Post-RYGB hypophagia was associated with enhanced leptin-induced feeding suppression and hypothalamic leptin signaling in diet-induced obese rats. (A) Weekly post-operative body weights of high-fat (HF) DIO rats that underwent Roux-en-Y gastric bypass (RYGB) surgery compared to sham-operated control groups. Post-operatively, the animals were maintained on a two-choice diet with standard chow (SC) and HFD. (B) Corresponding cumulative energy intake. (C) Plasma leptin concentration (ng/ml) at the twelfth post-operative week. (D–G) To test for leptin sensitivity, during the twelfth post-operative week, the animals were administered either leptin (i.p., 1 mg/kg per day, L) or vehicle (V) for 3 days. (D) Three-day cumulative energy intake of leptin- or vehicle-treated animals. (E) Percent change in body weight during 3-day leptin treatment vs vehicle control. (F) Hypothalamic phosphorylation of STAT3 and ERK at the twelfth post-operative week. (G) Corresponding hypothalamic mRNA expression of Pomc, Cartpt, Obrb, and Bdbf. (H) Corresponding protein expression of SOCS3 and PTP1B at 12 weeks post-operatively. Data are presented as mean ± SEM (n = 9–13 for A and B and n = 4–6 for C-G) with individual datapoints. ∗∗∗P < 0.001 for the effect of DIO vs RYGB, ##P < 0.05 for RYGB vs BWM for A and B; ∗P < 0.05 and ∗∗∗P < 0.001 for the effect of any indicated comparison for C and H; #P < 0.05 for SC intake comparison; ∗P < 0.05 for HFD intake comparison; §P < 0.05 for cumulative energy intake comparison for D; ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 for the effect of leptin-vs vehicle-treated animals.