New Target Emerges for Battling Obesity: Hepatic Ago2

Published September 2018 | Nature Communications

When mice do not express the protein Argonaute 2 (Ago2) in their livers, their risk of developing obesity-related diabetic conditions plummets, according to a study by a team of experts at Cincinnati Children’s that adds weight to an emerging way of thinking about obesity.

Argonaute proteins are essential components of the RNA-induced silencing complex (RISC). A team led by first author Cai Zhang, and senior author Takahisa Nakamura, PhD, found that that Ago2 plays a major role is slowing down glucose-driven energy production in the liver, but its cousin Ago1 does not.

Inactivating hepatic Ago2 improves systemic glucose metabolism, even during insulin insufficiency. When fed high-fat-diets to induce obesity, mice that lacked Ago2 in their livers exhibited lower body weight, lower triglyceride levels, increased mitochondrial capacity and improved energy expenditure compared to controls.

“This mechanism may be the core of a vicious cycle in disrupted energy metabolism in the obese liver,” the co-authors state. “While obesity is traditionally considered a state of over-nutrition, recent studies suggest that the obese liver may, in some aspects, resemble a condition of energy deprivation.”

The study also shows that the Ago2-mediated RNA silencing process stifles expression of genes involved in energy metabolism, specifically a subset of miRNAs including miR-802, miR-103/107, and miR-148a/152, which are known to negatively impact glucose and lipid metabolism. When knocked out, the team observed increased expression of genes including Hnf1β, Cav1, and Pgc1α.

“These Ago2-mediated molecular events may solve the paradox of protein biosynthesis in the obese liver, demonstrate a new mechanism in the regulation of basal metabolic activity, and provide a novel therapeutic target for metabolic diseases,” the co-authors say.