Altered Skeletal Muscle Lipase Expression and Activity Contribute to Insulin Resistance in Humans
- Pierre-Marie Badin1,2,
- Katie Louche1,2,
- Aline Mairal1,2,
- Gerhard Liebisch3,
- Gerd Schmitz3,
- Arild C. Rustan4,
- Steven R. Smith5,
- Dominique Langin1,2,6 and
- Cedric Moro1,2⇓
- 1INSERM, U1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France
- 2Paul Sabatier University, University of Toulouse, Toulouse, France
- 3Institute of Clinical Chemistry, University of Regensburg, Regensburg, Germany
- 4Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
- 5Translational Research Institute for Metabolism and Diabetes and the Burnham Institute, Florida Hospital, Winter Park, Florida
- 6Centre Hospitalier Universitaire de Toulouse, Biochemistry Laboratory, Biology Institute of Purpan, Toulouse, France
- Corresponding author: Cedric Moro, .
OBJECTIVE Insulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance.
RESEARCH DESIGN AND METHODS We first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling.
RESULTS Muscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = −0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (−30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance.
CONCLUSIONS Altogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1364/-/DC1.
- Received September 24, 2010.
- Accepted March 3, 2011.
- © 2011 by the American Diabetes Association.
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