The MC3R affects energy homeostasis through its role on central nervous system appetitive pathways but also appears to act on peripheral metabolic processes. We previously reported that knock-in mice replacing the murine Mc3r with hypoactive human double mutant (C17A + G241A) MC3R (MC3RhDM/hDM) had increased feeding efficiency, body weight and fat mass, along with surprisingly increased serum adiponectin compared to wild type human MC3R knock-in mice (MC3RhWT/hWT).


We cross-bred MC3RhWT/hWT and MC3RhDM/hDM mice with adiponectin knockout mice to generate MC3RhWT/hWT+Adipo-/- and MC3RhDM/hDM+Adipo-/- mice. Body composition was measured using DEXA. WAT was tested for adipogenesis, lipogenesis, and lipolysis to understand the role of adiponectin in the adipocyte expansion and obesity phenotype of MC3R insufficiency.


The high adiponectin of MC3RhDM/hDM became undetectable in MC3RhDM/hDM+Adipo-/-. Fat mass, bone measures and feeding efficiency partially normalized in MC3RhDM/hDM+Adipo-/-towards those of MC3RhWT/hWT+Adipo-/-. In adipose tissue, compared to MC3RhDM/hDM, MC3RhDM/hDM+Adipo-/- had reduced protein expression of ACC-1 and FASN (de-novo lipogenesis) and increased expression of multiple enzymes involved in lipolysis: pHSL, MAGL and ATGL. During differentiation, adipose-derived stem cells from MC3RhDM/hDM+Adipo-/- also accumulated significantly less neutral lipid and had lower mRNA expression of adipogenesis and lipogenesis markers compared to MC3RhDM/hDM cells.


These data suggest adiponectin signaling interacts with MC3R signaling to affect lipid turnover and nutrient partitioning. The MC3R genotype x adiponectin effects on lipolysis and lipogenesis suggest that there is crosstalk between the adiponectin and melanocortin 3 signaling pathways in the regulation of fat mass in adipose tissue. The hyperadiponectinemia observed in MC3RhDM/hDM is an important contributor to its obese phenotype.