Maid gene dysfunction promotes hyperobesity via the reduction of anti-inflammatory macrophages in Mc4r gene-deficient mice

Abstract The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Eight female mice were analyzed for each genotype: Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, the mice had fewer M1 inflammatory macrophages and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, the mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue, both of which involved in sympathetic nerve signaling. Maid and Mc4r gene-deficient mice are a useful new model of MASLD with hyperobesity and less adipose tissue inflammation for studying the mechanism of MASH progression.