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.
Recent genome-wide association studies aiming to identify genes responsible for diabetes mellitus described a strong link between variations in the FTO (fat mass-and obesity-associated) gene and body weight (1,2). The association with obesity is replicable in most populations (3)(4)(5), but the mechanism how variants in FTO lead to obesity is still not completely understood.FTO was originally described in a mouse model and is involved in cell death programming (6). In heterozygote mice, the mutation results in fused toes. Second, the thymus is enlarged whereas other organs or body weight are similar to the wild type (7). With detection of the association of this gene locus with human obesity, the Gene Nomenclature Committee renamed the gene FTO. Recently, it has been shown that the FTO gene encodes a Fe(II)-and 2-oxoglutarate-dependent oxygenase putatively involved in DNA demethylation (8,9).In humans, the FTO gene is located on the chromosome 16q12.2. Duplication of this region results in mental retardation, obesity, dysmorphic facies, and digital anomalies (10). It is known that FTO is expressed in the hypothalamic region (11) and may play a role in regulation of central body weight (12,13).In addition, carriers of the FTO allele which is associated with increased BMI exhibit a reduced basal fat cell lipolysis (14), suggesting that the FTO gene may also play a role in the adipose tissue metabolism.In the initial studies, the higher diabetes incidence of the risk allele carriers depended only on the strong association with obesity (1). The influence of the FTO gene on body composition and different fat compartments is still largely unknown. We used a whole body imaging approach enabling quantification of body fat stores to test whether the FTO polymorphism influences body composition or ectopic lipid storage in the liver. Furthermore, variation in the FTO locus may also affect weight loss during lifestyle intervention (15,16). We, therefore, studied the effect of variations in FTO on weight loss and body composition in a lifestyle intervention program. SubjectS and MethodS cross-sectional analysisWe studied 1,466 nondiabetic subjects from the southern part of Germany who participated in the ongoing Tübingen Family Study for type 2 diabetes mellitus, which currently includes ~2,000 individuals (17). Polymorphisms in the fat mass-and obesity-associated (FTO) gene have been identified to be associated with obesity and diabetes in large genome-wide association studies. We hypothesized that variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single-nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 s...
VAT did not show a positive correlation with BMI in our cohort of extremely obese subjects, indicating a pronounced fat deposition in subcutaneous tissue compartment. Moreover, this indicates that VAT is limited to a gender-dependent maximum volume for each individual and seems to be no further increasing in extremely obese subjects. This might be the reason that neither symptoms nor endoscopic findings of GERD nor LESP were significantly influenced by the stage of morbid obesity.
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