Background: 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.
Methods: Metabolic profiling was performed on diet induced obese (DIO) mice, lean mice and DIO mice that underwent sleeve gastrectomies. In addition, mice were subjected to i.p. injections with 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 an MCH antagonist and intrathecal administration of melanin-concentrating hormone were performed and weight loss was monitored.
Results: 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 sleeve gastrectomies (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 melanin-concentrating hormone.
Conclusions: 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.
All relevant data supporting the findings of this study are available as source data files.
- Stefan G Tullius
- Markus Quante
- Timm Heinbokel
- Felix Krenzien
- Yeqi Nian
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal use and care were in accordance with institutional and National Institutes of Health guidelines. The study protocol was approved by the Brigham and Women´s Hospital Institutional Animal Care and use Committee (IACUC) animal protocol (animal protocol 2016N000371).
Human subjects: Serum samples from patients prior to and 3 months post sleeve gastrectomy were obtained with approval of the Brigham and Women's Hospital (BWH) Institutional Review Board and through cooperation with Dr. Eric G. Sheu and the Center for Metabolic and Bariatric Surgery at BWH. Informed consent was obtained from all patients and samples were collected following BWH ethical regulations.
- Ralph J DeBerardinis, UT Southwestern Medical Center, United States
© 2021, Quante et al.
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