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Orthopedia regulates Melanocortin 4 Receptor transcription and energy homeostasis

ABSTRACT: Orthopedia regulates Melanocortin 4 Receptor transcription and energy homeostasis

PROVIDER: PRJNA1149300 | ENA |

REPOSITORIES: ENA

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Orthopedia regulates Melanocortin 4 Receptor transcription and energy homeostasis

Project description:Disruption of hypothalamic melanocortin 4 receptors (MC4Rs) causes obesity in mice and humans. Here, we investigate the transcriptional regulation of MC4R in the hypothalamus. In mice, we show that the homeodomain transcription factor Orthopedia (Otp) is enriched in Mc4r neurons in the paraventricular nucleus of the hypothalamus (PVN) and directly regulates Mc4r transcription. Deletion of Otp in PVN neurons during development or adulthood reduces Mc4r expression, causing increased food intake and obesity. In humans, four of five carriers of rare predicted functional OTP variants in UK Biobank had obesity. To explore a causal role for human OTP variants, we generated mice with a loss-of-function OTP mutation identified in a child with severe obesity. Heterozygous knock-in mice exhibit hyperphagia and obesity, reversed by treatment with an MC4R agonist. Our findings demonstrate that OTP regulates mammalian energy homeostasis and enable the diagnosis and treatment of people with obesity due to OTP deficiency.

2025-01-15 | GSE275099 | GEO

MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis

Project description:MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis

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A Brain-Melanocortin-Vagus axis mediates adipose tissue expansion independently of energy intake.

Project description:The melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by increasing Sympathetic Nervous input to adipose tissue. In contrast, calorie-independent mechanisms favoring energy storage are less understood. Here we demonstrate that obesogenic signals, including reduction of brain-melanocortin signaling or high-fat feeding, actively promote fat mass gain independently of caloric intake via efferent nerve fibers conveyed by the common hepatic branch of the vagus nerve. These signals promote adipose tissue expansion by activating lipogenic program and adipocyte and endothelial cell proliferation independently of insulin action or the sympathetic tone to adipose tissue. These data reveal a novel physiological mechanism whereby the brain controls energy stores that may contribute to increased susceptibility to obesity.

2019-04-18 | GSE128383 | GEO

CREBH Regulates Mitochondrial Unfolded Protein Response to Maintain Energy Homeostasis

Project description:CREBH Regulates Mitochondrial Unfolded Protein Response to Maintain Energy Homeostasis

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MAD2-dependent insulin receptor endocytosis regulates metabolic homeostasis

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Loss of the Melanocortin 4 Receptor in mice causes dilated cardiomyopathy.

Project description:Deletion of the melanocortin-4 receptor in mice causes dilated cardiomyopathy that is independent of obesity.

2018-05-01 | GSE98439 | GEO

Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications

Project description:Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications

| PRJNA1047047 | ENA

CREBH Regulates Mitochondrial Unfolded Protein Response to Maintain Energy Homeostasis

Project description:The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.

2024-11-15 | GSE281608 | GEO

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

Project description: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.

2024-01-04 | GSE252366 | GEO

OTUD3 regulates energy metabolism

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