Regulation of vascular insulin signaling by protein tyrosine phosphatase 1B (PTP1B) in mouse models of obesity

Insulin resistance is a major risk factor in obese individuals, and PTP1B is a crucial negative regulator of insulin signaling in metabolic tissues but the role of PTP1B in the development of vascular insulin resistance is unknown. Previously, we have found that PTP1B impairs the insulin‐induced activation of anti‐mitogenic pathways (Akt) while enhancing insulin‐induced activation of mitogenic pathways (p42/44 MAPK) in cultured vascular smooth muscle cells. In this study we tested the hypothesis that deletion of PTP1B improves insulin‐induced activation of Akt while decreasing activation of p42/44 MAPK in the aorta of mouse models of obesity. On a high fat (35.5%) diet, PTP1B knockout (KO) mice were protected from weight gain and had improved insulin‐induced activation of Akt compared to those observed in aortae from wild type (WT) mice on the same diet. Activation of p42/44 MAPK was not statistically different between WT and PTP‐1B KO mice. In contrast, deletion of PTP1B did not correct weight gain in leptin receptor mutant ( db/db ) mice and did not improve the insulin‐induced activation of Akt in aortae of db/db mice. Moreover, insulin‐induced activation of p42/44 MAPK in aortae was not different in all groups. These data suggest that, in the absence of a functional leptin receptor, PTP1B does not contribute to vascular insulin resistance as assessed by activation of Akt. (NIH Grants HL58139 and DK616874)