Testosterone interacts with the feedback mechanisms engaged by Tyr985 of the leptin receptor and diet-induced obesity

Inhibitory signaling through Tyr985 of the leptin receptor contributes to the attenuation of anorectic leptin action in obese animals. Leptin receptor (LEPR-B) Tyr985Leu homozygote mutant mice (termed l/l) were previously generated to study Tyr985's contributions to inhibition of LEPR-B signaling; young female l/l mice display a lean, leptin-sensitive phenotype, while young male l/l are not significantly different from wild-type. We report here that testosterone (but not estrogen) determines the sex-specificity of the l/l phenotype. This provides additional insight into the cellular mechanism by which gonadal hormones determine central sensitivity to leptin, and may help elucidate the long-noted sex differences in leptin sensitivity. Additionally, we observed that Tyr985 signaling protects against a diet-dependent switch that exacerbates obesity with high fat feeding, such that the enhanced leptin sensitivity of l/l mice on a normal diet leads to increased adiposity in the face of chronic high-fat diet.

► Leptin receptor Tyr985 mutants display a phenotype that is sex-biased. ► Testosterone interacts with Tyr985-incepted signaling of the leptin receptor. ► Leptin receptor Tyr985 mutants are highly susceptible to diet-induced obesity. ► The susceptibility to diet-induced obesity is also sex-biased.