Leptin antagonist reveals leptin still functions in obese rats

Aged‐obese F344xBN rats have reduced hypothalamic leptin signaling and are refractory to exogenous leptin, and hence considered leptin resistant. We hypothesized that the consequences of a leptin antagonist would be diminished or absent in rats already leptin resistant. Hypothalamic leptin signaling was assessed 1 hr after leptin (100ng), leptin (100ng) plus antagonist (5ug or 20ug), or vehicle (icv, lateral ventricle). Leptin increased phosphorylated STAT3 (P‐STAT3) by 4‐fold, which was fully blocked by co‐administration of either dose of antagonist. Young (5m) and aged‐obese (24m) were infused with antagonist (25 ug/day, lateral ventricle) or vehicle by mini pump for 7d. Cumulative food intake increased over control in both young (28.2±9.5g) and aged‐obese (18.2±7.9g) as did body weight (16.4±6.4g;10.2±2.2). Adiposity was elevated, but only significant in young. These data indicate that, although diminished, the orexigenic‐like effects of a leptin antagonist are qualitatively similar in lean leptin‐responsive and aged‐obese leptin resistant rats suggesting that leptin maintains a energy homeostatic role even in moderately obese animals. VA Medial Research and NIH, AG20985.