolog 1) has been shown to have significant and opposing effects on insulin resistance, leptin resistance, and body weight in the periphery and the brain. In the hypothalamic arcuate nucleus (ARC) of the brain, Sirt1 increases in the obese state and acts to promote weight gain as well as insulin and leptin resistance by increasing the orexigenic neuropeptides Agouti-related protein (AgRP) and neuropeptide Y (NPY), and in a distinct set of ARC neurons, by decreasing POMC and thus its anorexigenic derivative alpha-melanocyte stimulating hormone (alpha-MSH) (1). Sirt1’s actions on these neuropeptides are mediated at least in part by the deacetylation of the transcription factor forkhead box O1 (FOXO1). Another mechanism by which Sirt1 regulates body weight appears to be through mediating changes in the synapses of these neuropeptide-producing ARC neurons. For example, a previous study demonstrated that Sirt1 inhibition with the specific Sirt1 inhibitor, Ex-527, decreased AgRP-NPY inhibitory synaptic input on POMC neurons, which suggests that the obesity-induced increase in ARC Sirt1 would increase AgRP-NPY inhibition of POMC neurons thus promoting weight gain (2). The present study investigated how Sirt1 regulates synapses specifically in POMC-producing N43-5 neurons. Results reveal that inhibition of Sirt1 with Ex-527 significantly increased the presynaptic marker Synapsin 1 (Syn1) in N43-5 neurons. Furthermore, we investigated whether the Sirt1 target, FOXO1, mediates these synaptic changes. FOXO1 overexpression significantly decreased Syn1 and transfection of mutant FOXO1 significantly increased Syn1. Overall, our results suggest that Sirt1 regulates synapses of POMC neurons and does so in a manner that differs from Sirt1’s regulation of AgRP-NPY neuronal synapses. Future work will elucidate the mechanisms and consequences of Sirt1 and FOXO1 regulation of POMC neuron synapses under different nutritional conditions in vitro and in vivo. (1) Cyr, N. E., Steger, J. S., Toorie, A. M., Yang, J. Z., Stuart, R., Nillni, E. A. (2014). Central Sirt1 Regulates Body Weight and Energy Expenditure Along With the POMC-Derived Peptide α-MSH and the Processing Enzyme CPE Production in Diet-Induced Obese Male Rats, Endocrinology, 155(7), 2423–2435. (2) Dietrich, M. O., Antunes, C., Geliang, G., Liu, Z., Borok, E., Nie, Y., . . . Horvath, T. L. (2010). Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: Roles for Sirt1 in neuronal firing and synaptic plasticity. The Journal of Neuroscience, 30(35), 11815–11825.

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Shibata, Miyuki, Ryoichi Banno, Mariko Sugiyama, Takashi Tominaga, Takeshi Onoue, Taku Tsunekawa, Yoshinori Azuma, et al. "AgRP Neuron-Specific Deletion of Glucocorticoid Receptor Leads to Increased Energy Expenditure and Decreased Body Weight in Female Mice on a High-Fat Diet." Endocrinology 157, no. 4 (February 18, 2016): 1457–66. http://dx.doi.org/10.1210/en.2015-1430.

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Abstract Agouti-related protein (AgRP) expressed in the arcuate nucleus is a potent orexigenic neuropeptide, which increases food intake and reduces energy expenditure resulting in increases in body weight (BW). Glucocorticoids, key hormones that regulate energy balance, have been shown in rodents to regulate the expression of AgRP. In this study, we generated AgRP-specific glucocorticoid receptor (GR)-deficient (knockout [KO]) mice. Female and male KO mice on a high-fat diet (HFD) showed decreases in BW at the age of 6 weeks compared with wild-type mice, and the differences remained significant until 16 weeks old. The degree of resistance to diet-induced obesity was more robust in female than in male mice. On a chow diet, the female KO mice showed slightly but significantly attenuated weight gain compared with wild-type mice after 11 weeks, whereas there were no significant differences in BW in males between genotypes. Visceral fat pad mass was significantly decreased in female KO mice on HFD, whereas there were no significant differences in lean body mass between genotypes. Although food intake was similar between genotypes, oxygen consumption was significantly increased in female KO mice on HFD. In addition, the uncoupling protein-1 expression in the brown adipose tissues was increased in KO mice. These data demonstrate that the absence of GR signaling in AgRP neurons resulted in increases in energy expenditure accompanied by decreases in adiposity in mice fed HFD, indicating that GR signaling in AgRP neurons suppresses energy expenditure under HFD conditions.

