Document Detail


Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling.
MedLine Citation:
PMID:  23376793     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Katsuhiko Funai; Haowei Song; Li Yin; Irfan J Lodhi; Xiaochao Wei; Jun Yoshino; Trey Coleman; Clay F Semenkovich
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-08
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-04     Completed Date:  2013-05-13     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1229-40     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adenylate Kinase / metabolism
Animals
Calcium Signaling*
Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
Cell Line
Diet, High-Fat / adverse effects
Enzyme Activation
Enzyme Induction
Fatty Acid Synthases / genetics,  metabolism
Humans
Insulin Resistance*
Intracellular Membranes / metabolism
Lipogenesis*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Fibers, Skeletal / enzymology
Muscle Relaxation
Muscle Strength
Muscle, Skeletal / enzymology,  metabolism*
Obesity / enzymology,  etiology,  metabolism
PPAR alpha / agonists,  metabolism
Phenotype
Phospholipids / metabolism
Pyrimidines / pharmacology
Sarcoplasmic Reticulum / metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
Transcriptional Activation
Grant Support
ID/Acronym/Agency:
DK076729/DK/NIDDK NIH HHS; DK088083/DK/NIDDK NIH HHS; DK20579/DK/NIDDK NIH HHS; DK56341/DK/NIDDK NIH HHS; P30 DK056341/DK/NIDDK NIH HHS; P41 GM103422/GM/NIGMS NIH HHS; P41-RR00954/RR/NCRR NIH HHS; R01 DK076729/DK/NIDDK NIH HHS; R01 DK088083/DK/NIDDK NIH HHS; T32 DK007120/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/PPAR alpha; 0/Phospholipids; 0/Pyrimidines; 86C4MRT55A/pirinixic acid; EC 2.3.1.85/Fatty Acid Synthases; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Kinase; EC 2.7.4.3/Adenylate Kinase; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases
Comments/Corrections
Erratum In:
J Clin Invest. 2013 Aug 1;123(8):3634

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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