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OBJECTIVE-Long-chain fatty acids (LCFAs) contribute to metabolic homeostasis in part via gene regulation. This study's objective was to identify novel LCFA target genes in human skeletal muscle cells (myotubes).
RESEARCH DESIGN AND METHODS-In vitro methods included culture and treatment of human myotubes and C2C12 cells, gene array analysis, real-time RT-PCR, Western blotting, ELISA, chromatin immunoprecipitation, and RNA interference. Human subjects (two cohorts) were characterized by oral glucose tolerance test, hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and spectroscopy, and standard blood analyses (glucose, insulin, C-peptide, and plasma lipids).
RESULTS-We show here that ANGPTL4 (encoding angiopoietin-like protein 4) represents a prominent LCFA-responsive gene in human myotubes. LCFA activated peroxisome proliferator-activated receptor (PPAR)-δ, but not PPAR-α or -γ, and pharmacological activation of PPAR-δ markedly induced ANGPTL4 production and secretion. In C2C12 myocytes, knockdown of PPARD, but not of PPARG, blocked LCFA-mediated ANGPTL4 induction, and LCFA treatment resulted in PPAR-δ recruitment to the ANGPTL4 gene. In addition, pharmacological PPAR-δ activation induced LIPE (encoding hormone-sensitive lipase), and this response crucially depended on ANGPTL4, as revealed by ANGPTL4 knockdown. In a human cohort of 108 thoroughly phenotyped subjects, plasma ANGPTL4 positively correlated with fasting nonesterified fatty acids (P = 0.0036) and adipose tissue lipolysis (P = 0.0012). Moreover, in 38 myotube donors, plasma ANGPTL4 levels and adipose tissue lipolysis in vivo were reflected by basal myotube ANGPTL4 expression in vitro (P = 0.02, both).
CONCLUSIONS-ANGPTL4 is produced by human myotubes in response to LCFA via PPAR-δ, and muscle-derived ANGPTL4 seems to be of systemic relevance in humans. Diabetes 58:579-589, 2009
The metabolic syndrome, a cluster of health problems including visceral obesity, subclinical inflammation, insulin resistance, and type 2 diabetes, is the prevailing metabolic disorder in Western industrialized countries. The syndrome is caused by environmental factors (high-caloric food intake, sedentary lifestyle) combined with a genetic predisposition. Elevated plasma nonesterified fatty acid (NEFA) levels are frequently observed in metabolic syndrome patients and result from increased Iipolysis of insulin-resistant white adipose tissue (WAT) and/or chronically excessive dietary fat intake (1).
Among the major plasma long-chain fatty acid (LCFA) species, the saturated fatty acids palmitate and stearate are of particular interest with respect to their potential involvement in metaboUc disarrangements, such as hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and β-cell dysfunction: administered chronically, they reduce muscular glucose disposal...