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DEEM, JENNIFER D., CHELSEA L. FABER, CHRISTIAN PEDERSEN, BAO ANH N. PHAN, KAYOKO OGIMOTO, SARAH A. LARSEN, MEGAN A. TRAN, et al. "209-OR: Evidence that Agrp Neuron Activation Drives Cold-Induced Hyperphagia." Diabetes 69, Supplement 1 (June 2020): 209—OR. http://dx.doi.org/10.2337/db20-209-or.

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Krashes, Michael J., Bhavik P. Shah, Joseph C. Madara, David P. Olson, David E. Strochlic, Alastair S. Garfield, Linh Vong, et al. "An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger." Nature 507, no. 7491 (February 2, 2014): 238–42. http://dx.doi.org/10.1038/nature12956.

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Thomas, M. Alex, and Bingzhong Xue. "Mechanisms for AgRP neuron-mediated regulation of appetitive behaviors in rodents." Physiology & Behavior 190 (June 2018): 34–42. http://dx.doi.org/10.1016/j.physbeh.2017.10.006.

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Atala, Anthony. "Re: AgRP to Kiss1 Neuron Signaling Links Nutritional State and Fertility." Journal of Urology 200, no. 3 (September 2018): 501. http://dx.doi.org/10.1016/j.juro.2018.05.101.

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Lorch, Carolyn M., Nikolas W. Hayes, Jessica L. Xia, Stefan W. Fleps, Hayley E. McMorrow, Haley S. Province, Joshua A. Frydman, Jones G. Parker, and Lisa R. Beutler. "Sucrose overconsumption impairs AgRP neuron dynamics and promotes palatable food intake." Cell Reports 43, no. 2 (February 2024): 113675. http://dx.doi.org/10.1016/j.celrep.2024.113675.

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Su, Zhenwei, Amber L. Alhadeff, and J. Nicholas Betley. "Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity." Cell Reports 21, no. 10 (December 2017): 2724–36. http://dx.doi.org/10.1016/j.celrep.2017.11.036.

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Rau, Andrew R., and Shane T. Hentges. "The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release." Journal of Neuroscience 37, no. 31 (June 30, 2017): 7362–72. http://dx.doi.org/10.1523/jneurosci.0647-17.2017.

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Li, Peixin, Zhijian Rao, Brenton Thomas Laing, Wyatt Bunner, Taylor Landry, Amber Prete, Yuan Yuan, Zhong-Tao Zhang, and Hu Huang. "Vertical sleeve gastrectomy improves liver and hypothalamic functions in obese mice." Journal of Endocrinology 241, no. 2 (May 2019): 135–47. http://dx.doi.org/10.1530/joe-18-0658.

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Vertical sleeve gastrectomy (VSG) is an effective surgery to treat obesity and diabetes. However, the direct effect of VSG on metabolic functions is not fully understood. We aimed to investigate if alterations in hypothalamic neurons were linked with perturbations in liver metabolism after VSG in an energy intake-controlled obese mouse model. C57BL/6 and hrNPY-GFP reporter mice received HFD for 12 weeks and were then divided into three groups: Sham (ad lib), Sham (pair-fed) with VSG and VSG. Food intake was measured daily, and blood glucose levels were measured before and after the study. Energy expenditure and body composition were determined. Serum parameters, liver lipid and glycogen contents were measured and gene/protein expression were analyzed. Hypothalamic POMC, AgRP/NPY and tyrosine hydroxylase-expressing neurons were counted. The following results were obtained. VSG reduced body weight gain and adiposity induced by HFD, increased energy expenditure independent of energy intake. Fed and fasted blood glucose levels were reduced in the VSG group. While serum active GLP-1 level was increased, the active ghrelin and triglycerides levels were decreased along with improved insulin resistance in VSG group. Liver lipid accumulation, glycogen content and gluconeogenic gene expression were reduced in the VSG group. In the hypothalamus, TH-expressing neuron population was decreased, and the POMC-expressing neuron population was increased in the VSG group. In conclusion, our data suggest that VSG improves metabolic symptoms by increasing energy expenditure and lowering lipid and glycogen contents in the liver. These physiological alterations are possibly related to changes in hypothalamic neuron populations.

