Exercise and Weight Loss Improve Muscle Mitochondrial Respiration, Lipid Partitioning, and Insulin Sensitivity After Gastric Bypass Surgery

Paul M. Coen; Elizabeth V. Menshikova; Giovanna Distefano; Donghai Zheng; Charles J. Tanner; Robert A. Standley; Nicole L. Helbling; Gabriel S. Dubis; Vladimir B. Ritov; Hui Xie; Marisa E. Desimone; Steven R. Smith; Maja Stefanovic-Racic; Frederico G.S. Toledo; Joseph A. Houmard; Bret H. Goodpaster

Disclosures

Diabetes. 2015;64(11):3737-3750. 

In This Article

Abstract and Introduction

Abstract

Both Roux-en-Y gastric bypass (RYGB) surgery and exercise can improve insulin sensitivity in individuals with severe obesity. However, the impact of RYGB with or without exercise on skeletal muscle mitochondria, intramyocellular lipids, and insulin sensitivity index (SI) is unknown. We conducted a randomized exercise trial in patients (n = 101) who underwent RYGB surgery and completed either a 6-month moderate exercise (EX) or a health education control (CON) intervention. SI was determined by intravenous glucose tolerance test. Mitochondrial respiration and intramyocellular triglyceride, sphingolipid, and diacylglycerol content were measured in vastus lateralis biopsy specimens. We found that EX provided additional improvements in SI and that only EX improved cardiorespiratory fitness, mitochondrial respiration and enzyme activities, and cardiolipin profile with no change in mitochondrial content. Muscle triglycerides were reduced in type I fibers in CON, and sphingolipids decreased in both groups, with EX showing a further reduction in a number of ceramide species. In conclusion, exercise superimposed on bariatric surgery–induced weight loss enhances mitochondrial respiration, induces cardiolipin remodeling, reduces specific sphingolipids, and provides additional improvements in insulin sensitivity.

Introduction

Roux-en-Y gastric bypass (RYGB) is the most commonly performed bariatric procedure in the U.S. and provides large and sustained weight loss, increases insulin sensitivity in multiple organs, and leads to diabetes remission in a significant percentage of patients.[1] Improvements in glycemic control and tissue-specific insulin sensitivity after RYGB surgery occur over two discrete phases.[2] The first phase is immediately (weeks to months) after surgery wherein glycemic control is normalized; in the second phase (up to ~18 months), peripheral tissue (principally muscle) insulin sensitivity slowly improves. However, even after substantial postoperative weight loss, peripheral tissue insulin sensitivity typically remains much lower than in metabolically healthy lean individuals.[3] Exercise is another treatment option that we have recently demonstrated to be a feasible and an effective adjunct therapy to improve insulin sensitivity and glucose effectiveness in bariatric surgery patients with severe obesity.[4]

Although a heavily studied area over the past decade, the precise mechanisms that mediate skeletal muscle insulin resistance in human obesity remain unclear. Impairments in mitochondrial oxidation have been implicated,[5] and evidence points to a reduced capacity for mitochondria to oxidize fatty acids, which in turn leads to incomplete fatty acid oxidation (FAO)[6] and accumulation of long-chain acyl-CoA, sphingolipids, and diacylglycerol (DAG).[7] Experiments in cell culture and animal models suggest that intramyocellular sphingolipids and DAGs contribute to insulin resistance by inhibition of Akt/protein kinase B and insulin receptor substrate 1/2 signaling.[8] Studies in human muscle are equivocal, with some showing that muscle ceramide content is elevated in insulin resistance and obesity[9,10] and others reporting no association.[11,12] The extent to which muscle DAG content is related to insulin resistance is also unclear,[12,13] with one report of elevated muscle DAG in insulin-sensitive athletes.[14] A lack of clarity also exists regarding the nature of mitochondrial dysfunction contributing to muscle insulin resistance in obesity and whether calorie restriction interventions that improve insulin sensitivity also improve mitochondrial function.[15] Weight loss by dietary caloric restriction alone has been reported to either induce mitochondrial biogenesis,[16] reduce mitochondrial respiration,[17] or have no effect on mitochondrial content and electron transport chain (ETC) activity.[18] Weight loss by bariatric surgery induces greater changes in weight and insulin sensitivity than observed with diet-based weight loss. However, whether surgery-induced weight loss improves peripheral tissue insulin sensitivity through favorable changes in mitochondria and muscle lipids has not been extensively studied.[19–21] Moreover, whether adding exercise training modulates the response in this setting is unknown.

Exercise has previously been demonstrated to improve muscle insulin sensitivity concomitant with improved mitochondrial function and reduced intramyocellular DAG and ceramide.[22,23] To date, no studies have been done on the effects of exercise on muscle mitochondria, intramuscular lipids, and insulin sensitivity in the context of bariatric surgery–induced weight loss. To address this paucity in the literature, we conducted a 6-month prospective randomized exercise trial with percutaneous skeletal muscle biopsy specimens and intravenous glucose tolerance tests (IVGTTs) to examine the effects of a moderate exercise intervention on muscle mitochondria respiration, intramyocellular lipids (sphingolipids, DAGs, cardiolipin [CL]), and insulin sensitivity during bariatric surgery–induced weight loss. We hypothesized that RYGB surgery–induced weight loss with and without exercise would affect mitochondrial energetics and intramyocellular lipid partitioning and that this would be associated with improved insulin sensitivity. The exercise intervention was specifically focused on the period following surgery when significant weight loss improves peripheral tissue insulin sensitivity (~3–9 months postsurgery).

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