p66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans

Stefano Ciciliot, Mattia Albiero, Lisa Menegazzo, Nicol Poncina, Valentina Scattolini, Andrea Danesi, Elisa Pagnin, Manuela Marabita, Bert Blaauw, Marco Giorgio, Mirella Trinei, Mirto Foletto, Luca Prevedello, Donato Nitti, Angelo Avogaro, Gian Paolo Fadini

Research output: Contribution to journalArticlepeer-review

Abstract

Aims/hypothesis: 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/interpretation: In mice and humans, reduced p66Shc levels protect from obesity, but not from ectopic fat accumulation, glucose intolerance and insulin resistance.

Original languageEnglish
Pages (from-to)2352-2360
Number of pages9
JournalDiabetologia
Volume58
Issue number10
DOIs
Publication statusPublished - Jun 30 2015

Keywords

  • Diabesity
  • Inflammation
  • Longevity
  • Oxidative stress

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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