Abstract Background The hypothalamus is involved in regulation of food intake (FI) and fat deposition. Molecular mechanisms of weight loss after Roux-en-Y gastric bypass (RYGB) were studied by correlating changes in gene expression profiles in hypothalamic arcuate nucleus (ARC) and subcutaneous abdominal fat (SAF). Method Diet-induced obese rats were divided into RYGB, sham-operated (SO-Obese), and sham-operated pair-fed (PF) groups. A non-obese group on a regular chow diet served as control. Body weight (BW) and FI were measured. Rats were killed 10 days after the operation. Plasma was analyzed for biochemical indices, ARC and SAF were analyzed for gene expression profiles. Body SAF was also weighed. Data were analyzed by ANOVA and factor analysis. Results BW and FI decreased in RYGB versus SO-Obese, as reflected by decreased SAF (53%). Genes similarly expressed in ARC and SAF after RYGB were limited to several genes that predominantly related to metabolic pathways of carbohydrate, fat, neuropeptide, and cytokines. These expression profiles were similar to those seen in chow control and to those seen in a comparison of PF and SO-Obese. Conclusions RYGB-induced weight loss is associated with changes in gene profile expressions that could influence metabolic changes, contributing to weight loss.