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Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice.

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed tyrosine phosphatase implicated in the negative regulation of leptin and insulin receptor signaling. PTP1B(-/-) mice possess a lean metabolic phenotype attributed at least partially to improved hypothalamic leptin sensitivity. Interestingly, mice lacking both leptin and PTP1B (ob/ob:PTP1B(-/-)) have reduced body weight compared with mice lacking leptin only, suggesting that PTP1B may have important leptin-independent metabolic effects. We generated mice with PTP1B deficiency specifically in leptin receptor (LepRb)-expressing neurons (LepRb-PTP1B(-/-)) and compared them with LepRb-Cre-only wild-type (WT) controls and global PTP1B(-/-) mice. Consistent with PTP1B's role as a negative regulator of leptin signaling, our results show that LepRb-PTP1B(-/-) mice are leptin hypersensitive and have significantly reduced body weight when maintained on chow or high-fat diet (HFD) compared with WT controls. LepRb-PTP1B(-/-) mice have a significant decrease in adiposity on HFD compared with controls. Notably, the extent of attenuated body weight gain on HFD, as well as the extent of leptin hypersensitivity, is similar between LepRb-PTP1B(-/-) mice and global PTP1B(-/-) mice. Overall, these results demonstrate that PTP1B deficiency in LepRb-expressing neurons results in reduced body weight and adiposity compared with WT controls and likely underlies the improved metabolic phenotype of global and brain-specific PTP1B-deficient models. Subtle phenotypic differences between LepRb-PTP1B(-/-) and global PTP1B(-/-) mice, however, suggest that PTP1B independent of leptin signaling may also contribute to energy balance in mice.