title: Caloric restriction in leptin deficiency does not correct myocardial steatosis: failure to normalize PPAR{alpha}/PGC1{alpha} and thermogenic glycerolipid/fatty acid cycling.
abstract: OBJECTIVE
  Evidence supports an antilipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin-deficient mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction versus leptin repletion in obese leptin-deficient (ob/ob) mice.
  
  
  METHODS
  Echocardiography was performed on 7 mo old C57BL/6 wild-type mice (WT) and ob/ob mice fed ad libitum, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for 4 wk. Ventricular tissue was examined by electron microscopy (EM), triglyceride (TAG) content, oil red O staining, mitochondrial coupling assay, and microarray expression profiling.
  
  
  RESULTS
  LR and CR-ob/ob mice showed decreased body and heart weight, and LV wall thickness compared with ad libitum ob/ob mice. LV fractional shortening was decreased in ad libitum ob/ob mice, but restored to WT in LR and CR groups. However, myocardial lipid content by EM and TAG analysis revealed persistent cardiac steatosis in the CR-ob/ob group. Although CR restored mitochondrial coupling to WT levels, PPARα was suppressed and genes associated with oxidative stress and cell death were upregulated in CR-ob/ob animals. In contrast, LR eliminated cardiac steatosis, normalized mitochondrial coupling, and restored PGC1α and PPARα expression, while inducing core genes involved in glycerolipid/free fatty acid (GL/FFA) cycling, a thermogenic pathway that can reduce intracellular lipids.
  
  
  CONCLUSIONS
  Thus, CR in the absence of leptin fails to normalize cardiac steatosis. GL/FFA cycling may be, at least in part, leptin-dependent and a key pathway that protects the heart from lipid accumulation.
authors.affiliation: Cardiovascular Medicine Division, University of Pennsylvania, Philadelphia, USA. eduardo.rame@uphs.upenn.edu
authors.forename: J Eduardo
authors.initials: JE
authors.lastname: Rame
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lynn
authors.forename: Mones
authors.initials: M
authors.lastname: Abu-Asab
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kern
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Barb
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Karen L
authors.initials: KL
authors.lastname: Miller
authors.forename: Karen
authors.initials: K
authors.lastname: Fox-Talbot
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
authors.forename: Michael A
authors.initials: MA
authors.lastname: Solomon
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001835:Body Weight; D031204:Caloric Restriction / Q000379:methods*; D004452:Echocardiography; D020869:Gene Expression Profiling; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology*; D020738:Leptin / Q000008:administration & dosage / Q000172:deficiency*; D008055:Lipids / Q000032:analysis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D046228:Microarray Analysis; D008854:Microscopy, Electron; D009206:Myocardium / Q000737:chemistry* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D047493:PPAR alpha / Q000378:metabolism*
chemical_list: D020738:Leptin; D008055:Lipids; D047493:PPAR alpha