Decreased sensitivity to satiation signals has been proposed to play a role in the increased energy consumption and weight gain during obesity. We have recently shown that dietary induced obese rats fed a high fat (HF) diet exhibit diminished feeding responses following intragastric lipid loads or exogenous GLP‐1. To further determine the role of gut peptides in impaired satiation responses in obesity, we examined the effects of intraintestinal nutrients on food intake, peptide release, and neuronal activation in rats prone (OP) or resistant (OR) to obesity maintained on either chow or HF diet. Intraintestinal infusions of isocaloric, glucose, intralipid, and Ensure loads (4 and 8 Kcal) resulted in a reduced suppression of food intake in OP rats compared to OR rats, only during HF‐feeding. This reduced responsiveness in OP rats was associated with altered release of gut peptides, including GLP‐1, and diminished Fos expression in the dorsal hindbrain. Additionally, pre‐treatment with a GLP‐1R antagonist, exendin‐9, failed to attenuate Ensure‐induced reduction of food intake in OP, but not OR rats, during HF feeding. These results demonstrate that susceptibility to obesity coupled with HF‐feeding results in a host of signaling deficits, ultimately contributing to excess intake and weight gain.Grant Funding Source: INRA