MicroRNAs are involved in the hypothalamic leptin sensitivity

Abstract

The central nervous system monitors modifications in metabolic parameters or hormone levels (leptin) and elicits adaptive responses such as food intake and glucose homeostasis regulation. Particularly, within the hypothalamus, pro-opiomelanocortin (POMC) neurons are crucial regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the Pomc gene causes hyperphagia and obesity. Pomc gene expression is tightly controlled by different mechanisms. Interestingly, recent studies pointed to a key role for micro ribonucleic acid (miRNAs) in the regulation of gene expression. However, the role of miRNAs in the leptin sensitivity in hypothalamic melanocortin system has never been assessed. We developed a transgenic mouse model (PDKO) with a partial deletion of the miRNA processing enzyme DICER specifically in POMC neurons. PDKO mice exhibited a normal body weight but a decrease of food intake. Interestingly, PDKO mice had decreased metabolic rate by reduction of VO 2 consumption and CO 2 production which could explain that PDKO mice have normal weight while eating less. Interestingly, we observed an increase of leptin sensitivity in the POMC neurons of PDKO mice which could explain the decrease of food intake in this model. We also observed an increase in the expression of genes involved in the function of brown adipose tissue that is in polysynaptic contact with the POMC neurons. In summary, these results support the hypothesis that Dicer-derived miRNAs may be involved in the effect of leptin on POMC neurons activity.

Function of Dicer with regard to Energy Homeostasis Regulation, Structural Modification, and Cellular Distribution

“…Indeed, monoallelic depletion of Dicer in POMC neurons incurs reduced metabolic rates in mice by reduction of O 2 consumption and CO 2 production. However, food intake is decreased due to elevated leptin sensitivity in POMC neurons demonstrated by increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) in POMC neurons upon leptin administration [22]. Leptin, an adipokine secreted by adipocytes, acts on POMC and AgRP/NPY neurons to suppress food intake and promote energy expenditure [23].…”

“…Leptin, an adipokine secreted by adipocytes, acts on POMC and AgRP/NPY neurons to suppress food intake and promote energy expenditure [ 23 ]. The discrepancy that, by manipulation of Dicer, food intake does not coincide [ 10 , 11 , 22 ] might be explained by the fact that partial Dicer defect predominantly affects metabolic rates. And as a compensator, leptin sensitivity is subsequently increased to maintain normal body weight.…”

“…Currently, the reasons leading to the contradictory alterations of Dicer level or activities by nutrient depletion are not well exploited [ 10 , 11 , 22 ]. This may be due to different experimental contexts or models and awaits further confirmation.…”

DNA Hypomethylation of miR-30a Mediated the Protection of Hypoxia Postconditioning Against Aged Cardiomyocytes Hypoxia/Reoxygenation Injury Through Inhibiting Autophagy

“…MicroRNAs (miRNAs) are a class of endogenous, non-coding small ribonucleic acids containing 21-24 nucleotides. 7 Evidence has indicated that miRNAs involved T he incidence and mortality of cardiovascular diseases keep increasing due to aging population in the intensification, as old patients with aged myocardial are more prone to myocardial infarction (MI) and heart failure. 1,2 After MI, ischemia/reperfusion (I/R) can cause additional injury such as cellular metabolic dysfunction and structural damage due to rapid reperfusion of the ischemic or hypoxia myocardium.…”

Leptin Modulates the Expression of miRNAs-Targeting POMC mRNA by the JAK2-STAT3 and PI3K-Akt Pathways

“…It is essential to identify the intracellular mediators that allow these POMC neurons to respond to energy status modifications. In this context, we and others observed that miRNAs can be important intracellular mediators in the modulation of POMC neurons activity [1,[13][14][15][16][17]. So far, only two teams have identified mir-488 as miRNA that physically interact with the 3 UTR of POMC mRNA [29,32].…”