Mice Lacking Enzyme Renin Stay Lean On High-fat Diet, With Little Exercise

The findings suggest that renin-blocking drugs designed for treating high blood pressure might also improve obesity and insulin resistance, according to the researchers. Renin plays an important rate-limiting role in the production of a hormone called angiotensin II (Ang II) that increases blood pressure by constricting blood vessels.

"An overactive renin-angiotensin system has also been associated with obesity and the metabolic syndrome," said Nobuyuki Takahashi of The University of North Carolina at Chapel Hill. "Now we've gained new insight into the mechanism responsible."

The metabolic syndrome is characterized by central obesity, hypertension, abnormally high blood lipid levels, and impaired glucose tolerance, the researchers explained. It also increases the risk of heart disease and type 2 diabetes. While most theories to explain the condition have focused on primary defects of insulin action, the renin-angiotensin system has also been implicated.

Clinical trials have shown that drugs that block other parts of the renin-angiotensin system improve insulin sensitivity and decrease the incidence of type 2 diabetes. Studies have also revealed that mice lacking angiotensinogen, the substrate that renin acts on, are lean and resistant to diet-induced obesity.

In the current study, the researchers generated mice with a predisposition for obesity that were also deficient for renin. They found that the renin-less mice were lean, resistant to diet-induced obesity, and more insulin sensitive than normal mice.

"This metabolically favorable state results partly from an increased metabolic rate and partly from gastrointestinal loss of dietary fat, but not from increased physical activity or decreased food intake," they said. The metabolic effects were explained almost entirely by a lack of Ang II in the absence of renin. Renin's other effects on metabolism were minimal.

"Our findings are particularly relevant since they suggest that renin inhibitors recently approved or under development for the treatment of hypertension are likely to have favorable effects on obesity, insulin sensitivity, and their associated metabolic and cardiovascular consequences," the researchers said.

The researchers include Nobuyuki Takahashi, Feng Li, Kunjie Hua, Jianbei Deng, Chih-Hong Wang, Hyung-Suk Kim, and Joyce B. Harp, of The University of North Carolina at Chapel Hill, in Chapel Hill, NC, USA; Robert R. Bowers, and Timothy J. Bartness, of the Center for Behavioral Neuroscience, Georgia State University, Atlanta, GA, USA.