Sci. Aging Knowl. Environ., 26 January 2005
Coming Back for Seconds
Extra doses of lipin protein spur obesity
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/4/nf7
Frequent trips through the buffet line can contribute to obesity. For mice, additional servings of a different kind--copious amounts of a protein called lipin--promote corpulence, new results reveal. Previous studies had shown that deficiencies in the protein prevent animals from making fat tissue, and the new work clarifies how it controls fat storage and metabolism.
Packing too much fat is unhealthy, but having too little isn't good either. For instance, a mouse line that lacks fat tissue develops nerve problems. The rodents are also resistant to insulin, a hormone that encourages glucose storage; this condition often presages diabetes. Four years ago, Reue and Phan discovered that the animals are lean because of a glitch in the gene that encodes lipin. They know that this protein appears in fat and muscle, as well as other tissues, but they haven't discerned how it works.
To flesh out lipin's function, the researchers augmented lipin production in either fat or muscle tissue of mice. Both types of engineered animals grew tubby when fed a high-fat diet. Mice without lipin don't make fat-stowing cells, so the team investigated whether mice with bonus lipin churn out extra fat containers. They found that mice producing supplementary lipin in fat tissue don't build more fat cells than normal, but they activated genes that promote fat storage in existing fat cells. These animals responded normally to insulin. That finding might seem counterintuitive because obesity often spurs insulin resistance, but other lines of hefty mice also keep blood glucose in check. Animals with lipin-replete muscle tissue did not crank up fat-storage genes and developed insulin resistance, suggesting that lipin influences metabolism in different ways in muscle and fat.
To explore those differences, the team measured oxygen consumption by the mice, a gauge of metabolic activity. Lipin-deficient mice consume more oxygen than normal, whereas mice with extra lipin in muscle process less oxygen than normal, indicating that muscle lipin slows metabolism. Next, the team determined what source of fuel each animal uses to generate energy. Animals without lipin burn more fat than normal animals do, whereas mice that churn out prodigious quantities of lipin in their muscles burned less fat. Hiking lipin output in fat didn't change oxygen use or preference for burning fat. When the team engineered mice without lipin to make the protein in their muscles, the animals consumed less oxygen and burned less fat but did not gain weight. Together, the results suggest that lipin encourages fat storage in fat tissue and influences overall metabolism in muscle.
Researchers still don't understand how lipin operates, but the new study gets them a step closer, says Marc Reitman, an endocrinologist at Merck Research Laboratories in Rahway, New Jersey. To clarify how lipin's absence depletes fat, scientists need to eliminate it from particular tissues. In humans, lipin mutations don't appear to trigger diseases in which fat tissue is missing, but variations in lipin production might contribute to differences in body weight between people, Reitman says. Further work should give researchers another helping of knowledge about how lipin works.
January 26, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150