Abstract
Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Metabolic profiling was performed on diet-induced obese (DIO) mice, lean mice, and DIO mice that underwent sleeve gastrectomies (SGx). In addition, mice were subjected to intraperitoneal (i.p.) injections with taurodeoxycholic acid (TDCA) and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite-regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with a melanin-concentrating hormone (MCH) antagonist and intrathecal administration of MCH were performed and weight loss was monitored. Mass spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the MCH. In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders. This work has been supported in part by a grant from NIH (UO-1 A1 132898 to S.G.T., DP and MA). M.Q. was supported by the IFB Integrated Research and Treatment Centre Adiposity Diseases (Leipzig, Germany) and the German Research Foundation (QU 420/1-1). J.I. was supported by the Biomedical Education Program (BMEP) of the German Academic Exchange Service (DAAD). T.H. (HE 7457/1-1) and F.K. (KR 4362/1-1) were supported by the German Research Foundation (DFG). H.R.C.B. was supported the Swiss Society of Cardiac Surgery. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. H.U., T.M. and R.M. were supported by the Osaka Medical Foundation. C.S.F. was supported by the German Research Foundation (DFG, SFB738, B3).
Highlights
Obesity is a global epidemic with broad clinical and economic consequences
Bariatric surgery is effective in 80-90% of obese individuals and leads to sustained weight loss and significant improvement of co-morbidities[5, 6, 10]
Sham-operated Diet induced obese (DIO) mice re-gained their preoperative weight by postoperative day 14
Summary
Obesity is a global epidemic with broad clinical and economic consequences. Data by the GlobalBurden of Disease Study (GBD) estimate that overweight and obesity are causing 3.4 million deaths and 3.8 % of disability-adjusted life-years (DALYs) worldwide[1]. Obesity is promoting numerous disorders including diabetes, cardiovascular disease (CVD) and cancer[2, 3]. Bariatric surgery including sleeve gastrectomies (SGx) have been successful in achieving a sustained body weight loss[6]. These procedures display an effective treatment of obesity associated type 2 diabetes (T2D)(7) with durable HbA1C remissions [8], improved insulin sensitivity and glycemic control[9], all resulting into long-term reduction of overall mortality and obesity related risk factors[5, 10]. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities
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