Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure.

Abstract

Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with higher energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes.

• Authors: Mako Yasuda-Yamahara, Shinji Kume, Kosuke Yamahara, Jun Nakazawa, Masami Chin-Kanasaki, Hisazumi Araki, Shin-ichi Araki, Daisuke Koya, Masakzu Haneda, Satoshi Ugi, Hiroshi Maegawa, Takashi Uzu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 465 Issue 2 Pg. 249-55 (Sep 18 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26271596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Dietary Fats
• Lysosomal-Associated Membrane Protein 2
• PPAR alpha
• RNA, Messenger
• fibroblast growth factor 21
• Fibroblast Growth Factors

Topics

• Adipose Tissue, Brown (metabolism, pathology)
• Animals
• Autophagy (genetics)
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (etiology, genetics, pathology, prevention & control)
• Diet, High-Fat
• Dietary Fats (adverse effects)
• Energy Metabolism (genetics)
• Fibroblast Growth Factors (genetics, metabolism)
• Gene Expression
• Glycogen Storage Disease Type IIb (genetics, metabolism)
• Lysosomal-Associated Membrane Protein 2 (genetics, metabolism)
• Lysosomes (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PPAR alpha (genetics, metabolism)
• Phagosomes (metabolism, pathology)
• Protective Factors
• RNA, Messenger (genetics, metabolism)