title: Liver and muscle in morbid obesity: the interplay of fatty liver and insulin resistance.
abstract: BACKGROUND
  Nonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. The muscle is a central player in the adaptation to energy overload, and there is an association between fatty-muscle and -liver. We aimed to correlate muscle morphology, mitochondrial function and insulin signaling with NAFLD severity in morbid obese patients.
  
  
  METHODS
  Liver and deltoid muscle biopsies were collected during bariatric surgery in NAFLD patients. NAFLD Activity Score and Younossi's classification for nonalcoholic steatohepatitis (NASH) were applied to liver histology. Muscle evaluation included morphology studies, respiratory chain complex I to IV enzyme assays, and analysis of the insulin signaling cascade. A healthy lean control group was included for muscle morphology and mitochondrial function analyses.
  
  
  RESULTS
  Fifty one NAFLD patients were included of whom 43% had NASH. Intramyocellular lipids (IMCL) were associated with the presence of NASH (OR 12.5, p<0.001), progressive hepatic inflammation (p = 0.029) and fibrosis severity (p = 0.010). There was a trend to an association between IMCL and decreased Akt phosphorylation (p = 0.059), despite no association with insulin resistance. In turn, hepatic steatosis (p = 0.015) and inflammation (p = 0.013) were associated with decreased Akt phosphoryation. Citrate synthase activity was lower in obese patients (p = 0.047) whereas complex I (p = 0.040) and III (p = 0.036) activities were higher, compared with controls. Finally, in obese patients, complex I activity increased with progressive steatosis (p = 0.049) and with a trend with fibrosis severity (p = 0.056).
  
  
  CONCLUSIONS
  In morbid obese patients, presence of IMCL associates with NASH and advanced fibrosis. Muscle mitochondrial dysfunction does not appear to be a major driving force contributing to muscle fat accumulation, insulin resistance or liver disease. Importantly, insulin resistance in muscle might occur at a late point in the insulin signaling cascade and be associated with IMCL and NAFLD severity.
authors.affiliation: Departamento de Gastrenterologia, Unidade de Nutrição e Metabolismo, Hospital Santa Maria, Faculdade de Medicina de Lisboa, IMM, Lisbon, Portugal.
authors.forename: Mariana Verdelho
authors.initials: MV
authors.lastname: Machado
authors.forename: Duarte M S
authors.initials: DM
authors.lastname: Ferreira
authors.forename: Rui E
authors.initials: RE
authors.lastname: Castro
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Silvestre
authors.forename: Teresinha
authors.initials: T
authors.lastname: Evangelista
authors.forename: João
authors.initials: J
authors.lastname: Coutinho
authors.forename: Fátima
authors.initials: F
authors.lastname: Carepa
authors.forename: Adília
authors.initials: A
authors.lastname: Costa
authors.forename: Cecília M P
authors.initials: CM
authors.lastname: Rodrigues
authors.forename: Helena
authors.initials: H
authors.lastname: Cortez-Pinto
mesh_terms: D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005234:Fatty Liver / Q000473:pathology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology; D009132:Muscles / Q000473:pathology*; D009767:Obesity, Morbid / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D007328:Insulin