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Cedernaes, J., W. Huang, K. M. Ramsey, N. Waldeck, B. Marcheva, C. Bien Peek, D. C. Levine, et al. "Transcriptional basis for rhythmic control of hunger and metabolism within the AgRP neuron." Sleep Medicine 64 (December 2019): S57—S58. http://dx.doi.org/10.1016/j.sleep.2019.11.159.

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Yang, Liang, Yong Qi, and Yunlei Yang. "Astrocytes Control Food Intake by Inhibiting AGRP Neuron Activity via Adenosine A1 Receptors." Cell Reports 11, no. 5 (May 2015): 798–807. http://dx.doi.org/10.1016/j.celrep.2015.04.002.

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Cedernaes, Jonathan, Wenyu Huang, Kathryn Moynihan Ramsey, Nathan Waldeck, Lei Cheng, Biliana Marcheva, Chiaki Omura, et al. "Transcriptional Basis for Rhythmic Control of Hunger and Metabolism within the AgRP Neuron." Cell Metabolism 29, no. 5 (May 2019): 1078–91. http://dx.doi.org/10.1016/j.cmet.2019.01.023.

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Landry, Taylor, Brenton Thomas Laing, Peixin Li, Wyatt Bunner, Zhijian Rao, Amber Prete, Julia Sylvestri та Hu Huang. "Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice". Diabetes 69, № 7 (24 квітня 2020): 1368–81. http://dx.doi.org/10.2337/db19-0941.

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Marcelin, Geneviève, Young-Hwan Jo, Xiaosong Li, Gary J. Schwartz, Ying Zhang, Nae J. Dun, Rong-Ming Lyu, Clémence Blouet, Jaw K. Chang, and Streamson Chua. "Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism." Molecular Metabolism 3, no. 1 (February 2014): 19–28. http://dx.doi.org/10.1016/j.molmet.2013.10.002.

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Ren, Hongxia. "OR08-4 Endocrine Mechanisms of an Orphan G Protein-Coupled Receptor Regulating Metabolic Homeostasis." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A522. http://dx.doi.org/10.1210/jendso/bvac150.1087.

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Abstract G protein-coupled receptors (GPCRs) are the largest protein family and amenable for pharmacological manipulation. GPCRs in the neuroendocrine and enteroendocrine systems respond to various biological cues and in turn exert crucial roles in maintaining whole body metabolic homeostasis. For example, GPCRs in the gastrointestinal tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We recently identified that an orphan GPCR, Gpr17, was co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. We reported that acute genetic ablation of Gpr17 in intestinal epithelium (iKO) improved oral glucose tolerance and glucose-stimulated insulin secretion (GSIS) in female and male mice through increased secretion of incretin hormone in response to nutrient ingestion (Cell Reports, 2022). In the neuroendocrine system, we previously identified Gpr17 as the transcription target of Forkhead box protein O1 (FoxO1) in the hypothalamus and generated hypothalamic neuron specific Gpr17 knockout animals (Cell, 2012). Our results demonstrated that agouti-related peptide (AgRP) neuron Gpr17 knockout mice had increased satiety during fasting-refeeding challenge (Diabetes, 2015) and that proopiomelanocortin (POMC) neuron Gpr17 knockout mice had increased alpha-melanocyte stimulating hormone (aMSH) processing and increased firing of POMC neurons (Nutrition & Diabetes, 2019). However, how Gpr17 may regulate energy balance especially regarding leptin hormone signaling is unclear. To address this question, we used genetic knockout approach to generate Gpr17 conditional knockout in leptin receptor expressing neurons in the brain. We found Gpr17 deficiency in leptin receptor expressing neurons increased leptin sensitivity in animals and resulted in reduced food intake, which corresponded with reduced inflammatory response in the hypothalamus. Moreover, male Gpr17 whole body knockout mice have improved intraperitoneal glucose tolerance, and increased insulin sensitivity in hyperinsulinemic-euglycemic clamp studies. In conclusion, our collective body of work showed that ablation of Gpr17 signaling in the neuroendocrine and enteroendocrine systems led to improved neurohormonal regulation to maintain metabolic homeostasis, indicating functionally targeting this GPCR may lead to better therapeutic outcome of diabetes and obesity. Presentation: Saturday, June 11, 2022 12:15 p.m. - 12:30 p.m.

