title: Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats.
abstract: OBJECTIVE
  Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats.
  
  
  METHODS
  Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344 x BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 mug leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined.
  
  
  RESULTS
  The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptin-resistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls.
  
  
  CONCLUSIONS
  The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA. scarpace@ufl.edu
authors.forename: P J
authors.initials: PJ
authors.lastname: Scarpace
authors.forename: M
authors.initials: M
authors.lastname: Matheny
authors.forename: N
authors.initials: N
authors.lastname: Tümer
authors.forename: K Y
authors.initials: KY
authors.lastname: Cheng
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001835:Body Weight; D018076:DNA, Complementary / Q000235:genetics; D004032:Diet; D005247:Feeding Behavior; D005951:Glucose Tolerance Test; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D018076:DNA, Complementary; D007328:Insulin; D020738:Leptin