title: High-fat diet-induced adipocyte cell death occurs through a cyclophilin D intrinsic signaling pathway independent of adipose tissue inflammation.
abstract: OBJECTIVE
  Previous studies have demonstrated that mice fed a high-fat diet (HFD) develop insulin resistance with proinflammatory macrophage infiltration into white adipose tissue. Concomitantly, adipocytes undergo programmed cell death with the loss of the adipocyte-specific lipid droplet protein perilipin, and the dead/dying adipocytes are surrounded by macrophages that are organized into crown-like structures. This study investigated whether adipocyte cell death provides the driving signal for macrophage inflammation or if inflammation induces adipocyte cell death.
  
  
  METHODS
  Two knockout mouse models were used: granulocyte/monocyte-colony stimulating factor (GM-CSF)-null mice that are protected against HFD-induced adipose tissue inflammation and cyclophilin D (CyP-D)-null mice that are protected against adipocyte cell death. Mice were fed for 4-14 weeks with a 60% HFD, and different markers of cell death and inflammation were analyzed.
  
  
  RESULTS
  HFD induced a normal extent of adipocyte cell death in GM-CSF-null mice, despite a marked reduction in adipose tissue inflammation. Similarly, depletion of macrophages by clodronate treatment prevented HFD-induced adipose tissue inflammation without any affect on adipocyte cell death. However, CyP-D deficiency strongly protected adipocytes from HFD-induced cell death, without affecting adipose tissue inflammation.
  
  
  CONCLUSIONS
  These data demonstrate that HFD-induced adipocyte cell death is an intrinsic cellular response that is CyP-D dependent but is independent of macrophage infiltration/activation.
authors: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Daorong
authors: D
authors: Feng
authors: Yan
authors: Y
authors: Tang
authors: Hyokjoon
authors: H
authors: Kwon
authors: Haihong
authors: H
authors: Zong
authors: Meredith
authors: M
authors: Hawkins
authors: Richard N
authors: RN
authors: Kitsis
authors: Jeffrey E
authors: JE
authors: Pessin
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000473:pathology*; D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000502:physiology*; D004041:Dietary Fats / Q000008:administration & dosage* / Q000009:adverse effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency*; D007249:Inflammation / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D004041:Dietary Fats; C000631446:PPIF protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D021983:Cyclophilins