Hefetz, L. | bioRxiv Science

bioRxiv2023

Inhibition of somatostatin enhances the long-term metabolic outcomes of sleeve gastrectomy in mice

Bariatric surgery is an effective obesity treatment, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. Here, we investigated the role of somatostatin (Sst) in bariatric surgery outcomes using a mouse model of sleeve gastrectomy (SG). Sst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally, and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of Glp1. Mathematical modeling of the feedback inhibition between Sst and Glp1 showed that Sst exerts its maximal effect on Glp1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of Glp1 compared with heterozygous SG-operated controls. Accordingly, SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months, had higher Glp1 levels, regained less weight, and improved glycemia compared to saline- treated SG-operated controls. Our results suggest that Sst signaling inhibition enhances and maintains the long-term favorable metabolic outcomes of bariatric surgery.

physiology↗

bioRxiv2022

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.

physiology↗