Hypophagia induced by inflammation is associated with JAK2-STAT3 signaling and leptin-mediated hypophagia is also mediated by JAK2-STAT3 pathway. We have previously reported that lipopolysaccharide (LPS) did not reduce food intake in leptin-resistant high-fat diet (HFD) rats, but maintained body weight loss. We investigated if changes in p-STAT3 expression in the hypothalamus and brainstem could account for the desensitization of hypophagia in HFD animals after a low LPS dose (100μg/Kg). Wistar rats fed standard diet (3.95Kcal/g) or HFD (6.3Kcal/g) for 8 weeks were assigned into control diet-saline, control diet-LPS, HFD-saline and HFD-LPS groups. LPS reduced feeding in the control diet, but not HFD. This group showed no p-STAT3 expression in the PVN and VMH, but sustained, though lower than control, p-STAT3 in the NTS and RPA. LPS decreased body weight in HFD rats, and increased Fos expression in the NTS. LPS increased body temperature, oxygen consumption and energy expenditure in both control diet and HFD rats, and this response was more pronounced in HFD-LPS group. BAT thermogenesis and increased energy expenditure seem to contribute to body weight loss in HFD-LPS. This response might be related with increased brainstem activation. In conclusion, LPS activates STAT3-mediated pathway in the hypothalamus and brainstem, leading to hypophagia, however LPS effects on food intake, but not body weight loss, are abolished by leptin resistance induced by HFD. The preserved STAT3 phosphorylation in the brainstem suggests that unresponsiveness to LPS on STAT3 activation under HFD might be selective to the hypothalamus.