The role of lipin as a modulator of adiposity and energy homeostasis: Insights from the fatty liver dystrophy mouse

Both an overabundance of fat mass (obesity) and insufficient fat mass (lipodystrophy) confer increased risk of metabolic disorders such as insulin resistance, dyslipidemia, and the development of diabetes. The fatty liver dystrophy (fld) mutant mouse represents a model of lipodystrophy, with dramatically reduced adipose tissue mass and the development of insulin resistance. We have recently identified the fld mutation in a gene that encodes a novel nucleo cytoplasmic protein, named lipin. Lipin is abundantly expressed in metabolically active and insulin-sensitive tissues such as adipose and skeletal muscle. Through the use of lipin-deficient and lipin transgenic mouse models, we demonstrate that diminished or increased lipin levels have pronounced, and opposite, effects on body weight and fat mass. Whereas lipin deficiency prevents both diet-induced and genetic obesity, enhanced lipin expression promotes adiposity and accelerates obesity on a high fat diet. Lipin exerts these effects through distinct mechanisms in adipose tissue and skeletal muscle. In adipocytes, lipin is induced at two separate temporal stages during adipogenesis, corresponding to distinct roles for lipin in preadipocytes and mature adipocytes. In preadipocytes, lipin is critical for normal adipocyte differentiation and acts to optimize PPARgamma expression and action. In mature adipocytes, lipin expression levels influence the efficiency of fat accumulation, and positively correlate with lipogenic and triglyceride synthesis gene expression. In skeletal muscle, lipin levels are a determinant of whole-body energy expenditure and fatty acid utilization, with lipin deficiency and enhanced lipin expression causing increased or decreased metabolic rate and fatty acid oxidation, respectively. Beyond its role as a modulator of fat mass, lipin levels in liver, muscle and adipose tissue also influence glucose and lipid homeostasis. Whereas lipin deficiency in adipose tissue impairs glucose homeostasis and increases insulin resistance, lipin deficiency in liver and muscle improves insulin sensitivity and protects against the development of insulin resistance. These effects may be partially due to an inhibitory role for lipin on leptin and adiponectin action in peripheral tissues. These findings establish lipin as a determinant of adiposity and metabolic fuel homeostasis, with potential implications for increasingly prevalent 21 st century health disorders in humans such as obesity, diabetes, and the metabolic syndrome.