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 VO₂ consumption and CO₂ 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.

KEYWORDS:

• Pro-opiomelanocortin
• microRNA
• hypothalamus
• brown adipose tissue
• leptin
• DICER

Acknowledgments

A.D. was the recipient of a doctoral fellowship from the Ministry of Education. The authors are grateful to C. Airault, B. Bariohay, K. Poirot and N. Moulard for technical assistance. We also thank the Aix-Marseille University Microscopy Center CP2M for the access to confocal Microscopy and the AVB platform (Analyse et Valorisation de la Biodiversité, iSm2, UMR 7313, Marseille).

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

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Additional information

Funding

This research was supported by funding obtained from Aix-Marseille University, INRA, INSERM, the ‘Région Provence-Alpes-Côte d’Azur’, the ‘Conseil Général des Bouches-du-Rhône’ (PACA, CG13) and Benjamin Delessert foundation.