Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure.
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.
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Mako
M
Yasuda-Yamahara
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. Electronic address: skume@belle.shiga-med.ac.jp.
Shinji
S
Kume
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Kosuke
K
Yamahara
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Jun
J
Nakazawa
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Masami
M
Chin-Kanasaki
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Hisazumi
H
Araki
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Shin-ichi
S
Araki
Department of Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa, Japan.
Daisuke
D
Koya
Division of Metabolism and Biosystemic Science, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Masakzu
M
Haneda
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Satoshi
S
Ugi
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Hiroshi
H
Maegawa
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Takashi
T
Uzu
D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects; D004734:Energy Metabolism / Q000235:genetics*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D052120:Glycogen Storage Disease Type IIb / Q000235:genetics* / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism / Q000473:pathology; D065840:Protective Factors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D052119:Lysosomal-Associated Membrane Protein 2; D047493:PPAR alpha; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
Autophagy; Diabetes; Lysosome; Lysosome-associated membrane protein-2; Obesity