Combined PTP-1B and PTPN2 inhibition for weight loss in obesity

INDICATION: Obesity

Combined inhibition of PTP-1B and PTPN2, which regulate leptin and insulin signaling, could promote weight loss in obese patients. In mice with high fat diet-induced obesity, knockout of both targets from the arcuate nucleus of the hypothalamus reduced subcutaneous and epididymal white adipose tissue weight compared with knockout of either protein alone. PTP-1B plus PTPN2 knockout reduced daily food intake and increased energy expenditure compared with normal expression of both genes. Combined knockout also improved glucose homeostasis, measured by insulin and glucose tolerance tests and fasting blood glucose levels. In the mice, intracerebroventricular or intranasal delivery of mifepristone, a glucocorticoid antagonist that reduces PTPN2 expression, plus a PTP-1B inhibitor tool compound decreased adiposity and weight. Intranasal delivery of the combination also improved glucose tolerance...