MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis.
Mary P LaPierreKatherine L LawlerSvenja GodbersenI Sadaf FarooqiMarkus StoffelPublished in: Nature communications (2022)
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.
Keyphrases
- long non coding rna
- cell proliferation
- poor prognosis
- long noncoding rna
- high fat diet induced
- genome wide
- body weight
- genome wide identification
- insulin resistance
- metabolic syndrome
- type diabetes
- weight loss
- adipose tissue
- dna methylation
- spinal cord
- signaling pathway
- gene expression
- body mass index
- weight gain
- spinal cord injury
- physical activity
- cancer therapy
- drug delivery
- skeletal muscle
- genome wide analysis
- fatty acid
- wild type