Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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The Role of Autophagy in Systemic Metabolism and Human-Type Diabetes

  • Kim, Jinyoung (Severance Biomedical Science Institute & Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Lim, Yu-Mi (Severance Biomedical Science Institute & Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Lee, Myung-Shik (Severance Biomedical Science Institute & Department of Internal Medicine, Yonsei University College of Medicine)
  • Received : 2017.09.27
  • Accepted : 2017.10.12
  • Published : 2018.01.31
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Abstract

Autophagy is critical for the maintenance of organelle function and intracellular nutrient environment. Autophagy is also involved in systemic metabolic homeostasis, and its dysregulation can lead to or accelerate the development of metabolic disorders. While the role of autophagy in the global metabolism of model organisms has been investigated mostly using site-specific genetic knockout technology, the impact of dysregulated autophagy on systemic metabolism has been unclear. Here, we review recent papers showing the role of autophagy in systemic metabolism and in the development of metabolic disorders. Also included are data suggesting the role of autophagy in human-type diabetes, which are different in several key aspects from murine models of diabetes. The results shown here support the view that autophagy modulation could be a new modality for the treatment of metabolic syndrome associated with lipid overload and human-type diabetes.

Keywords

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Fig. 1. Infiltration of IL-1-producing macrophages into the adipose tissue of Atg7+/--ob/obmice. Paraffin-embedded adipose tissue sections were stained with anti-IL-1β and anti-F4/80 antibodies as the primary antibodies, and confocal microscopy was done (left). The number of IL-1β-producing macrophages in the adipose tissue of Atg7 +/--ob/ob mice was higher than in the adipose tissue of Atg7 +/+-ob/ob mice (right). (HPF, high-power field)

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Fig. 2. Accumulation of hIAPP oligomers in hIAPP+ mice with β-cell autophagy knockout (hIAPP+Atg7Δb-cell mice). Confocal mi-croscopy after immunofluorescent staining of pancreas sectionsemploying anti-insulin and anti-hIAPP oligomer (I11) antibodies.hIAPP oligomer accumulation was not seen when autophagy iscompetent, despite transgenic expression of hIAPP (left).

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Fig. 3. Proposed model for the development of diabeteswith lipid overload or human-type diabetes with autoph-agy insufficiency. Metabolic stress in the presence ofautophagy insufficiency causes increased lipid accumu-lation due to compromised lipophagy. Autophagy insuf-ficiency leads to delayed clearance of dysfunctionalmitochondria, which causes increased inflammasomeactivation when the cell is challenged with an inflam-masome activator, such as lipids (green arrow). Au-tophagy insufficiency also leads to accumulation ofhuman IAPP (hIAPP) oligomers in pancreatic β-cells,since hIAPP clearance is dependent on autophagy. Thecombined effects of these three axes and their interac-tions finally culminates in the development of insulinresistance, β-cell failure and diabetes.

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