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Bunner, Wyatt P., Brenton T. Laing, and Hu Huang. "The Effects Of Acute Exercise On Npy/AgRP And POMC Neuron Activity In The Mouse Hypothalamus." Medicine & Science in Sports & Exercise 50, no. 5S (May 2018): 840. http://dx.doi.org/10.1249/01.mss.0000538766.62883.64.

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Decourtye-Espiard, Lyvianne, Maud Clemessy, Patricia Leneuve, Erik Mire, Tatiana Ledent, Yves Le Bouc, and Laurent Kappeler. "Stimulation of GHRH Neuron Axon Growth by Leptin and Impact of Nutrition during Suckling in Mice." Nutrients 15, no. 5 (February 21, 2023): 1077. http://dx.doi.org/10.3390/nu15051077.

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Nutrition during the early postnatal period can program the growth trajectory and adult size. Nutritionally regulated hormones are strongly suspected to be involved in this physiological regulation. Linear growth during the postnatal period is regulated by the neuroendocrine somatotropic axis, whose development is first controlled by GHRH neurons of the hypothalamus. Leptin that is secreted by adipocytes in proportion to fat mass is one of the most widely studied nutritional factors, with a programming effect in the hypothalamus. However, it remains unclear whether leptin stimulates the development of GHRH neurons directly. Using a Ghrh-eGFP mouse model, we show here that leptin can directly stimulate the axonal growth of GHRH neurons in vitro in arcuate explant cultures. Moreover, GHRH neurons in arcuate explants harvested from underfed pups were insensitive to the induction of axonal growth by leptin, whereas AgRP neurons in these explants were responsive to leptin treatment. This insensitivity was associated with altered activating capacities of the three JAK2, AKT and ERK signaling pathways. These results suggest that leptin may be a direct effector of linear growth programming by nutrition, and that the GHRH neuronal subpopulation may display a specific response to leptin in cases of underfeeding.

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Wu, Junguo, Canjun Zhu, Liusong Yang, Zhonggang Wang, Lina Wang, Songbo Wang, Ping Gao, et al. "N-Oleoylglycine-Induced Hyperphagia Is Associated with the Activation of Agouti-Related Protein (AgRP) Neuron by Cannabinoid Receptor Type 1 (CB1R)." Journal of Agricultural and Food Chemistry 65, no. 5 (January 30, 2017): 1051–57. http://dx.doi.org/10.1021/acs.jafc.6b05281.

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Phillips, Colin T., and Richard D. Palmiter. "Role of Agouti-Related Protein-Expressing Neurons in Lactation." Endocrinology 149, no. 2 (November 1, 2007): 544–50. http://dx.doi.org/10.1210/en.2007-1153.

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Hypothalamic neurons that express agouti-related protein (AgRP) and neuropeptide Y (NPY) are thought to be important for regulation of feeding, especially under conditions of negative energy balance. The expression of NPY and AgRP increases during lactation and may promote the hyperphagia that ensues. We explored the role of AgRP neurons in reproduction and lactation, using a mouse model in which AgRP-expressing neurons were selectively ablated by the action of diphtheria toxin. We show that ablation of AgRP neurons in neonatal mice does not interfere with pregnancy, parturition, or lactation, suggesting that early ablation allows compensatory mechanisms to become established. However, ablation of AgRP neurons after lactation commences results in rapid starvation, indicating that both basal feeding and lactation-induced hyperphagia become dependent on AgRP neurons in adulthood. We also show that constitutive inactivation of Npy and Agrp genes does not prevent pregnancy or lactation, nor does it protect lactating dams from diphtheria toxin-induced starvation.

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Mandelblat-Cerf, Yael, Rohan N. Ramesh, Christian R. Burgess, Paola Patella, Zongfang Yang, Bradford B. Lowell, and Mark L. Andermann. "Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales." eLife 4 (July 10, 2015). http://dx.doi.org/10.7554/elife.07122.

