(A) Mechanisms of resistin action on hepatic GP. Increased circulating levels of resistin lead to impaired hepatic insulin action, though whether this is mediated in part via pathways initiated in the hypothalamus is unknown. Here we investigate this “indirect” pathway; arrows interrupted by double bars indicate our attempt to block pathway using Rs Ab. (B) Experimental design for hyperinsulinemic-euglycemic clamp studies. Resistin infusion studies lasted 360 minutes. Recombinant mouse resistin or aCSF was infused into Sprague-Dawley rats via icv (300 ng total; 8 ng/μl at 5 μl/h) or IH (16 ng total; 8 ng/μl at 0.33 μl/h) cannulae. At 120 minutes, rats received a primed-constant infusion of [³H-3]glucose (0.4 μCi/min). Hyperinsulinemic-euglycemic pancreatic/insulin clamp was initiated at 240 minutes, with a constant infusion of insulin (3 mU/kg/min) and somatostatin (3 μg/kg/min); infusion of 10% glucose solution was periodically adjusted to maintain steady plasma glucose concentration. SRIF, somatostatin. (C) Glucose infusion rates necessary to maintain euglycemia in the presence of hyperinsulinemia (3 mU/kg/min) were significantly lower in resistin-treated groups compared with vehicle. (D) Rates of glucose uptake were unaffected by central infusion of resistin. (E) Rates of endogenous GP for resistin-infused animals were nearly 2-fold greater than those of vehicle. (F) Percentage suppression of endogenous GP induced by insulin infusion (3 mU/kg/min), a clear readout of whole-body insulin sensitivity, was reduced 50% in resistin-treated groups compared with vehicle. *P < 0.05 compared with vehicle (Veh.).