Modification of the gut-brain dopamine axis as a cause of altered food reward processing and weight loss maintenance after Roux-en-Y gastric bypass surgery in a rodent model

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Obesity relapse following calorie-restrictive weight loss is a major problem in the management of the growing obesity threat. Bariatric surgery differs from non-invasive weight loss strategies in that it produces a pronounced and longterm bodyweight (BW) reduction over years. It has been proposed that reward hyposensitivity as a consequence of excessive fat intake exacerbates weight (re)gain by provoking compensatory overfeeding. A changed reward value of palatable, energy-dense foods after bariatric surgery like Roux-en-Y gastric bypass (RYGB) is thought to critically contribute to postoperative stabilization of lower BW. However, while robust dopamine (DA) function in the striatum is known to be required for the expression of normal reward-seeking behaviors, it still remains elusive how anatomical rerouting of nutrient passage through the gut modifies central food reward processing and what is its functional role in the prevention of weight regain.Reduced intestinal synthesis of the ethanolamide oleoylethanolamide (OEA) following overindulgence of high-fat (HF) foods has recently been shown to be associated with blunted feeding-induced DA release in the dorsal striatum, whilst exogenous replenishment with OEA restores striatal DA levels leading to reduced food intake, modified hedonic evaluation of fatty diet and BW reduction. The influence, however, of RYGB surgery on HF feeding-induced OEA mobilization and its role in the surgery-related alterations in dietary fat reward and BW are unknown. Furthermore, the signaling pathway relaying RYGB-induced remodeling of gut nutrient sensing to the dopaminergic reward system, resulting in postoperatively modified hedonic eating behavior is still completely lacking. Our main hypothesis is that postoperative changes in the mobilization of gut-derived lipid messengers like OEA importantly contribute to post-RYGB weight loss maintenance by functional modification of striatal dopaminergic reward circuits.To determine in the proposed project the underlying mechanisms of modified gut-DA signaling post RYGB and its role in the altered reward value of HF foods and stable BW reduction, diet-induced obese rodent models of RYGB surgery will be used to (i) investigate the effect of surgery on aberrant dopaminergic striatal function and HF feeding-induced gut OEA synthesis, (ii) characterize the role of gut OEA signaling and dorsostriatal DA transmission in postoperatively altered food intake and hedonic processing, and (iii) to define the influence of chemical modification of striatal neuron activity on post-RYGB maintained weight reduction. Together our study of the altered interaction among intestinal nutrient sensing and hedonic food perception post RYGB surgery will provide novel insights into the specific signaling pathway, underlying altered reward sensation in DIO and may identify new targets for more efficient "knifeless" treatment strategies for obesity in the future.