Over the past decade, central melanocortin system has proven to be an essential regulator of energy homeostasis and glucose metabolism. However little is known about the physiological role of systemic melanocortin peptides, in particular α-melanocyte stimulating hormone (α-MSH) in peripheral glucose regulation. Recent evidence suggests another source of α-MSH coming from a group of glucose-sensing cells within the anterior pituitary similar to pro-opiomelanocortin cells in the arcuate nucleus1 . Here, we investigate the in vivo effects of systemic α-MSH.
We demonstrated that constant intravenous infusion of α-MSH during glucose tolerance test (GTT) increases glucose disposal in lean mice but the effect was not observed in diet-induced obese (DIO) mice. Intriguingly, during hyperinsulinemic-euglycemic clamp lean mice infused with α-MSH require significantly higher glucose infusion rate to reach euglycemia and the overall rate of glucose disappearance (Rd) was markedly increased. We also found that α-MSH has an additive effect to insulin-mediated glucose disposal indicating that the two mechanisms towards glucose uptake in skeletal muscles are distinctly different. In addition, systemic α-MSH did not alter hepatic glucose production.
GTT profiles of lean mice were exacerbated with venous administration of anti-α-MSH antibody rendering them glucose intolerant. Interestingly, the change was not observed when antibody was given centrally. In addition, we found that MC5R, but not others subtypes were highly expressed in skeletal muscle and α-MSH induced glucose disposal was completely abolished in MC5RKO mice.
We also found that the failure of α-MSH-mediated glucose disposal in DIO mice was a consequence of elevated phosphodiesterase activity In particular, phosphodiesterase (PDE)4B protein expression was significantly higher in the soleus of DIO mice. Blocking PDE activity using selective and non-selective PDE inhibitors restores α-MSH-induced glucose disposal in obese mice during GTT. Overall, we have identified a novel, insulin-independent endocrine circuit that regulates peripheral glucose homeostasis.