Cited by 186Peroxisome Proliferator-Activated ReceptorsLipid metabolism and disordersAdipose Tissue and Metabolism

Muscle-Derived Angiopoietin-Like Protein 4 Is Induced by Fatty Acids via Peroxisome Proliferator–Activated Receptor (PPAR)-δ and Is of Metabolic Relevance in Humans

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Staiger, Harald, Haas, Carina, Machann, Jürgen, Werner, Roman, Weisser, Melanie, Schick, Fritz, Machicao, Fausto, Stefan, Norbert +2 more·2009·Diabetes

Abstract

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)-delta, but not PPAR-alpha or -gamma, and pharmacological activation of PPAR-delta 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-delta recruitment to the ANGPTL4 gene. In addition, pharmacological PPAR-delta 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-delta, and muscle-derived ANGPTL4 seems to be of systemic relevance in humans.

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Authors
Staiger, H., Haas, C., Machann, J., Werner, R., Weisser, M., Schick, F., Machicao, F., Stefan, N., Fritsche, A., & Häring, H.-U.
Affiliations
  • University of Tübingen (DE)
  • Department of Experimental Radiology, Eberhard-Karls-University Tübingen, Tübingen, Germany
  • Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany
Corresponding author
Staiger, Harald
Venue
Diabetes
Published
2009-03-01
Volume
58
Issue
3
Pages
579-589
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
OpenAlex
W2127054137
Cited by
183
References
49
Citations by year
2026: 1 · 2025: 8 · 2024: 11 · 2023: 5 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 12 · 2016: 12 · 2015: 10 · 2014: 15 · 2013: 17 · 2012: 15
FWCI
3.70
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft (KFO 114/1, KFO 114/1-2, KFO 114)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
ANGPTL4, long-chain fatty acids, PPARδ, skeletal muscle, myotubes, hormone-sensitive lipase, LIPE, adipose tissue lipolysis, free fatty acids, lipoprotein lipase inhibition
MeSH terms
Angiopoietin-Like Protein 4, Blood Glucose, C-Peptide, Gene Expression Regulation, Glucose Tolerance Test, Humans, Insulin, Lipids, RNA, Messenger, Glucose Clamp Technique, Muscle, Skeletal, Muscle Fibers, Skeletal, Palmitic Acid, Linoleic Acid, Oligonucleotide Array Sequence Analysis, Angiopoietins, PPAR alpha, PPAR delta

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