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PERK in POMC neurons connects celastrol with metabolism.

ABSTRACT: ER stress and activation of the unfolded protein response in the periphery as well as the central nervous system have been linked to various metabolic abnormalities. Chemically lowering protein kinase R-like ER kinase (PERK) activity within the hypothalamus leads to decreased food intake and body weight. However, the cell populations required in this response remain undefined. In the current study, we investigated the effects of proopiomelanocortin-specific (POMC-specific) PERK deficiency on energy balance and glucose metabolism. Male mice deficient for PERK in POMC neurons exhibited improvements in energy balance on a high-fat diet, showing decreased food intake and body weight, independent of changes in glucose and insulin tolerances. The plant-based inhibitor of PERK, celastrol, increases leptin sensitivity, resulting in decreased food intake and body weight in a murine model of diet-induced obesity (DIO). Our data extend these observations by demonstrating that celastrol-induced improvements in leptin sensitivity and energy balance were attenuated in mice with PERK deficiency in POMC neurons. Altogether, these data suggest that POMC-specific PERK deficiency in male mice confers protection against DIO, possibly providing a new therapeutic target for the treatment of diabetes and metabolic syndrome.

SUBMITTER: He Z

PROVIDER: S-EPMC8492333 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis.

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Glycogen Metabolism Drives Sensory Activation of Pomc Neurons

Project description:In this study, we aimed at uncovering the molecular mechanisms underlying POMC neuron sensory activation and the mediated behavioral and metabolic processes. Unexpectedly, we found that glycogen metabolism is rapidly engaged in POMC neurons upon sensory food perception. Genetic deletion of glycogen synthase, the sole enzyme able to make glycogen in vivo, in POMC neurons impedes food-related sensory activation while causing impairments in food awareness, short-term food intake and insulin release. These perturbations associate with whole-body metabolic defects, including overweight and insulin resistance, that are exacerbated by high-dense diets or ageing. Collectively, our study identifies glycogen metabolism as an unanticipated mechanistic driver of POMC neuron sensory activation and provides paradigm-shift evidences of the importance of neuronal glycogen for physiology.

2024-01-31 | GSE224274 | GEO

Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism.

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DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance.

Project description:We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection.

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mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptin.

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Glycogen Metabolism Drives Sensory Activation of Pomc Neurons

Project description:Glycogen Metabolism Drives Sensory Activation of Pomc Neurons

| PRJNA930442 | ENA

Modulation of Lipid Metabolism by Celastrol.

Project description:Hyperlipidemia, characterized by high serum lipids, is a risk factor for cardiovascular disease. Recent studies have identified an important role for celastrol, a proteasome inhibitor isolated from Tripterygium wilfordii Hook. F., in obesity-related metabolic disorders. However, the exact influences of celastrol on lipid metabolism remain largely unknown. Celastrol inhibited the terminal differentiation of 3T3-L1 adipocytes and decreased the levels of triglycerides in wild-type mice. Lipidomics analysis revealed that celastrol increased the metabolism of lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), sphingomyelins (SMs), and phosphatidylethanolamines (PEs). Further, celastrol reversed the tyloxapol-induced hyperlipidemia induced associated with increased plasma LPCs, PCs, SMs, and ceramides (CMs). Among these lipids, LPC(16:0), LPC(18:1), PC(22:2/15:0), and SM(d18:1/22:0) were also decreased by celastrol in cultured 3T3-L1 adipocytes, mice, and tyloxapol-treated mice. The mRNAs encoded by hepatic genes associated with lipid synthesis and catabolism, including Lpcat1, Pld1, Smpd3, and Sptc2, were altered in tyloxapol-induced hyperlipidemia, and significantly recovered by celastrol treatment. The effect of celastrol on lipid metabolism was significantly reduced in Fxr-null mice, resulting in decreased Cers6 and Acer2 mRNAs compared to wild-type mice. These results establish that FXR was responsible in part for the effects of celastrol in controlling lipid metabolism and contributing to the recovery of aberrant lipid metabolism in obesity-related metabolic disorders.

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Hypothalamic POMC neurons promote cannabinoid-induced feeding.

Project description:Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB1R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.

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RNAseq of mouse POMC neurons

Project description:From the arcuate nucleus of mice, we have dissociated neurons that express Proopiomelanocortin(POMC) and captured them on the Fluidigm C1 platform. These neuronsplay important roles in the regulation of appetite and sexual behavior. Here we propose tosequence RNA from 96 single POMC-expressing neurons to understand the variance in theirtranscriptomes.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

2015-04-28 | E-ERAD-357 | biostudies-arrayexpress

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