One of the hypothalamic neuropeptides involved in the sensation of satiety (feeling full and therefore not desiring food) is called alpha-melanocyte stimulating hormone (a-MSH) and it is derived through cell-type specific enzymatic processing from the precursor protein, pro-opiomelanocortin (POMC). a-MSH is member of the melanocortins which are derived from POMC. Genetic mutations in humans as well as in animals that disrupt the expression and processing of POMC peptides are associated with changes in energy balance and can lead to obesity and type 2 diabetes. In humans there have been mutations identified in prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), as well as in the a-MSH degrading enzyme prolylcarboxypeptidase (PRCP) that are associated with energy imbalance and a propensity for obesity.
Now a just published report in the Journal of Biological Chemistry demonstrates that obesity can lead to a vicious spiral of more eating and worsening of obesity due to changes in the hypothalamic processing of a-MSH from POMC.
Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing
Previous studies by the same group had shown that diet-induced obesity (DIO) is associated with decreases in hypothalamic a-MSH levels but that the level of the mRNA for the precursor protein, POMC remain unaltered. The current study goes on to show that DIO induces endoplasmic reticulum (ER) stress which plays a role in the regulation of energy balance. When the ER becomes stressed because of an excessive accumulation of newly synthesized unfolded proteins, the unfolded protein response (UPR) is activated. These UPR pathways in the pancreas are associated with impaired insulin processing. Within the hypothalamus the UPR impairs the processing of a-MHC from POMC due to defects in the enzyme prohormone convertase 2 (PC2).
The net effect of DIO on hypothalamic feeding circuits is, unfortunately, a decreased ability to respond normally to what should be a normal cessation of the desire to eat, resulting in more eating, and more obesity. As these authors point out, our ability to more accurately dissect the central control of energy-regulating neuropeptides during DIO will be critical to the development of new therapeutic targets to prevent and/or mitigate obesity and its associated pathophysiology such as the development of type 2 diabetes.