Body weight is determined by the balance between energy input and expenditure. Skeletal muscle is major site of mitochondrial oxidative metabolism of fatty acids and glucose and thereby plays a central role in whole body energy expenditure. Accordingly, preservation or promotion of skeletal muscle metabolism could play a critical role in protection from diet induced obesity. Understanding the mechanisms that regulate skeletal muscle metabolism and their relationship to those controlling fatty storage and mobilization is therefore a critical goal in metabolic disease research. Lipinl is a phosphatidic acid (PA) phosphatase enzyme that catalyzes the penultimate step in triglyceride synthesis at the cytoplasmic surface of the endoplasmic reticulum and also serves as a nuclear transcriptional co-activator of PPAR-a responsive genes. Lipinl deficient mice (fatty liver dystrophy mice, fid mice) exhibit impaired adipocyte differentiation, circulating hyperlipidemia and neonatal hepatic steatosis associated with diminished rates of hepatic fatty acid oxidation. Lipinl is also expressed in skeletal muscle and transgenic overexpression of lipinl in this tissue reverses many ofthe phenotypes of lipinl deficient fid mice. Interestingly, humans with heritable lipinl null mutations present with severe rhabdomyolysis (skeletal, muscle degeneration) characterized by impaired carnitine palmitoyi acyltransferase (CPT) activity, decreased mitochondrial fatty oxidation and respiratory chain function and the consequent destruction of skeletal muscle fibers. We made the seminal observation that lipinl is recruited to the mitochondrial surface where it promotes mitochondrial fission and remodels mitochondrial lipids, suggesting that lipinl deficiency impacts directly on mitochondrial function. Based on these observations we propose that lipinl is poised to function as a link between fatty acid and carbohydrate metabolism in muscle and fat. Accordingly, we hypothesize that recruitment of lipinl to mitochondria directly promotes mitochondrial respiratory function and beta-oxidation through effects on mitochondrial homeostasis and lipid composition and that this is particularly important for skeletal muscle function in energy metabolism. In direct support of our hypothesis, we found mitochondrial respiratory function is impaired in lipinl deficient mouse embryo fibroblasts and mitochondria isolated from skeletal muscle of lipinl deficient rnice. The broad goal of this research is to define the role of Lipinl in mitochondrial function and skeletal muscle physiology.
Aim 1 defines the role of muscle cell lipinl PA phosphatase activity in regulating mitochondrial lipid composition and function, while Aim 2 examines deletion of skeletal muscle lipinl in lean and obese mice.
Lipin l is emerging as a master regulator of metabolism. Inter-individual variation in lipinl expression and alterations in lipinl mRNA processing have been associated with human susceptibility to diet induced obesity. Our proposed studies promise to reveal a new facet of lipinl function in skeletal muscle and to define the role of lipinl as a link between fat storage in adipose tissue and consumption of mobilized fatty acids by skeletal muscle mitochondrial oxidative metabolism.
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