title: Altered skeletal muscle lipase expression and activity contribute to insulin resistance in humans.
abstract: 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.
  
  
  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.
authors.affiliation: INSERM, U1048, Obesity Research Laboratory, Institute of Metabolicand Cardiovascular Diseases (I2MC), Toulouse, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Badin
authors.forename: Katie
authors.initials: K
authors.lastname: Louche
authors.forename: Aline
authors.initials: A
authors.lastname: Mairal
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: Arild C
authors.initials: AC
authors.lastname: Rustan
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.forename: Cedric
authors.initials: C
authors.lastname: Moro
mesh_terms: D000328:Adult; D002849:Chromatography, Gas; D004075:Diglycerides / Q000378:metabolism; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D021241:Spectrometry, Mass, Electrospray Ionization; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult; D000217:Acyltransferases
chemical_list: D004075:Diglycerides; D008049:Lipase; D002787:Sterol Esterase; D014280:Triglycerides; C494794:PNPLA2 protein, human; D000217:Acyltransferases