A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Area of Science:

• Genetics
• Metabolic Diseases
• Evolutionary Biology

Background:

• The 2q21.3 locus in Europeans shows positive selection, linked to lactase persistence for famine survival.
• This locus is also associated with human obesity and type 2 diabetes, suggesting a dual role in adaptation and disease.

Purpose of the Study:

• To investigate the role of microRNA-128-1 (miR-128-1), located within the 2q21.3 locus, as a regulator of mammalian metabolism.
• To explore the connection between miR-128-1, energy storage, ancient famine adaptation, and modern metabolic maladaptation.

Main Methods:

• Utilized antisense targeting and genetic ablation of miR-128-1 in mouse models of metabolic disease.
• Assessed the impact of miR-128-1 manipulation on energy expenditure, diet-induced obesity, and glucose tolerance.

Main Results:

• Genetic ablation or inhibition of miR-128-1 led to increased energy expenditure in mouse models.
• These interventions ameliorated high-fat-diet-induced obesity and significantly improved glucose tolerance.

Conclusions:

• miR-128-1 is identified as a critical metabolic regulator in mammals.
• A 'thrifty phenotype' linked to miR-128-1-dependent energy storage may bridge evolutionary adaptation to famine with modern metabolic diseases due to nutritional excess.