Hypothalamic miR-103 protects from hyperphagic obesity in mice

Area of Science:

• Neuroscience
• Molecular Biology
• Metabolism

Background:

• The arcuate nucleus (ARC) in the hypothalamus is crucial for regulating food intake and body weight.
• The precise role of neuronal noncoding RNAs, specifically microRNAs, in energy homeostasis remains unclear.

Purpose of the Study:

• To investigate the function of microRNAs in hypothalamic neurons controlling energy balance.
• To elucidate the molecular mechanisms by which microRNAs regulate feeding behavior and body weight.

Main Methods:

• Generation of Dicer-conditional knockout (DicerCKO) mice with microRNA deficiency in ARC neurons.
• Pharmacological inhibition of the PI3K-Akt-mTOR pathway using rapamycin.
• Oligonucleotide-based restoration of microRNA function in vivo and in vitro.
• Analysis of neuropeptide levels, signaling pathway activation, and body weight changes.

Main Results:

• DicerCKO mice exhibited severe hyperphagic obesity due to PI3K-Akt-mTOR pathway overactivation and neuropeptide imbalance.
• Pten deletion in adult forebrain neurons also led to significant weight gain via the same pathway.
• Rapamycin treatment normalized obesity in DicerCKO and Pten-deficient mice.
• Hypothalamic delivery of microRNA mimics attenuated adiposity in DicerCKO mice.
• Loss of miR-103 upregulated the PI3K-Akt-mTOR pathway and Pik3cg mRNA, and its restoration reversed these effects and reduced obesity.

Conclusions:

• Neuronal microRNAs are essential regulators of energy homeostasis.
• The PI3K-Akt-mTOR signaling pathway is a key target through which microRNAs control feeding behavior and body weight.
• Targeting microRNA-pathway interactions offers potential therapeutic strategies for obesity.