A neuron-specific deletion of the microRNA-processing enzyme DICER induces severe but transient obesity in mice.

Géraldine M Mang,Sylvain Pradervand,David Gatfield,Paul Franken,Leonore Wigger,Ngoc-Hien Du,Alaaddin Bulak Arpat,Frédéric Preitner

doi:10.1371/journal.pone.0116760

Géraldine M Mang, Sylvain Pradervand + Show 6 more

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https://doi.org/10.1371/journal.pone.0116760

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Abstract

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. MiRNAs are implicated in various biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. We used a neuronal-specific inhibition of miRNA maturation in adult mice to study the consequences of miRNA loss on obesity development. Camk2a-CreERT2 (Cre+) and floxed Dicer (Dicerlox/lox) mice were crossed to generate tamoxifen-inducible conditional Dicer knockouts (cKO). Vehicle- and/or tamoxifen-injected Cre+;Dicerlox/lox and Cre+;Dicer+/+ served as controls. Four cohorts were used to a) measure body composition, b) follow food intake and body weight dynamics, c) evaluate basal metabolism and effects of food deprivation, and d) assess the brain transcriptome consequences of miRNA loss. cKO mice developed severe obesity and gained 18 g extra weight over the 5 weeks following tamoxifen injection, mainly due to increased fat mass. This phenotype was highly reproducible and observed in all 38 cKO mice recorded and in none of the controls, excluding possible effects of tamoxifen or the non-induced transgene. Development of obesity was concomitant with hyperphagia, increased food efficiency, and decreased activity. Surprisingly, after reaching maximum body weight, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Weight loss was accompanied by lowered O2-consumption and respiratory-exchange ratio. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin) and in metabolism (e.g. Bmp4, Bmp7, Ptger1, Cox7a1). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis.

Highlights

MicroRNAs are small, non-coding RNA molecules that act as post-transcriptional repressors of gene expression
The level of Dicer mRNA seemed down-regulated in the hippocampus of conditional knockout (cKO) mice, as exemplified by the reduction in exon 21 (Fig. 1E), consistent with the results reported by Konopka et al [10]
Identifying the processes that are implicated in the return to normal body weight will bring a new perspective in the treatment of obesity and metabolic disorders

Summary

Introduction

MicroRNAs (miRNAs) are small, non-coding RNA molecules that act as post-transcriptional repressors of gene expression. They promote mRNA decay and inhibit translation by base pairing to the 30 untranslated regions of target transcripts. In mammals, they may target as much as 50% of all protein-coding mRNAs [1]. MiRNAs are involved in most cellular processes investigated far [2] and their dysregulation contributes to many human diseases [3,4]. MiRNAs gain growing attention in the field of diabetes and obesity research

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