MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis

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.

ciRS-7 and miR-7 regulate ischemia induced neuronal death via glutamatergic signaling

“…Previous studies have identified the involvement of miR-7 in response to oxidative stress 37 , in particular to low glucose 38 . To establish the possible functional link between the upregulation of miR-7 in ciRS-7 KO mice in conditions of ischemic stroke, we subjected cre-loxP inducible miR-7 KO mice 39 to tMCAo (Figure 5A, Supplementary Figure S4A,B). We failed to detect changes in the lesion volume as measured by MRI between miR-7 KO and WT mice at acute timepoint (1dpi) (Supplementary Figure S4C).…”

“…Of note is that murine neuroblastoma cell lines express negligible amounts of ciRS-7 even when differentiated with retinoic acid, suggesting a more direct effect of miR-7 in the absence of its regulator. A recent study has highlighted a potential role of miR-7 in controlling energy homeostasis in hypothalamic neurons 39 , linking this miRNA to conditions in which the energetic balance is strongly altered, such as in ischemic stroke. However, alteration in the levels of miR-7 in hypothalamic neurons were not accompanied by changes in the expression of ciRS-7 or Cyrano 39 .…”

“…A recent study has highlighted a potential role of miR-7 in controlling energy homeostasis in hypothalamic neurons 39 , linking this miRNA to conditions in which the energetic balance is strongly altered, such as in ischemic stroke. However, alteration in the levels of miR-7 in hypothalamic neurons were not accompanied by changes in the expression of ciRS-7 or Cyrano 39 . Together with our data showing how the type of ischemic insult activates ciRS-7 network with different dynamics, this suggests that the network responds in a stress type, strength, and duration dependent manner.…”

“…Before the animal studies, ciRS-7 KO and miR-7 KO mice were genotyped as before 9, 39 except for the tissue dissociation step. Briefly, ear puncture samples were digested in 50 mM Sodium Hydroxide solution for one hour at 95 °C.…”

“…Before tMCAo surgery, miR-7 inducible KO mice were injected with 2mg of Tamoxifen intraperitoneally once per day for 5 consecutive days at the age of 3 to 4 weeks as before 39 . Recombination was induced in both Cre+ and Cre-littermates.…”