Pancreatic neuronal melanocortin-4 receptor modulates serum insulin levels independent of leptin receptor

Abstract

The leptin-regulated melanocortin (MC) system modulates energy homeostasis and hypothalamic MC neuronal circuits regulate insulin secretion. We therefore hypothesized that MC system components were present in the pancreas. In order to determine the veracity of the hypothesis, we examined c-Fos, melanocortin-4 receptor (Mc4r), and alpha-melanocyte-stimulating hormone (α-MSH) expression levels in nondiabetic (intact leptin receptor signaling) and Zucker diabetic fatty (ZDF; leptin receptor deficiency) rats. We infused rats via the third ventricle with the α-MSH analog Nle4, D-Phe7-α-MSH (NDP-MSH), a Mc4r agonist. Subsequently, both hypothalamic and pancreatic c-Fos and Mc4r mRNAs were upregulated. Likewise, immunohistochemical analysis showed that an increased Mc4r and α-MSH expression in nerves surrounding the pancreatic vasculature and islets. Increases in c-Fos, α-MSH, and Mc4r expression were independent of leptin receptor function. Conversely, serum insulin was significantly reduced by NDP-MSH treatment, an effect which was reversed by the Mc4r specific blocker HS014. Finally, proopiomelanocortin (POMC) mRNA, the precursor of α-MSH, was detected by RT-PCR in pancreatic tissue homogenates. These findings suggest that pancreatic Mc4r and autonomic neurons participate in a communication pathway between the central MC system and pancreatic islets to regulate insulin secretion.

Effects of post-weaning diet on metabolic parameters and DNA methylation status of the cryptic promoter in the Avy allele of viable yellow mice

“…The rationale for the experiment was that a high methyl diet supplied to pregnant a/a mice carrying A vy /a conceptuses biases coat color of the pups by increasing the extent of CpG site methylation in the regulatory regions of the A vy allele [1, 3, 4, 13] and hence leads to potentially better health outcomes in offspring [33–38]. This increase in methylation within the cryptic promoter of the allele is presumed to reduce the promiscuous, ectopic production of ASIP both within the hair follicles, where melanization is affected, and at ectopic sites, such as the hypothalamus and pancreas, where ASIP may influence metabolism of fats and carbohydrates [8, 9, 39]. …”

“…These differences are due to the labile activation state of the A vy allele during conceptus development. The increased appetite and obesity of the yellower mice most likely arises from ectopic expression of ASIP outside the hair follicle, especially in the hypothalamus [5], where it antagonizes the melanocortin 4 receptor (MC4R) [8], and in the pancreas [9]. …”

MC4R rs17782313gene polymorphism was associated with glycated hemoglobin independently of its effect on BMI in Japanese: the Shimane COHRE study

“…MC4R is a seven-transmembrane G-protein coupled receptor that is expressed predominantly in the brain and, to an extent yet to fully clarified, in other metabolically important tissues such as adipose tissue (6) and pancreas (7). The MC4R is encoded by a single exon gene located on chromosome 18q22 at 56.19 Mb.…”

“…The dysfunction of MC4R gene has been demonstrated to lead to hyperphagia and obesity (5). Several functional studies have suggested that MC4R is involved in the regulation of insulin secretion, glucose utilization and production (5)(6)(7). Whether this effect is mediated by its pro-obesity effect is yet to be confirmed.…”

Maternal exposure to bisphenol A and genistein has minimal effect onAvy/aoffspring coat color but favors birth of agouti over nonagouti mice

“…The broad spectrum of coat colors among siblings, ranging from full yellow to pseudoagouti (brown), and the mottled patterning observed in the mice intermediate between these extremes, arises from the labile state of the A vy allele and its variable expression. The increased appetite and associated fat mass of the yellower mice, in turn, is due to ectopic expression of ASIP outside the hair follicle, most critically in the hypothalamus (11), where it antagonizes the melanocortin 4 receptor (MC4R) (15), and the pancreas (16).…”