Genetic Defect in Phospholipase Cδ1 Protects Mice From Obesity by Regulating Thermogenesis and Adipogenesis

OBJECTIVE: Regulation of obesity development is an important issue to prevent metabolic syndromes. Gene-disrupted mice of phospholipase Cδ1 (PLCδ1), a key enzyme of phosphoinositide turnover, seemed to show leanness. Here we examined whether and how PLCδ1 is involved in obesity. RESEARCH DESIGN AND METHODS: Weight gain, insulin sensitivity, and metabolic rate in PLCδ1(−/−) mice were compared with PLCδ1(+/−) littermate mice on a high-fat diet. Thermogenic and adipogenetic potentials of PLCδ1(−/−) immortalized brown adipocytes and adipogenesis of PLCδ1-knockdown (KD) 3T3L1 cells, or PLCδ1(−/−) white adipose tissue (WAT) stromal-vascular fraction (SVF) cells, were also investigated. RESULTS: PLCδ1(−/−) mice showed marked decreases in weight gain and mass of epididymal WAT and preserved insulin sensitivity compared with PLCδ1(+/−) mice on a high-fat diet. In addition, PLCδ1(−/−) mice have a higher metabolic rate such as higher oxygen consumption and heat production. When control immortalized brown adipocytes were treated with thermogenic inducers, expression of PLCδ1 was decreased and thermogenic gene uncoupling protein 1 (UCP1) was upregulated to a greater extent in PLCδ1(−/−) immortalized brown adipocytes. In contrast, ectopic expression of PLCδ1 in PLCδ1(−/−) brown adipocytes induced a decrease in UCP expression, indicating that PLCδ1 negatively regulates thermogenesis. Importantly, accumulation of lipid droplets was severely decreased when PLCδ1-KD 3T3L1 cells, or PLCδ1(−/−) WAT SVF cells, were differentiated, whereas differentiation of PLCδ1(−/−) brown preadipocytes was promoted. CONCLUSIONS: PLCδ1 has essential roles in thermogenesis and adipogenesis and thereby contributes to the development of obesity.