Weight loss-induced improvement in insulin sensitivity (IS) has been related to enhanced muscle energy metabolism. Thus, we hypothesized that weight loss due to bariatric surgery may induce epigenomic changes, which in turn modify mitochondrial function and intracellular lipids. We previously reported that IS fails to improve at 2 weeks (2 w), but then continuously increases until 52 weeks (52 w) after surgery. Now, we monitored muscle mitochondrial function and lipid intermediates in 49 obese humans (OBE; 40±10 years, BMI 51±7 kg/m2) before and for 52 w after bariatric surgery. Genome-wide gene expression and DNA methylation were analyzed in a subgroup of 16 OBE. Initial weight loss increases muscle oxidative capacity by 11% at 2 w, but transient elevation of certain muscle diacylglycerols resulting from unrestrained adipose lipolysis prevents from rapid improvement in IS. At 52 w, both mitochondrial function and intracellular lipids are comparable to lean humans. Acute alterations in expression of 1287 genes involved primarily in mitochondrial function, transcriptional regulation, protein transport, fatty acid metabolism and inflammatory processes, but not changes in DNA methylation, underlie the transient upregulation of mitochondrial function and lipolysis. At 52 w, 1091CpGs are differentially methylated, which relates to improved IS. Specifically, epigenetic alterations at 52 w in FTO gene, encoding an α-ketoglutarate dependent dioxygenase, and TOMM7 gene, encoding a translocase of the outer mitochondrial membrane, contribute to reprogramming transient changes in mRNA expression at 2 w.
In conclusion, initial metabolic changes after weight loss induce epigenetic modification of genes involved in muscle energy metabolism, which in turn leads to long-term beneficial changes in gene expression.
S. Gancheva: None. M. Ouni: None. C. Koliaki: None. T. Jelenik: None. D.F. Markgraf: None. J. Szendroedi: None. M. Schlensak: None. A. Schuermann: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.