title: Moderate calorie restriction to achieve normal weight reverses β-cell dysfunction in diet-induced obese mice: involvement of autophagy.
abstract: BACKGROUND
  Severe calorie restriction (CR) is shown to improve or even reverse β-cell dysfunction in patients with obesity and type 2 diabetes mellitus. However, whether mild to moderate CR can reverse β-cell dysfunction induced by obesity and the underlying mechanism remain unclear. Autophagy plays an important role in maintaining mass, architecture and function of β-cells. While the impact of CR on β-cell autophagy is unknown. This study aims to investigate the effects of moderate CR on β-cell function and autophagy activity in diet-induced obese (DIO) mice.
  
  
  METHODS
  DIO C57BL/6 mice were subjected to 3 weeks of switching to normal chow (HF → NC group) or normal chow with 40 % CR (HF → NC CR group). Then hematoxylin-eosin and immunohistochemistry staining were performed to observe β-cell morphology. β-cell function was evaluated by intraperitoneal glucose tolerance test in vivo and static GSIS (glucose-stimulated insulin secretion) in isolated islets. β-cell autophagy activity was determined by transmission electron microscope and western blot.
  
  
  RESULTS
  In the HF → NC CR group, CR normalized body weights, completely restored glucose tolerance, early-phase and second-phase insulin secretion, insulin sensitivity, and islet size. CR also normalized insulin content and glucose-stimulated insulin secretion in isolated islets in vitro. Furthermore, β-cell autophagy level was increased in the HF → NC CR group, but AMPK phosphorylation remained unchanged. Although HF → NC mice achieved moderate weight loss and normal glucose tolerance, their insulin secretion was not improved compared with obese control mice, and additionally, β-cell autophagy was not activated in these mice.
  
  
  CONCLUSIONS
  Moderate (40 %) CR to achieve normal weight reversed β-cell dysfunction and insulin resistance, and restored glucose homeostasis in DIO mice. Furthermore, the up-regulation of β-cell autophagy may play a role in this process, independent of AMPK activation.
authors.affiliation: Department of Endocrinology and Metabolism, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029 China ; Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, 100029 China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Endocrinology and Metabolism, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029 China ; Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, 100029 China.
authors.forename: Dien
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Endocrinology and Metabolism, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029 China ; Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, 100029 China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Endocrinology and Metabolism, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029 China ; Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, 100029 China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Endocrinology and Metabolism, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029 China ; Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, 100029 China.
authors.forename: Yingsheng
authors.initials: Y
authors.lastname: Zhou
keywords: Autophagy; Calorie restriction; β-cell function