The melanocortins are a family of neuropeptide hormones consisting of melanocyte-stimulating hormones, α-, β-, and γ-MSH, and adrenocorticotropic hormone (ACTH) as well as five different melanocortin receptors (MC1R - MC5R). These peptides are widely expressed in the body and are involved in a diverse number of physiological functions including pigmentation, steroidogenesis, exocrine function, energy homeostasis, inflammation, and immunomodulation. MC1R is abundantly expressed in the melanocytes, and leukocytes where it regulates skin pigmentation and, inflammatory responses respectively. MC1R is also expressed in the liver and white adipose tissue but its functional role in these metabolic tissues remain elusive. Therefore, the main aim of this thesis was to elucidate the regulatory role of MC1R signaling in cholesterol, bile acid, and fatty acid metabolism, particularly in the liver.

To address this objective, hepatocyte-specific MC1R knockout (Mc1r LKO), and global MC1R deficient (Mc1re/e) mice were fed either a chow or a Western-type diet, and characterized for body weight and composition, lipid metabolism, and liver morphology. First, MC1R was found to be expressed in hepatocytes as well as in other cell types in the mouse liver, and downregulated in mice fed a Western-type diet, and in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Mc1r LKO mice on a chow diet showed increased liver weight, elevated levels of cholesterol in the plasma and liver, and perturbed bile acid metabolism. Secondly, pharmacological activation of MC1R reduced the cellular cholesterol content, and increased the uptake of LDL and HDL particles in cultured hepatocytes. Lastly, in terms of adiposity and fatty acid metabolism, Mc1re/e mice on a Western diet showed increased white adipose tissue mass, adipocyte hypertrophy and plasma triglycerides (TG) concentration. This phenotype was recapitulated in Mc1r LKO mice, indicating a dependency of the phenotype on dysfunctional MC1R in the liver. Mc1r LKO mice also showed upregulation of markers of de novo lipogenesis (DNL), apoptosis, and inflammation as well as increased liver TG accumulation and fibrosis.

In conclusion, the results from this thesis identify a novel function of hepatic MC1R signaling in the regulation of cholesterol and fatty acid metabolism in the liver, suggesting that MC1R could be a promising therapeutic target for the management of metabolic diseases such as, MASLD.