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AgRP neurons are not indispensable for body weight maintenance in adult mice.

ABSTRACT: In addition to their role in promoting feeding and obesity development, hypothalamic arcuate agouti-related protein/neuropeptide Y (AgRP/NPY) neurons are widely perceived to be indispensable for maintaining normal feeding and body weight in adults, and consistently, acute inhibition of AgRP neurons is known to reduce short-term food intake. Here, we adopted complementary methods to achieve nearly complete ablation of arcuate AgRP/NPY neurons in adult mice and report that lesioning arcuate AgRP/NPY neurons in adult mice causes no apparent alterations in ad libitum feeding or body weight. Consistent with previous studies, loss of AgRP/NPY neurons blunts fasting refeeding. Thus, our studies show that AgRP/NPY neurons are not required for maintaining ad libitum feeding or body weight homeostasis in adult mice.

SUBMITTER: Cai J

PROVIDER: S-EPMC10909125 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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AgRP neurons are not indispensable for body weight maintenance in adult mice.

Cai Jing J Chen Jing J Ortiz-Guzman Joshua J Huang Jessica J Arenkiel Benjamin R BR Wang Yuchen Y Zhang Yan Y Shi Yuyan Y Tong Qingchun Q Zhan Cheng C

Cell reports 20230708 7

In addition to their role in promoting feeding and obesity development, hypothalamic arcuate agouti-related protein/neuropeptide Y (AgRP/NPY) neurons are widely perceived to be indispensable for maintaining normal feeding and body weight in adults, and consistently, acute inhibition of AgRP neurons is known to reduce short-term food intake. Here, we adopted complementary methods to achieve nearly complete ablation of arcuate AgRP/NPY neurons in adult mice and report that lesioning arcuate AgRP/N ...[more]

PMID: 37422762

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GIRK2 potassium channels expressed by the AgRP neurons decrease adiposity and body weight in mice.

Project description: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.

| S-EPMC10468093 | biostudies-literature

Regulation of body weight and food intake by AGRP neurons during opioid dependence and abstinence in mice.

Project description:Dysregulation of body weight maintenance and opioid dependence are often treated as independent disorders. Here, we assessed the effects of both acute and long-term administration of morphine with and without chemogenetic activation of agouti-related peptide (AGRP)-expressing neurons in the arcuate nucleus (ARCAGRP neurons) to elucidate whether morphine and neuronal activation affect feeding behavior and body weight. First, we characterized interactions of opioids and energy deficit in wild-type mice. We observed that opioid administration attenuated both fasting-induced refeeding and ghrelin-stimulated feeding. Moreover, antagonism of opioid receptors blocked fasting-induced refeeding behavior. Next, we interfaced chemogenetics with opioid dependence. For chemogenetic experiments of ARCAGRP neurons, we conducted a priori behavioral qualification and post-mortem FOS immunostaining verification of arcuate activation following ARCAGRP chemogenetic activation. We administered clozapine during short-term and long-term morphine administration paradigms to determine the effects of dependence on food intake and body weight. We found that morphine occluded feeding behavior characteristic of chemogenetic activation of ARCAGRP neurons. Notably, activation of ARCAGRP neurons attenuated opioid-induced weight loss but did not evoke weight gain during opioid dependence. Consistent with these findings, we observed that morphine administration did not block fasting-induced activation of the ARC. Together, these results highlight the strength of opioidergic effects on body weight maintenance and demonstrate the utility of ARCAGRP neuron manipulations as a lever to influence energy balance throughout the development of opioid dependence.

| S-EPMC9468932 | biostudies-literature

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight.

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The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors.

Project description:The BBSome, a complex of eight Bardet-Biedl syndrome (BBS) proteins involved in cilia function, has emerged as an important regulator of energy balance, but the underlying cellular and molecular mechanisms are not fully understood. Here, we show that the control of energy homeostasis by the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons require intact BBSome. Targeted disruption of the BBSome by Bbs1 gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the Bbs1 gene in POMC neurons is associated with hyperphagia. Mechanistically, we present evidence implicating the BBSome in the trafficking of G protein-coupled neuropeptide Y Y2 receptor (NPY2R) and serotonin 5-hydroxytryptamine (HT)2C receptor (5-HT2CR) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HT2CR, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HT2cR agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HT2CR to be stalled in the late endosome. Our results demonstrate the significance of the hypothalamic BBSome for the control of energy balance through regulation of trafficking of important metabolic receptors.

