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

TY - JOUR

T1 - Roux-en-Y gastric bypass contributes to weight loss-independent improvement in hypothalamic inflammation and leptin sensitivity through gut-microglia-neuron-crosstalk

AU - Chen, Jiesi

AU - Haase, Nadine

AU - Haange, Sven Bastiaan

AU - Sucher, Robert

AU - Münzker, Julia

AU - Jäger, Elisabeth

AU - Schischke, Kristin

AU - Seyfried, Florian

AU - von Bergen, Martin

AU - Hankir, Mohammed K.

AU - Krügel, Ute

AU - Fenske, Wiebke K.

N1 - Funding Information: The authors thank Anja Moll, Katharina Zeller, Anne Müglitz, and Anne-Kathrin Krause for excellent technical support. This study was supported by the German Federal Ministry of Education and Research (BMBF), Germany, grant number FKZ: 01EO1501 (to W.K.F.), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) AOBJ: 624808 (to W.K.F.) and AOBJ: 624810 (to U.K.), and DFG Collaborative Research Cooperation (Project number 209933838 - SFB 1052). J.M. received a PhD fellowship from the IFB Adiposity Diseases supported by the German Federal Ministry of Education and Research (BMBF). M.v.B is grateful for funding by the DFG Collaborative Research Centers (CRC) 1052 and 1382. W.K.F. is supported by grants from the DFG , the Else Kröner-Fresenius Foundation , and the IFB Adiposity Disease supported by the German Federal Ministry of Education and Research (BMBF). Funding Information: The authors thank Anja Moll, Katharina Zeller, Anne M?glitz, and Anne-Kathrin Krause for excellent technical support. This study was supported by the German Federal Ministry of Education and Research (BMBF), Germany, grant number FKZ: 01EO1501 (to W.K.F.), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) AOBJ: 624808 (to W.K.F.) and AOBJ: 624810 (to U.K.), and DFG Collaborative Research Cooperation (Project number 209933838 - SFB 1052). J.M. received a PhD fellowship from the IFB Adiposity Diseases supported by the German Federal Ministry of Education and Research (BMBF). M.v.B is grateful for funding by the DFG Collaborative Research Centers (CRC) 1052 and 1382. W.K.F. is supported by grants from the DFG, the Else Kr?ner-Fresenius Foundation, and the IFB Adiposity Disease supported by the German Federal Ministry of Education and Research (BMBF). Publisher Copyright: © 2021 The Authors

PY - 2021/6

Y1 - 2021/6

N2 - 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.

AB - 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.

KW - Bariatric surgery

KW - Endoplasmic reticulum stress

KW - Gut microbiota-brain axis

KW - Hypothalamic inflammation

KW - Roux-en-Y gastric Bypass

KW - Toll-like receptor 4

UR - http://www.scopus.com/inward/record.url?scp=85104748928&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2021.101214

DO - 10.1016/j.molmet.2021.101214

M3 - SCORING: Journal article

C2 - 33741533

AN - SCOPUS:85104748928

VL - 48

SP - 101214

JO - MOL METAB

JF - MOL METAB

SN - 2212-8778

M1 - 101214

ER -