Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Kook Hwan Kim, et al. Nat. Med. 19, 83–92 (2013)

Speaker: Han Lee (李　涵)                                           Time: 14:00~15:00, Apr. 24, 2013

Commentator: Dr. Yau-Sheng Tsai (蔡曜聲老師)        Place: Room 601

Abstract:

Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. In addition to its role in amino acid metabolism, autophagy is important in whole-body glucose and lipid homeosta­sis¹. However, the role of autophagy in glucose and lipid metabolism is unclear. In the present study, the authors generated skeletal muscle–specific autophagy-knockout (Atg7^Δsm) mice to address the role of muscle autophagy in glucose and lipid homeostasis. They observed that Atg7^Δsm mice had lower body weight and fat mass and that autophagy deficiency in skeletal muscle increases energy expenditure. To study the impact of metabolic stress, the authors fed Atg7^Δsm mice with a high-fat diet (HFD). An intraperitoneal glucose tolerance test (GTT) and insulin tolerance test (ITT) revealed that HFD-fed Atg7^Δsm mice had improved glucose tolerance and insulin sensitivity. Meanwhile, the authors found that Fgf21 gene expression was markedly up-regulated in gastrocnemius and soleus muscles. Fgf21, a myokine-like molecule that is expressed in tissues other than muscle, produced in autophagy-deficient muscle exerts a systemic effect as an endocrine factor. Fgf21 induction in autophagy-deficient cells depends on Atf4. Mitochondrial dysfunction is observed in autophagy defi­ciency and mitochondrial stress can induce Atf4 expression². HFD-fed Atg7^Δsm mice therefore showed improved glucose homeostasis and lower insulin level. These results are contrary to suggestions by other investigators that autophagy disruption leads to insulin resistance³. Thus, this paper provides the first evidence for endocrine metabolic effects of autophagy or its deficiency affecting the metabo­lism of distant organs or the whole body.

Refrences:

1.          Ebato, C. et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 8, 325-332, (2008).

2.          Bouman, L. et al. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ. 18, 769-782, (2011).

3.          Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467-478, (2010).