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Agouti-related-peptide (AgRP) neurons—interoceptive neurons in the arcuate nucleus of the hypothalamus (ARC)—are both necessary and sufficient for driving feeding behavior. To better understand the functional roles of AgRP neurons, we performed optetrode electrophysiological recordings from AgRP neurons in awake, behaving AgRP-IRES-Cre mice. In free-feeding mice, we observed a fivefold increase in AgRP neuron firing with mounting caloric deficit in afternoon vs morning recordings. In food-restricted mice, as food became available, AgRP neuron firing dropped, yet remained elevated as compared to firing in sated mice. The rapid drop in spiking activity of AgRP neurons at meal onset may reflect a termination of the drive to find food, while residual, persistent spiking may reflect a sustained drive to consume food. Moreover, nearby neurons inhibited by AgRP neuron photostimulation, likely including satiety-promoting pro-opiomelanocortin (POMC) neurons, demonstrated opposite changes in spiking. Finally, firing of ARC neurons was also rapidly modulated within seconds of individual licks for liquid food. These findings suggest novel roles for antagonistic AgRP and POMC neurons in the regulation of feeding behaviors across multiple timescales.

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De Solis, Alain J., Almudena Del Río-Martín, Jan Radermacher, Weiyi Chen, Lukas Steuernagel, Corinna A. Bauder, Fynn R. Eggersmann, et al. "Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism." Nature Metabolism, February 20, 2024. http://dx.doi.org/10.1038/s42255-024-00987-z.

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AbstractAgouti-related peptide (AgRP)-expressing and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combine non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons for comparing metabolic responses in male and female mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. We show that food intake is regulated by the additive effect of AgRP neuron activation and POMC neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated-versus-simultaneous regulation of AgRP and POMC neurons. We identify a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus, where activated AgRP neurons and inhibited POMC neurons cooperate to promote food consumption and activate Th+ neurons in the nucleus tractus solitarii. Collectively, these results unveil how food intake is precisely regulated by the simultaneous bidirectional interplay between AgRP and POMC neurocircuits.

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Sayar, Nilufer, Iltan Aklan, Yavuz Yavuz, Connor Laule, Hyojin kim, Jacob rysted, and Muhammed Ikbal Alp. "AgRP Neurons Encode Circadian Feeding Time." Physiology 39, S1 (May 2024). http://dx.doi.org/10.1152/physiol.2024.39.s1.733.

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Food intake follows a predictable daily pattern and synchronizes metabolic rhythms. Neurons expressing Agouti-related protein (AgRP) read out physiological energetic state and elicit feeding, but the regulation of these neurons across daily timescales is poorly understood. Using a combination of neuron-dynamics measurements and timed optogenetic activation in mice, we show that daily AgRP-neuron activity was not fully consistent with existing models of homeostatic regulation. Instead of operating as deprivation counter, AgRP-neuron activity primarily followed the circadian rest-activity cycle through a process that required an intact suprachiasmatic nucleus (SCN) and synchronization by light. Imposing novel feeding patterns through time-restricted food access or periodic AgRP-neuron stimulation was suffcient to resynchronize the daily AgRP-neuron activity rhythm and drive anticipatory-like behavior through a process that required DMHPDYN neurons. These results indicate that AgRP-neurons integrate time-of-day information of past feeding experience with current metabolic needs to predict circadian feeding time. This work is supported by NIH to D.A. R01DK126740. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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50

Chen, Yiming, Yen-Chu Lin, Christopher A. Zimmerman, Rachel A. Essner, and Zachary A. Knight. "Hunger neurons drive feeding through a sustained, positive reinforcement signal." eLife 5 (August 24, 2016). http://dx.doi.org/10.7554/elife.18640.

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The neural mechanisms underlying hunger are poorly understood. AgRP neurons are activated by energy deficit and promote voracious food consumption, suggesting these cells may supply the fundamental hunger drive that motivates feeding. However recent in vivo recording experiments revealed that AgRP neurons are inhibited within seconds by the sensory detection of food, raising the question of how these cells can promote feeding at all. Here we resolve this paradox by showing that brief optogenetic stimulation of AgRP neurons before food availability promotes intense appetitive and consummatory behaviors that persist for tens of minutes in the absence of continued AgRP neuron activation. We show that these sustained behavioral responses are mediated by a long-lasting potentiation of the rewarding properties of food and that AgRP neuron activity is positively reinforcing. These findings reveal that hunger neurons drive feeding by transmitting a positive valence signal that triggers a stable transition between behavioral states.

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