Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery
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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.
We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls.
Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice 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 melanin-concentrating hormone.
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.
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This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on December 17 2020, follows.
Summary
In the paper, the authors used metabolomics to identify Valine and TDCA as metabolites depleted in diet-induced obesity (DIO) and replenished after sleeve gastrectomies (SGx) in mice. Intraperioneal injection of these two metabolites mimics many of the benefits of SGx, including weight loss, reduced adipose stores and insulin sensitivity. These benefits are related to Val/TDCA's ability to reduce food intake without altering locomotor activity, leading to a negative energy balance. Val/TDCA injection eliminated the fasting-associated rise in hypothalamic MCH expression in obese mice, and central injections of recombinant MCH blunted weight loss induced by Val/TDCA. Overall, this paper reports …
This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on December 17 2020, follows.
Summary
In the paper, the authors used metabolomics to identify Valine and TDCA as metabolites depleted in diet-induced obesity (DIO) and replenished after sleeve gastrectomies (SGx) in mice. Intraperioneal injection of these two metabolites mimics many of the benefits of SGx, including weight loss, reduced adipose stores and insulin sensitivity. These benefits are related to Val/TDCA's ability to reduce food intake without altering locomotor activity, leading to a negative energy balance. Val/TDCA injection eliminated the fasting-associated rise in hypothalamic MCH expression in obese mice, and central injections of recombinant MCH blunted weight loss induced by Val/TDCA. Overall, this paper reports interesting and surprising observations related to the impact of metabolomic disturbances in obesity, and suggests a role for Val and/or TDCA in regulating food intake through MCH.
Essential Revisions
It is unclear from the data whether the effects are derived from valine, TDCA, or both. Both reviewers felt that any reader would want to see experiments where either of these metabolites is injected alone.
No quantitative metabolite concentration values are provided anywhere, making it difficult to evaluate the robustness of the data. How much do the levels of TDCA and valine change with SGx in mice and humans, and what levels are achieved with the injections of these metabolites in the mice?
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