Type 2 diabetes mellitus and obesity are closely linked metabolic disorders driven by insulin and leptin resistance. Current long-acting therapies capable of addressing both conditions are dominated by incretin-based agents, which primarily achieve efficacy through appetite suppression and are frequently associated with tolerability limitations and metabolic rebound after treatment discontinuation. Alternative strategies that correct underlying signaling defects without suppressing food intake remain lacking. Protein tyrosine phosphatases PTPN1 and PTPN2 act as coordinated intracellular negative regulators of insulin and leptin signaling by dephosphorylating key molecules within the IRS-AKT and JAK2-STAT3 pathways. Although genetic studies have established these phosphatases as attractive therapeutic targets, translation has been hindered by the absence of long-acting inhibitors with robust in vivo efficacy. Here we report the rational design of Y5, a chemically engineered BimBH3-derived peptide analogue that functions as a dual inhibitor of PTPN1 and PTPN2. Fatty-acid conjugation and hapten modification confer high enzymatic potency, enhanced proteolytic stability, strong albumin binding, and prolonged half-life and systemic exposure. Y5 restores cellular insulin and leptin signaling in vitro, leading to coordinated activation of IRS-1, AKT, and STAT3 under resistant conditions. In diabetic db/db mice, Y5 once-weekly administration induces sustained glycemic control, improves glucose tolerance, and reduces circulating insulin levels, consistent with enhanced insulin sensitivity. In DIO mice, Y5 induces pronounced and sustained weight loss while preserving food intake, demonstrating a potential mechanism distinct from incretin-based therapies. Y5 selectively reduces adiposity, improves hepatic steatosis, and is well tolerated across dosing regimens. These findings establish long-acting dual inhibition of PTPN1 and PTPN2 as a mechanistically distinct therapeutic strategy for T2DM and obesity. By reversing hormone resistance rather than suppressing appetite, Y5 defines an alternative paradigm for achieving long-acting glycemic control and weight loss in vivo.
