Dynamic changes of muscle insulin sensitivity after metabolic surgery

Sofiya Gancheva,Matthias Schlensak,Meriem Ouni,Julia Szendroedi,Markus Jähnert,Lucia Mastrototaro,Christian Herder,Elisabetta De Filippo,Klaus Strassburger,Tomas Jelenik,Jürgen Weiss,Daniel F Markgraf,Annette Schürmann,Michael Roden,Chrysi Koliaki,Frederico G S Toledo,Dominik H Pesta

doi:10.1038/s41467-019-12081-0

Abstract

The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity.

Highlights

The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear
Insulin sensitivity at the level of adipose tissue (AdipoIR) assessed from fasting free fatty acids (FFA) and insulin concentrations (Fig. 1a) and of whole body/skeletal muscle (M-value assessed from hyperinsulinemic-euglycemic clamps at steady state insulinemia of 58 ± 14 μU/ml; Fig. 1b) was lower in obese humans (OB) than in CON
This study provides insights into the mechanisms, by which metabolic surgery sequentially affects systemic and tissue-specific metabolism and its epigenetic regulation in obese humans

Summary

Introduction

The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. Alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity. Recent studies convincingly demonstrated that diet-induced weight loss rapidly improves hepatic, but not muscle insulin resistance in humans[10]. Gastric bypass surgery results in epigenetic alterations, but current data on DNA methylation are conflicting[13] It is unknown whether epigenetic alterations occur very early or rather late after metabolic surgery and relate to gene expression

Methods

Results

Conclusion