MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis

MicroRNAs (miRNAs) modulate physiological responses by simultaneously repressing the expression of gene networks. In this study, we found that global disruption of microRNA-7 (miR-7), the most enriched miRNA in the hypothalamus, causes obesity in mice. Targeted disruption of miR-7 in Single-minded homolog 1 (Sim1) neurons, a critical component of the hypothalamic melanocortin pathway, caused hyperphagia, obesity, and increased linear growth, mirroring Sim1 and MC4R haplo-insufficiency in mice and humans. We identified Snca (a-Synuclein) and Igsf8 (Immunoglobulin Superfamily Member 8) as miR-7 targets that act in Sim1 neurons to regulate body weight and endocrine axes. In humans, MIR-7-1 is located in the last intron of HNRNPK, whose promoter drives the expression of both genes. Genetic variants at the HNRNPK locus that reduce its expression are associated with increased height and truncal fat mass. We demonstrate that miR-7 suppresses gene networks involved in the hypothalamic melanocortin pathway to regulate mammalian energy homeostasis.