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

Zaida Abad-Jiménez,Carlos Morillas,Sandra López-Domènech,Rosa Falcón,Celia García-Gargallo,Teresa Vezza,Víctor M Víctor,Celia Bañuls,Pedro Díaz-Pozo,Milagros Rocha,Segundo Ángel Gómez-Abril

doi:10.3390/biomedicines10020430

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.

Highlights

When we focused on an acute phase inflammatiory reactant—high sensitivity C-reactive protein (hsCRP) (p < 0.001)—and systemic cytokines—interleukin 6 (IL6) and interleukin 1β (IL1β) phase inflammatiory reactant—hsCRP (p < 0.001)—and systemic cytokines—IL6 and IL1β (p < 0.05, for both)—we observed a significant decline in these inflammatory mediators
We have shown that an increase in AMPK expression after Roux-en-Y gastric bypass (RYGB) is associated with a reduction in mitochondrial membrane potential and an increase in the mitophagy mediator
The results of the present study extend our understanding of the molecular mechanisms underlying the metabolic improvements that obese patients display when weight loss is achieved by RYGB

Summary

Introduction

Obesity is a chronic low-grade inflammatory disease characterized by an imbalance between excessive intake and low expenditure of energy, which leads to metabolic overload. Per se, is associated with lower life expectancy, mainly due to related comorbidities, including metabolic (insulin resistance (IR), type 2 diabetes (T2D), and dyslipidemia) 4.0/). Biomedicines 2022, 10, 430 and cardiovascular disorders (hypertension, stroke, and endothelial dysfunction), musculoskeletal complications, physical disabilities and limitations, diverse mental illnesses, and cancer [1]. Strategies to treat obesity, including lifestyle interventions and pharmacotherapy, often produce unsatisfactory results [2]. Roux-en-Y gastric bypass (RYGB) is a weight loss surgical technique that has been shown to bring clear health benefits to obese patients [3], including improvement of classic metabolic syndrome outcomes as well as inflammatory and subclinical atherosclerotic parameters [4–6]. The underlying molecular mechanisms mediating these clinical improvements are poorly understood

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