Molecular and functional genetics of the proopiomelanocortin gene, food intake regulation and obesity

Abstract

A specter is haunting the world, the specter of obesity. During the last decade, this pandemia has skyrocketed threatening children, adolescents and lower income families worldwide. Although driven by an increase in the consumption of ultraprocessed edibles of poor nutritional value, the obesogenic changes in contemporary human lifestyle affect people differently, revealing that some individuals are more prone to develop increased adiposity. During the last years, we performed a variety of genetic, evolutionary, biochemical and behavioral experiments that allowed us to understand how a group of neurons present in the arcuate nucleus of the hypothalamus regulate the expression of the proopiomelanocortin (Pomc) gene and induce satiety. We disentangled the neuronal transcriptional code of Pomc by identifying the cisacting regulatory elements and primary transcription factors controlling hypothalamic Pomc expression and determined their functional importance in the regulation of food intake and adiposity. Altogether, our studies reviewed here shed light on the power and limitations of the mammalian central satiety pathways and may contribute to the development of individual and collective strategies to reduce the debilitating effects of the self-induced obesity pandemia.

The Homeodomain Transcription Factor NKX2.1 Is Essential for the Early Specification of Melanocortin Neuron Identity and ActivatesPomcExpression in the Developing Hypothalamus

“…The arcuate nucleus of the hypothalamus is a brain hub that integrates nutritional and hormonal information to promote food intake or satiety (Rubinstein and Low, 2017). A group of arcuate neurons expresses proopiomelanocortin (Pomc), a gene that encodes the anorexigenic neuropeptides ␣-, ␤-, and ␥melanocyte-stimulating hormone, collectively known as central melanocortins (Rubinstein and Low, 2017).…”

“…The arcuate nucleus of the hypothalamus is a brain hub that integrates nutritional and hormonal information to promote food intake or satiety (Rubinstein and Low, 2017). A group of arcuate neurons expresses proopiomelanocortin (Pomc), a gene that encodes the anorexigenic neuropeptides ␣-, ␤-, and ␥melanocyte-stimulating hormone, collectively known as central melanocortins (Rubinstein and Low, 2017). POMC neurons pro-mote satiety upon sensing variations in glucose (Ibrahim et al, 2003), leptin (Cowley et al, 2001), and insulin (Benoit et al, 2002) levels as well as in local temperature (Jeong et al, 2018).…”

LY3009120, a pan-Raf kinase inhibitor, inhibits adipogenesis of 3T3-L1 cells by controlling the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT‑3, FAS, ACC, perilipin�A, and AMPK

“…As a result, obesity is now among the leading contributors to global morbidity and mortality rates (2). Although the development of obesity is influenced by a number of factors, including excessive food intake, lack of physical activity, genetic susceptibility, medications, and endocrine abnormalities (2,3), increasing evidence indicates that it also arises from excessive preadipocyte differentiation in adipose tissue (4,5). Therefore, any compound that inhibits the disproportionate differentiation of these cells constitutes a potential therapeutic option for obesity.…”

DNA methylation and expression of proopiomelanocortin (POMC) gene in the hypothalamus of three‐week‐old chickens show sex‐specific differences

“…We aimed to provide insight into the central nervous/hypothalamic expression of proopiomelanocortin ( POMC ), a neurohormone with important physiological roles, for example, for food intake and body weight control (reviewed in ref. ), and examine the methylation profile at the CpG sites across the promoter region and the CpG island in the gene body of POMC in 3‐week‐old chickens. Additionally, we specifically chose to use brain samples in early adolescence, prior to the occurrence of sexual dimorphism in chicken , in order to identify sex‐specific differences and influences as we narrowed in on the control center for temperature and food intake//body weight regulation with a gene‐targeted approach.…”