Leptin Resistance Exacerbates Diet-induced Obesity and is Associated with Diminished Maximal Leptin Signalling Capacity in Rats

Aims/hypothesis: 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.

Materials And 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/interpretation: 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.