MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis

Mary P. LaPierre, Katherine Lawler, Svenja Godbersen, I. Sadaf Farooqi and Markus Stoffel ()
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Mary P. LaPierre: Institute of Molecular Health Sciences, ETH Zürich
Katherine Lawler: Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Svenja Godbersen: Institute of Molecular Health Sciences, ETH Zürich
I. Sadaf Farooqi: Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Markus Stoffel: Institute of Molecular Health Sciences, ETH Zürich

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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 (α-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.

Date: 2022
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DOI: 10.1038/s41467-022-33367-w

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