Speakers

Autophagy deficiency in insulin target tissues leads to protection from obesity and insulin resistance by inducing “Mitokines”

Myungshik_Lee
Myung-Shik Lee
Yonsei University, Korea
11:25~12:10,November 20th, 2015

Abstract:

 

Autophagy is an evolutionarily conserved process which delivers cytoplasmic components to lysosomes for degradation of aggregated proteins and damaged organelles such as mitochondria. To study the role of autophagy in insulin target tissues, we produced mice with deletion of Atg7, specifically in skeletal muscle (Atg7△sm mice).Atg7△sm mice fed normal chow diet showed reduced muscle/fat mass despite increased food intake, increased energy expenditure, reduced tissue ATP content, and evidence of mitochondrial abnormalities such as morphologically swollen mitochondria, decreased mitochondrial oxygen consumption, reduced ATP content, impaired COX activity together with reduced mtOxPhos gene expression. Atg7△sm mice fed high fat diet had markedly reduced adiposity and improved hepatic steatosis through increasing lipid oxidation, leading to marked improvement of insulin resistance. Metabolic studies including clamp study demonstrated that lipolysis from adipose tissue, fatty acid oxidation, body core temperature and glucose utilization were increased in Atg7△sm mice, suggesting release of a ‘myokine’ from autophagy-deficient skeletal muscle cells with mitochondrial dysfunction leading to improvement of glucose-lipid profile. In search for myokine released from autophagy-deficient muscle, we observed high induction of FGF21. Fgf21 induction was mediated by Atf4, a master regulator of the integrated stress response (ISR), which was in turn induced by mitochondrial dysfunction in autophagy deficiency. Mitochondrial stressors also induced Fgf21 in an Atf4-dependent manner. Induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance were also observed in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency in insulin target tissues leads to systemic amelioration of lipid injury and insulin resistance by inducing Fgf21, a ‘mitokine’, which is different from autophagy deficiency in insulin producing β-cells. Thus, metabolic impact of autophagy deficiency or mitochondrial dysfunction is dependent on the location, and severity of the deficiency, contrary to the current view that autophagy deficiency or mitochondrial dysfunction would deteriorate metabolic profile or lead to insulin resistance.

 

Professional  Activities:

 

  • 2015-present Professor, Severans Biomedical Research Institute & Dept. of Internal Medicine, Yonsei University College of Medicine
  • 2010-2013 Chairperson, Graduate School for Health Sciences & Technology, Sungkyunkwan University
  • 2010-2013 Chairperson, Graduate School for Health Sciences & Technology, Sungkyunkwan University
  • 2005-2009 Chairperson, Division of Endocrinology & Metabolism, Dept. of Medicine, Samsung Medical Center
  • 2002-2015 Professor, Dept. of Medicine, Sungkyunkwan University Medical School
  • 1997-2002 Associate Professor, Dept. of Medicine, Sungkyunkwan University Medical School
  • 1995-present Staff, Division of Endocrinology & Metabolism, Dept. of Medicine, Samsung Medical Center
  • 1992-1995 Postdoc, The Scripps Research Institute
  • 1990 Ph.D. at College of Medicine, Seoul National University
  • 1989-1991 Chief, Division of Endocrinology and Diabetes, Dept. of Internal Medicine, Korea Cancer Center Hospital
  • 1988-1989 Clinical fellowship in the Division of Endocrinology & Metabolism, Dept. of Internal Medicine, Seoul National University Hospital
  • 1985-1988 Chief, Dept. of Internal Medicine, the Seoul District Armed Force General Hospital
  • 1984 M.S. at College of Medicine, Seoul National University
  • 1981 M.D. at College of Medicine, Seoul National University