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Forebrain neuronal Smc3 regulates weight and metabolic parameters associated with regulation of hypothalamic Melanocortin 4 receptor

ABSTRACT: SMC3 is a major component of the cohesin complex that regulates higher-order chromatin organization and gene expression. Mutations in SMC3 gene are found in patients with Cornelia de Lange syndrome (CdLs). This syndrome is characterized by intellectual disabilities, behavioral patterns as self-injury, as well as metabolic dysregulation. Nonetheless, little is known about the role of neuronal SMC3 in gene expression and physiology in adulthood. This study determined the role of SMC3 in adulthood brain, by knocking out Smc3 specifically in adulthood forebrain excitatory neurons. Neuron-specific SMC3 knockout mice displayed a very strong metabolic phenotype in both male and female mice, including a robust overweight phenotype, loss of muscle mass, increased food consumption, lower respiratory exchange ratio, lower energy expenditure and hormonal changes. The hypothalamus of these mice displayed dysregulated morphology and RNA-seq in the hypothalamus reveals dysregulation in multiple cellular pathways, including decrease of Melanocortin 4 receptor (Mc4r) expression level, a main regulator of appetite. Treatment of these mice with Setmelanotide, a MC4r agonist, induced a decrease of weight and food consumption in these mice. Therefore, we have identified specific and reversable metabolic parameters that are regulated by neuronal Smc3 in adulthood.

ORGANISM(S): Mus musculus

PROVIDER: GSE252366 | GEO | 2024/01/04

REPOSITORIES: GEO

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Forebrain neuronal Smc3 regulates weight and metabolic parameters partly through regulation of hypothalamic Melanocortin 4 receptor

Project description:SMC3 is a major component of cohesin complex that regulates higher-order chromatin organization and gene expression. Mutations in SMC3 gene are found in patients with Cornelia de Lange syndrome (CdLs). This syndrome is characterized by intellectual disabilities, behavioral patterns as self-injury, as well as metabolic dysregulation. Nonetheless, little is known about the role of neuronal SMC3 in gene expression and physiology especially in adulthood. This study determined the role of SMC3 in adulthood brain, by knocking out Smc3 specifically in adulthood forebrain excitatory neurons. Neuron-specific SMC3 knockout mice displayed a very strong metabolic phenotype in both male and female mice, including a robust overweight phenotype, loss of muscle mass, increased food consumption, lower respiratory exchange ratio, lower energy expenditure and hormonal changes. The hypothalamus of these mice displayed dysregulated morphology and RNA-seq in the hypothalamus reveals dysregulation in multiple cellular pathways, including decrease of Melanocortin 4 receptor (Mc4r) expression level , a main regulator of appetite. Treatment of these mice with Setmelanotide, a MC4r agonist, induced a decrease of weight and food consumption in these mice. Therefore, we have identified specific metabolic pathways that are regulated by Smc3 in forebrain neurons, and specific mechanisms that are involved.

2023-09-18 | GSE243287 | GEO

Protection against overfeeding-induced weight gain in mice is preserved in obesity but does not require FGF21 or MC4R

Project description:Experimental overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we utilized intragastric overfeeding in mice to investigate the physiological and molecular responses to forced weight gain. Both lean and diet-induced obese (DIO) mice exhibited a potent and prolonged lowering of voluntary food intake following overfeeding-induced weight gain. Although overfeeding resulted in a marked increase in circulating fibroblast growth factor 21 (FGF21), experiments with FGF21 knockout (KO) mice demonstrated that FGF21 is dispensable for the homeostatic defense against experimental weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease legumain (LGMN). Notably, administration of recombinant LGMN lowered body weight and food intake in DIO mice. The protection against weight gain was also associated with reduced vascularization in the hypothalamus and sustained reductions in transcript levels of the orexigenic neuropeptides, Npy and AgRP, suggesting a role of hypothalamic signaling in the homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice showed that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R.

2024-01-12 | GSE247825 | GEO

Estrogen Drives Melanocortin Neurons To Reduce Sedentary Behavior

Project description:Estrogen depletion in both rodents and humans leads to inactivity, unhealthy fat accumulation, and metabolic syndrome, underscoring the conserved metabolic benefits of estrogen signaling that inevitably decline with aging. Here, we uncover a hypothalamic node that integrates estrogen and melanocortin-4 receptor (MC4R) signaling to drive episodic bursts in activity prior to ovulation. Skirting the estrogen-dependent gating of this node by CRISPR activation of Mc4r reduces sedentary behavior long-term in both males and females. Our findings expand the impact of MC4R signaling beyond food intake regulation and rationalize reported sex-differences in melanocortin signaling including increased disease severity for women with MC4R-insuffciency. This newly identified hormone-dependent activity node illustrates the potency of estrogen in maintaining an active lifestyle.

2021-03-01 | GSE141434 | GEO

A neural basis for melanocortin-4 receptor-regulated appetite.

Project description:Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.

2016-12-03 | GSE90809 | GEO

Expression data from hypothalamic samples of WT mice fed normal diet vs high fat diet

Project description:The consumption of a 60% high fat diet leads to increased body weight and the development of the metabolic syndrome. We analyzed hypothalamic samples of WT mice as it has been previously shown that the hypothalamus plays a crucial role in the regulation of energy homeostasis. We used microarrays to detail the global programme of gene expression affected by the consumption of a high fat diet specifically in the hypothalamus of WT mice.

2019-05-01 | GSE127056 | GEO

Mus musculus

Project description:Chronic alcohol consumption from adolescence-to-adulthood in mice — Effect on gene expression in the hypothalamus

| PRJNA183191 | ENA

Sensory Food Perception Rapidly Primes Postprandial ER-Homeostasis through Melanorcortin-Dependent Control of Liver mTOR Activation

Project description:Adaptation of liver to the postprandial state requires coordinate regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR-signaling, Xbp1-splicing, increased expression of ER-stress genes and phosphatidylcholine synthesis, which translate into a rapid morphological ER-remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increase upon nutrient supply. Sensory food perception activates POMC-neurons in the hypothalamus, optogenetic activation of POMC-neurons activates hepatic mTOR-signaling and Xbp1-splicing and lack of MC4R-expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinatly primes postprandrial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s-axis

2018-10-31 | GSE118973 | GEO

Genome-wide analysis of hypothalamic gene expression in prenatally undernourished male rat offspring under high fat diet

Project description:Based on the developmental origin of health of disease hypothesis, we previously showed that prenatal 70% maternal food restriction (FR30) predisposes the offspring to development of pathologies in adulthood. In the present study, we focused on the hypothalamus gene expression profile of standard and high fat (HF)-fed FR30 adult offspring.

2013-01-17 | GSE43547 | GEO

Hypothalamic REV-ERBs Control Circadian Food Intake and Leptin Sensitivity [RNA-seq]

Project description:Obesity occurs when energy expenditure is outweighed by food intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), regulate feeding amount as well as energy expenditure. Here we report that mice lacking circadian nuclear receptors REV-ERBa and b in the tuberal hypothalamus (HDKO) gain excessive weight on an obesogenic diet due both to decreased energy expenditure and increased food consumption during the light phase. Moreover, rebound food intake after fasting is markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior is due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity is impaired in HDKO mice on an obesogenic diet in a circadian manner. Thus, REV-ERBs play a crucial role in hypothalamic regulation of food intake and circadian leptin sensitivity in diet-induced obesity.

2020-10-11 | GSE148641 | GEO

Hypothalamic REV-ERBs Control Circadian Food Intake and Leptin Sensitivity [ChIP-seq]

2020-10-11 | GSE148599 | GEO

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