title: Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling.
abstract: Exogenous dietary fat can induce obesity and promote diabetes, but endogenous fat production is not thought to affect skeletal muscle insulin resistance, an antecedent of metabolic disease. Unexpectedly, the lipogenic enzyme fatty acid synthase (FAS) was increased in the skeletal muscle of mice with diet-induced obesity and insulin resistance. Skeletal muscle-specific inactivation of FAS protected mice from insulin resistance without altering adiposity, specific inflammatory mediators of insulin signaling, or skeletal muscle levels of diacylglycerol or ceramide. Increased insulin sensitivity despite high-fat feeding was driven by activation of AMPK without affecting AMP content or the AMP/ATP ratio in resting skeletal muscle. AMPK was induced by elevated cytosolic calcium caused by impaired sarco/endoplasmic reticulum calcium ATPase (SERCA) activity due to altered phospholipid composition of the sarcoplasmic reticulum (SR), but came at the expense of decreased muscle strength. Thus, inhibition of skeletal muscle FAS prevents obesity-associated diabetes in mice, but also causes muscle weakness, which suggests that mammals have retained the capacity for lipogenesis in muscle to preserve physical performance in the setting of disrupted metabolic homeostasis.
authors: Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors: Katsuhiko
authors: K
authors: Funai
authors: Haowei
authors: H
authors: Song
authors: Li
authors: L
authors: Yin
authors: Irfan J
authors: IJ
authors: Lodhi
authors: Xiaochao
authors: X
authors: Wei
authors: Jun
authors: J
authors: Yoshino
authors: Trey
authors: T
authors: Coleman
authors: Clay F
authors: CF
authors: Semenkovich
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects; D004789:Enzyme Activation; D004790:Enzyme Induction; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007333:Insulin Resistance; D007425:Intracellular Membranes / Q000378:metabolism; D050155:Lipogenesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000201:enzymology; D009126:Muscle Relaxation; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009765:Obesity / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D047493:PPAR alpha; D010743:Phospholipids; D011743:Pyrimidines; C006253:pirinixic acid; D064429:Fatty Acid Synthases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000263:Adenylate Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
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