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Backgroundα-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). α-MSH is predominantly expressed in the pituitary gland, but it is also found in several peripheral tissues such as the skin and heart. However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Therefore, we sought to investigate whether α-MSH could be involved in the regulation of pathological cardiac remodeling.MethodsTissue α-MSH concentrations and the effects of chronic α-MSH administration were investigated in mice subjected to transverse aortic constriction (TAC). Rat H9c2 cells, neonatal mouse ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were used to study the effects of α-MSH and selective MC-R agonists. Inducible cardiomyocyte-specific melanocortin 5 receptor (MC5-R) knockout mouse model was engineered to investigate the role of MC5-R in cardiac hypertrophy.Resultsα-MSH was highly expressed in the mouse heart, particularly in the ventricles, and its level was reduced in the left ventricles of TAC-operated mice. Administration of a stable α-MSH analogue protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction.In vitroexperiments revealed that cardiomyocytes serve as effector cells for the α-MSH mediated antihypertrophic signaling and that selective activation of MC5-R mimics the actions of α-MSH. In keeping with these findings, MC5-R was downregulated in the failing mouse heart and stressed hiPSC-CMs. Silencing of MC5-R in mouse cardiomyocytes induced hypertrophy and fibrosis markersin vitroand aggravated TAC-induced cardiac hypertrophy and fibrosisin vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice.Conclusionsα-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogues of naturally occurring α-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.

Melanocortin 1 receptor (MC1-R) is widely expressed in melanocytes and leukocytes, and is thus strongly implicated in the regulation of skin pigmentation and inflammation. MC1-R mRNA has also been found in the rat and human liver, but its functional role has remained elusive. We hypothesized that MC1-R is functionally active in the liver and involved in the regulation of cholesterol and bile acid metabolism. We generated hepatocyte-specific MC1-R knock-out (L-Mc1r-/-) mice and phenotyped the mouse model for lipid profiles, liver histology and bile acid levels.L-Mc1r-/-mice had significantly increased liver weight, which was accompanied by elevated levels of total cholesterol and triglycerides in the liver as well as in the plasma. These mice demonstrated also enhanced liver fibrosis and a disturbance in bile acid metabolism as evidenced by markedly reduced bile acid levels in the plasma and feces. Mechanistically, using HepG2 cells as anin vitromodel, we found that selective activation of MC1-R in HepG2 cells reduced cellular cholesterol content and enhanced uptake of low- and high-density lipoprotein particlesviaa cAMP-independent mechanism. In conclusion, the present results demonstrate that MC1-R signaling in hepatocytes regulates cholesterol and bile acid metabolism and its deficiency leads to hypercholesterolemia and enhanced lipid accumulation and fibrosis in the liver.

Seasonal rhythms influence mood and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we studied the seasonal effects on brain MOR availability via analysing a dataset (n=204) of [11C]carfentanil positron emission tomography (PET) scans of healthy volunteers. We found that seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. Causal effect of daylength on brain MOR availability was further verified by a post hoc experiment with repeated PET imaging of rats (n=9) under seasonal photoperiodic simulation. Therefore, the in vivo brain MOR availability in normal humans shows significant seasonal variation, which aligns with expected seasonal variation in mood and suicidality.