title: p66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans.
abstract: OBJECTIVE
  Oxygen radicals generated by p66Shc drive adipogenesis, but contradictory data exist on the role of p66Shc in the development of obesity and the metabolic syndrome. We herein explored the relationships among p66Shc, adipose tissue remodelling and glucose metabolism using mouse models and human adipose tissue samples.
  
  
  METHODS
  In wild-type (WT), leptin-deficient (ob/ob), p66Shc(-/-) and p66Shc(-/-) ob/ob mice up to 30 weeks of age, we analysed body weight, subcutaneous and visceral adipose tissue histopathology, glucose tolerance and insulin sensitivity, and liver and muscle fat accumulation. A group of mice on a high fat diet (HFD) was also analysed. A parallel study was conducted on adipose tissue collected from patients undergoing elective surgery.
  
  
  RESULTS
  We found that p66Shc(-/-) mice were slightly leaner than WT mice, and p66Shc(-/-) ob/ob mice became less obese than ob/ob mice. Despite their lower body weight, p66Shc(-/-) mice accumulated ectopic fat in the liver and muscles, and were glucose intolerant and insulin resistant. Features of adverse adipose tissue remodelling induced by obesity, including adipocyte enlargement, apoptosis, inflammation and perfusion were modestly and transiently improved by p66Shc (also known as Shc1) deletion. After 12 weeks of the HFD, p66Shc(-/-) mice were leaner than but equally glucose intolerant and insulin resistant compared with WT mice. In 77 patients, we found a direct correlation between BMI and p66Shc protein levels. Patients with low p66Shc levels were less obese, but were not protected from other metabolic syndrome features (diabetes, dyslipidaemia and hypertension).
  
  
  CONCLUSIONS
  In mice and humans, reduced p66Shc levels protect from obesity, but not from ectopic fat accumulation, glucose intolerance and insulin resistance.
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.|Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ciciliot
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.|Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.|Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Menegazzo
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.|Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Nicol
authors.initials: N
authors.lastname: Poncina
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.|Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Scattolini
authors.affiliation: Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Danesi
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.affiliation: Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Marabita
authors.affiliation: Venetian Institute of Molecular Medicine, Padua, Italy.|Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: European Institute of Oncology, IFOM-IEO Campus, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.affiliation: European Institute of Oncology, IFOM-IEO Campus, Milan, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Trinei
authors.affiliation: Department of Surgical, Oncologic Gastroenterologic Sciences, University of Padua, Padua, Italy.
authors.forename: Mirto
authors.initials: M
authors.lastname: Foletto
authors.affiliation: Department of Surgical, Oncologic Gastroenterologic Sciences, University of Padua, Padua, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Prevedello
authors.affiliation: Department of Surgical, Oncologic Gastroenterologic Sciences, University of Padua, Padua, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Nitti
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.|Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
authors.affiliation: Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy. Gianpaolo.fadini@unipd.it.|Venetian Institute of Molecular Medicine, Padua, Italy. Gianpaolo.fadini@unipd.it.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D001786:Blood Glucose; D007328:Insulin; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
keywords: Diabesity; Inflammation; Longevity; Oxidative stress