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Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons.

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Leptin-independent programming of adult body weight and adiposity in mice.

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| S-EPMC3884597 | biostudies-literature

Rapid, reversible activation of AgRP neurons drives feeding behavior in mice.

Project description:Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.

| S-EPMC3069789 | biostudies-literature

DNA methylation in AgRP neurons regulates voluntary exercise behavior in mice.

Project description:DNA methylation regulates cell type-specific gene expression. Here, in a transgenic mouse model, we show that deletion of the gene encoding DNA methyltransferase Dnmt3a in hypothalamic AgRP neurons causes a sedentary phenotype characterized by reduced voluntary exercise and increased adiposity. Whole-genome bisulfite sequencing (WGBS) and transcriptional profiling in neuronal nuclei from the arcuate nucleus of the hypothalamus (ARH) reveal differentially methylated genomic regions and reduced expression of AgRP neuron-associated genes in knockout mice. We use read-level analysis of WGBS data to infer putative ARH neural cell types affected by the knockout, and to localize promoter hypomethylation and increased expression of the growth factor Bmp7 to AgRP neurons, suggesting a role for aberrant TGF-β signaling in the development of this phenotype. Together, these data demonstrate that DNA methylation in AgRP neurons is required for their normal epigenetic development and neuron-specific gene expression profiles, and regulates voluntary exercise behavior.

| S-EPMC6889160 | biostudies-literature

Activation of Agrp neurons modulates memory-related cognitive processes in mice.

Project description:Hypothalamic Agrp neurons are critical regulators of food intake in adult mice. In addition to food intake, these neurons have been involved in other cognitive processes, such as the manifestation of stereotyped behaviors. Here, we evaluated the extent to which Agrp neurons modulate mouse behavior in spatial memory-related tasks. We found that activation of Agrp neurons did not affect spatial learning but altered behavioral flexibility using a modified version of the Barnes Maze task. Furthermore, using the Y-maze test to probe working memory, we found that chemogenetic activation of Agrp neurons reduced spontaneous alternation behavior mediated by the neuropeptide Y receptor-5 signaling. These findings suggest novel functional properties of Agrp neurons in memory-related cognitive processes.

| S-EPMC6400640 | biostudies-literature

Weight maintenance from young adult weight predicts better health outcomes.

Project description:ObjectiveDefining groups of individuals within a larger population with similar patterns of weight change over time may provide insight into influences of weight stability or gain.MethodsLatent class growth modeling was used to define subgroups of weight change in adult members of the Gila River Indian Community participating in at least four non-diabetic health exams including OGTTs (N = 1,157, 762F/395M; 78.4 ± 19.0 kg). In a separate study, 152 individuals had 24-h EE measured in a respiratory chamber.ResultsEight groups with baseline weights of 54.6 ± 7.3 (n = 124), 64.2 ± 7.7 (n = 267), 73.6 ± 7.8 (n = 298), 86.1 ± 10.2 (n = 194), 95.5 ± 6.7 (n = 90), 97.9 ± 10.4 (n = 92), 110.9 ± 11.9 (n = 61), and 122.1 ± 13.6 (n = 31) kg (P < 0.001) were delineated. Group 5, (initial weight = 95.5 ± 6.7 kg) maintained a comparatively stable weight over time (+3.3 ± 10.3 kg, +3.8 ± 11.2% of initial weight; median follow-up time: 13.1 years). All other groups gained weight over time (+29.9 ± 21.1% of initial weight; median follow-up time: 16.3 years). Higher starting weight defined weight gain in most groups, but higher 2 h glucose predicted membership in the lower weight trajectories. The weight stable group had higher rates of impaired glucose regulation at baseline and higher 24-h EE.ConclusionsWeight in young adulthood defined weight gain trajectory underscoring the importance of intervening early to prevent weight gain.

| S-EPMC4224987 | biostudies-literature

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