Roux-en-Y Gastric Bypass Modulates AMPK, Autophagy and Inflammatory Response in Leukocytes of Obese Patients

Abstract

Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic and metabolic improvements following bariatric surgery. In this cohort study, we investigated the effect of RYGB on molecular pathways involving energy homeostasis in leukocytes in 43 obese subjects one year after surgery. In addition to clinical and biochemical parameters, we determined protein expression of systemic proinflammatory cytokines by Luminex®, different markers of inflammation, endoplasmic reticulum (ER) stress, autophagy/mitophagy by western blot, and mitochondrial membrane potential by fluorescence imaging. Bariatric surgery induced an improvement in metabolic outcomes that was accompanied by a systemic drop in hsCRP, IL6, and IL1β levels, and a slowing down of intracellular inflammatory pathways in leukocytes (NF-κB and MCP-1), an increase in AMPK content, a reduction of ER stress (ATF6 and CHOP), augmented autophagy/mitophagy markers (Beclin 1, ATG5, LC3-I, LC3-II, NBR1, and PINK1), and a decrease of mitochondrial membrane potential. These findings shed light on the specific molecular mechanisms by which RYGB facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis as key mediators of these outcomes. In addition, since leukocytes are particularly exposed to physiological changes, they could be used in routine clinical practice as a good sensor of the whole body’s responses.

FoxG1 as a Potential Therapeutic Target for Alzheimer’s Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway

“…This suggests that FoxG1 could be a potential target for treating brain glioma in humans (Xiao et al 2021 ). AMPK, which serves as a key controller of cellular energy balance, is frequently documented to promote autophagy by directly suppressing mTOR function or through alternative pathways (Abad-Jiménez et al 2022 ). During this investigation, it was discovered that the increase in FoxG1 expression triggers the activation of the AMPK signaling pathway, subsequently leading to the suppression of mTOR signaling.…”

Effect of Bariatric Surgery on Plasma Cell-Free Mitochondrial DNA, Insulin Sensitivity and Metabolic Changes in Obese Patients

“…Additionally, bariatric surgery induced alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function, which were associated with subsequent distinct methylation patterns at 52 weeks after surgery [ 18 ]. Furthermore, a recent study demonstrated that laparoscopic Roux-en-Y gastric bypass augmented autophagy/mitophagy markers and decreased mitochondrial membrane potential in leukocytes, improving mitochondrial turnover as a consequence [ 19 ].…”

Impact of Roux-en-Y Gastric Bypass on Mitochondrial Biogenesis and Dynamics in Leukocytes of Obese Women

“…Interestingly, evidence suggests that AMPK activity is reduced in obesity, suggesting it may be a therapeutic target [ 48 ]. In this regard, we have recently reported an upregulation of this kinase after RYGB surgery [ 29 ]. This tightly coordinated process implicates several transcriptional regulators (mainly PGC1α, NRF1 and NRF2) that activate TFAM [ 49 ], thus, leading to mitochondrial transcription and mitochondrial genome replication and, in turn, to the generation of new organelles.…”

“…It is important to note that this study has arisen as part of a wider project, registered in clinicaltrials.gov under the study number NCT05071391. During the course of this project, we have revealed the implication of inflammation and oxidative stress in the pathogenesis of obesity and its comorbidities and have explored in depth the mechanisms associated with RYGB-induced weight loss [ 6 , 29 ].…”