MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis
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Date
2022-09-29
Publication Type
Journal Article
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yes
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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.
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published
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Journal / series
Volume
13
Pages / Article No.
5733
Publisher
Nature
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Organisational unit
03739 - Stoffel, Markus / Stoffel, Markus
01559 - Lehre Biologie
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Funding
182880 - NCCR RNA#38;Disease (51NF40-182880): Flexibility Grant (SNF)