title: Re-patterning of skeletal muscle energy metabolism by fat storage-inducing transmembrane protein 2.
abstract: Triacylglyceride stored in cytosolic lipid droplets (LDs) constitutes a major energy reservoir in most eukaryotes. The regulated turnover of triacylglyceride in LDs provides fatty acids for mitochondrial β-oxidation and ATP generation in physiological states of high demand for energy. The mechanisms for the formation of LDs in conditions of energy excess are not entirely understood. Fat storage-inducing transmembrane protein 2 (FIT2/FITM2) is the anciently conserved member of the fat storage-inducing transmembrane family of proteins implicated to be important in the formation of LDs, but its role in energy metabolism has not been tested. Here, we report that expression of FIT2 in mouse skeletal muscle had profound effects on muscle energy metabolism. Mice with skeletal muscle-specific overexpression of FIT2 (CKF2) had significantly increased intramyocellular triacylglyceride and complete protection from high fat diet-induced weight gain due to increased energy expenditure. Mass spectrometry-based metabolite profiling suggested that CKF2 skeletal muscle had increased oxidation of branched chain amino acids but decreased oxidation of fatty acids. Glucose was primarily utilized in CKF2 muscle for synthesis of the glycerol backbone of triacylglyceride and not for glycogen production. CKF2 muscle was ATP-deficient and had activated AMP kinase. Together, these studies indicate that FIT2 expression in skeletal muscle plays an unexpected function in regulating muscle energy metabolism and indicates an important role for lipid droplet formation in this process.
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: Diego A
authors: DA
authors: Miranda
authors: Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, North Carolina 27704.
authors: Timothy R
authors: TR
authors: Koves
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: David A
authors: DA
authors: Gross
authors: Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, 40225 Dusseldorf, Germany.
authors: Alexandra
authors: A
authors: Chadt
authors: Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, 40225 Dusseldorf, Germany.
authors: Hadi
authors: H
authors: Al-Hasani
authors: Diabetes Endocrinology Research Center, Yale University School of Medicine, New Haven, Connecticut 06520.
authors: Gary W
authors: GW
authors: Cline
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461.
authors: Gary J
authors: GJ
authors: Schwartz
authors: Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, North Carolina 27704.
authors: Deborah M
authors: DM
authors: Muoio
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461. Electronic address: david.silver@einstein.yu.edu.
authors: David L
authors: DL
authors: Silver
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003433:Crosses, Genetic; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D014280:Triglycerides / Q000737:chemistry
chemical_list: C526205:FIT2 protein, mouse; D008055:Lipids; D008565:Membrane Proteins; D014280:Triglycerides; D000263:Adenylate Kinase; D005947:Glucose