Novel Insight on Fat Cell Regulation May Hold Key for Anti-Obesity Drugs

By: Almas Eftekhari

Association-funded researchers at the University of Michigan have recently shed light on important biological processes contributing to obesity and metabolic complications like diabetes. Ormond A. MacDougald, PhD, and fellow, Hiroyuki Mori, MD, PhD, have uncovered a surprising role of a pro­tein markedly secreted by fat tissue during obesity, called Sfrp5. The discovery may explain why fat expands and metabolism slows as obesity progresses. 

The regulation of fat metabolism is facilitated through an intricate pathway known as WNT signaling. As obesity sets in, however, fat cells increase their production of secreted frizzled-related protein-5 (Sfrp5), which interferes with WNT’s ability to suppress fat accumulation.

When Dr. MacDougald and Dr. Mori noticed high concentrations of Sfrp5 in the fat tissue of obese animals, the scientists narrowed in on the protein to determine its specific role in adipose tissue. The scientists bred Sfrp5-deficient mice and fed them an excessive, high-fat diet for several weeks, expecting to observe leaner body composition due to their inability to suppress WNT and create new fat cells. As anticipated, the mice did not gain weight as rapidly and had actually become obesity-resistant, despite their high caloric intake. 

Yet upon closer look at their fat tissue, the mice without Sfrp5 still had a similar number of fat cells as the obese mice; however, their cells contained far less fat and were therefore much smaller. After conducting further genetic testing to pinpoint the impact of blocking Sfrp5, the researchers found that the smaller fat cells had a surge in mitochondrial activity, or fat-burning metabolic rate.

“From our results, we believe that Sfrp5 is an important moderator of mitochondrial activity. This is the first time that this has been seen for the WNT signaling pathway in adipocytes,” said Dr. Mori, first author of the July 2012 publication in the Journal of Clinical Investigation.          

The Sfrp5-deficient mice also showed a mild improvement in glucose tolerance, whereas the obese mice suffered from higher incidence of fatty liver and severe glucose intolerance. While the researchers indicate that further studies are needed, Sfrp5 could potentially hold the key for anti-obesity drugs if the findings can translate to humans.

“Obesity is associated with resistance to insulin and diabetes. Thus, furthering our understanding of fat cell development and metabolism at the molecular level will ultimately lead to additional therapeutic targets to improve treatments for obesity and diabetes,” Dr. MacDougald concluded.

(Mori H, Prestwich TC, Reid MA, Longo KA, Gerin I, Cawthorn WP, Susulic VS, Krishnan V, Greenfield A, MacDougald OA. Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition. J Clin Invest. 2012 Jul 2;122(7):2405-16. doi: 10.1172/JCI63604. Epub 2012 Jun 25.)