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

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 for morbid obesity, but mechanisms underlying sustained feeding suppression remain largely elusive. This study investigated whether Roux-en-Y gastric bypass (RYGB) interacts with obesity-associated hypothalamic inflammation to restore central leptin signaling as a mechanistic account for post-operative 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 signaling, microglia reactivity, and the inflammatory pathways were examined to be under the control of gut microbiota-derived circulating signaling. RESULTS: RYGB, other than CR-induced adiposity reduction, ameliorates hypothalamic gliosis, inflammatory signaling, and ER stress, which are linked to enhanced hypothalamic leptin signaling and responsiveness. Mechanistically, we demonstrate that RYGB interferes with hypothalamic ER stress and toll-like receptor 4 (TLR4) signaling 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 signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the post-surgical altered gut microbial environment.

Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain µ-opioid Receptor Availability in Diet-Induced Obese Male Rats.

Brain µ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [11C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [11C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.