A multiomics comparison of weight loss interventions shows the distinct effects of bariatric surgery and intermittent fasting on hepatic metabolism

The prevalence of obesity and non-alcoholic fatty liver (NAFL) is steadily increasing. Weight loss can lead to improvement in NAFL in patients and in model organisms. Weight loss can be achieved through either dietary and lifestyle interventions, pharmacotherapy, and bariatric surgery. Some interventions, such as intermittent fasting, have been purported to have benefits beyond those conferred by weight loss alone. In this study, rats were provided a high-fat, high-sucrose diet for 7 weeks and then were assigned to strict caloric restriction with intermittent fasting (IF-CR) or to sleeve gastrectomy (SG) bariatric surgery, achieving equivalent weight loss. The two interventions were compared to ad-libitum fed controls. The metabolome of the blood entering the liver was analyzed in the three experimental groups, as well as the metabolome and transcriptome of the liver under fasting conditions, to test how different means of weight loss affect the input of the liver and hepatic metabolism. Surprisingly, the two interventions had different and often opposite effects on the composition of portal blood and liver metabolites. IF-CR resulted in sweeping changes across multiple central metabolic pathways, including an increase in de novo lipogenesis and triglyceride export, and upregulation of glycolysis, citric acid cycle, and the pentose phosphate pathway, as well as an increase in glycogen storage. Meanwhile, the effects of SG concentrated on one-carbon metabolic pathways, with changes in metabolite and transcript levels pointing to decreased transmethylation and methionine cycle activity, with downstream effects on levels of glutathione and the hepatic oxidative state. In conclusion, our study highlights how different means of weight loss affect distinct metabolic pathways and demonstrates a unique effect of bariatric surgery on hepatic one-carbon and redox pathways.