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 cis-acting 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.

Keywords: melanocortins; enhancer; epigenetics; exaptation; gene expression; mutant mice; transcription; transgenic mouse.

Fig. 1.

(A) Schematic of Pomc gene expression and peptide profiles in the rodent brain and pituitary. Pituitary expression (Pit, green color) is driven by the proximal promoter (mainly to intermediate lobe melanotrophs) and the −7 kb enhancer (mainly to anterior lobe corticotrophs). Pomc expression in the arcuate nucleus of the hypothalamus (Arc, blue color) is controlled by the distal neuronal enhancers nPE1 and nPE2 that were exapted from a Mammalian-apparent LTR and a CORE-SINE retroposon, respectively, at different time points along the lineage leading to mammals. Pomc exons are in black boxes. Coding sequences for the POMC prohormone and the peptides obtained after endoproteolytic cleavage are indicated in colored boxes. The asterisk next to β-MSH denotes that this peptide is not released in mice. (B) Schematic of the transgenes nPE1Pomc-tomato and nPE2Pomc-EGFP described in Ref. [64]. Expression of tomato (left), EGFP (center), and a merged photograph (right) in a coronal hemisection of the arcuate nucleus of an adult compound transgenic mouse showing extensive colocalization of both reporter fluorescent proteins.

Fig. 2.

(A) Schematic of the mouse Pomc and nPE mutant Pomc alleles as shown in Ref. [72]. (B) Body weight of wild-type, and homozygous mutants for nPE1, nPE2 and for both enhancers along the first 16 weeks. nPE1 mutants are mildly overweight and nPE1/nPE2 mutants are obese [72]. (C) Comparison of a wild-type and a homozygous adult mutant sibling male lacking both nPE1 and nPE2 [72].