Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis.

Leptin regulates energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. However, the whole spectrum of signaling actions through the 3 cytoplasmic tyrosines of mouse Ob-Rb remains to be completely defined in vivo. Here, we generated 2 knockin lines of mice expressing mutant leptin receptors with phenylalanine substitution for all 3 tyrosines (Y123F) or for Tyr(1138) alone (Y3F). Y123F animals developed overt obesity similar to that of Y3F animals with abrogated hypothalamic activation of STAT3 by leptin, but they exhibited more severe impairment in glucose tolerance. In striking contrast to db/db mice, however, both Y123F and Y3F mice showed attenuated adiposity with reduced hyperphagia, marked improvement in physical activity and adaptive thermogenesis, and significantly ameliorated glycemic control. Further, Y123F mice had hypothalamic neuropeptide Y/agouti-related protein expression maintained at prominently lower levels compared with db/db mice. Thus, these results provide direct physiological evidence that Ob-Rb exerts crucial metabolic actions not only through tyrosine-dependent, but also tyrosine-independent mechanisms in control of energy balance and glucose homeostasis.