MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis

The hypothalamus controls systemic energy homeostasis. Here, the authors show that loss of microRNA-7 in hypothalamic neurons causes obesity, increased growth and endocrine dysfunction in mice, and report genetic evidence that links microRNA-7 to height and adiposity in humans. MicroRNAs (miRNAs) modulate physiological responses by repressing the expression of gene networks. We found that global deletion of microRNA-7 (miR-7), the most enriched miRNA in the hypothalamus, causes obesity in mice. Targeted deletion of miR-7 in Single-minded homolog 1 (Sim1) neurons, a critical component of the hypothalamic melanocortin pathway, causes hyperphagia, obesity and increased linear growth, mirroring Sim1 and Melanocortin-4 receptor (MC4R) haplo-insufficiency in mice and humans. We identified Snca (alpha-Synuclein) and Igsf8 (Immunoglobulin Superfamily Member 8) as miR-7 target genes 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. These findings demonstrate that miR-7 suppresses gene networks involved in the hypothalamic melanocortin pathway to regulate mammalian energy homeostasis.

Automated summary

The loss of microRNA-7 in hypothalamic neurons causes obesity, increased growth, and endocrine dysfunction in mice. The study also found genetic evidence linking microRNA-7 to height and adiposity in humans. These findings provide insights into the role of microRNA-7 in regulating mammalian energy homeostasis.