Roux-en-Y gastric bypass contributes to weight loss-independent improvement in hypothalamic inflammation and leptin sensitivity through gut-microglia-neuron-crosstalk.

Abstract Objective Hypothalamic inflammation and endoplasmic reticulum (ER) stress are extensively linked to leptin resistance and overnutrition-related diseases. Surgical intervention remains the most efficient long-term weight loss strategy in morbid obesity, but mechanisms underlying sustained feeding suppression remain largely elusive. This study investigates whether Roux-en-Y gastric bypass (RYGB) interacts with obesity-associated hypothalamic inflammation to restore central leptin signalling as a mechanistic account for postoperative appetite suppression. Methods RYGB or sham surgery was performed in high-fat diet-induced obese Wistar rats. Sham-operated rats were fed ad libitum or by weight matching to RYGB via calorie restriction (CR), before hypothalamic leptin signalling, microglia reactivity and inflammatory pathways were examined to be under the control of gut microbiota-derived circulating signalling. Results RYGB-, other than CR-induced adiposity reduction, ameliorates hypothalamic gliosis, inflammatory signalling and ER stress, which is linked to enhanced hypothalamic leptin signalling and responsiveness. Mechanistically, we demonstrate that RYGB interferes with hypothalamic ER stress and toll-like receptor 4 (TLR4) signalling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the altered gut microbial environment upon RYGB surgery. Conclusions Our data demonstrate that RYGB interferes with hypothalamic TLR4 signalling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the post-surgery altered gut microbial environment.