SHU9119 and MBP10 are biased ligands at the human melanocortin-4 receptor.

The melanocortin-4 receptor (MC4R), a G protein-coupled receptor, is critically involved in regulating energy homeostasis as well as modulation of reproduction and sexual function. Two peptide antagonists (SHU9119 and MBP10) were derived from the endogenous agonist α-melanocyte stimulating hormone. But their pharmacology at human MC4R is not fully understood. Herein, we performed detailed pharmacological studies of SHU9119 and MBP10 on wild-type (WT) and six naturally occurring constitutively active MC4Rs. Both ligands had no or negligible agonist activity in Gαs-cAMP signaling on WT MC4R, but stimulated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation on WT and mutant MC4Rs. Mechanistic studies revealed that SHU9119 and MBP10 stimulated ERK1/2 signaling of MC4R by different mechanisms, with SHU9119-stimulated ERK1/2 signaling mediated by phosphatidylinositol 3-kinase (PI3K) and MBP10-initiated ERK1/2 activation through PI3K and ß-arrestin. In summary, our studies demonstrated that SHU9119 and MBP10 were biased ligands for MC4R, preferentially activating ERK1/2 signaling through different mechanisms. SHU9119 acted as a biased ligand and MBP10 behaved as a biased allosteric modulator.

Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds.

PURPOSE OF REVIEW: The global obesity epidemic has become a major public health concern, necessitating comprehensive research into its adverse effects on various tissues within the human body. Among these tissues, skeletal muscle has gained attention due to its susceptibility to obesity-related alterations. Mitochondria are primary source of energy production in the skeletal muscle. Healthy skeletal muscle maintains constant mitochondrial content through continuous cycle of synthesis and degradation. However, obesity has been shown to disrupt this intricate balance. This review summarizes recent findings on the impact of obesity on skeletal muscle mitochondria structure and function. In addition, we summarize the molecular mechanism of mitochondrial quality control systems and how obesity impacts these systems. RECENT FINDINGS: Recent findings show various interventions aimed at mitigating mitochondrial dysfunction in obese model, encompassing strategies including caloric restriction and various dietary compounds. Obesity has deleterious effect on skeletal muscle mitochondria by disrupting mitochondrial biogenesis and dynamics. Caloric restriction, omega-3 fatty acids, resveratrol, and other dietary compounds enhance mitochondrial function and present promising therapeutic opportunities.