Restored TDCA and valine levels imitate the effects of bariatric surgery
Markus Quante,
Jasper Iske,
Timm Heinbokel,
Bhavna N Desai,
Hector Rodriguez Cetina Biefer,
Yeqi Nian,
Felix Krenzien,
Tomohisa Matsunaga,
Hirofumi Uehara,
Ryoichi Maenosono,
Haruhito Azuma,
Johann Pratschke,
Christine S Falk,
Tammy Lo,
Eric Sheu,
Ali Tavakkoli,
Reza Abdi,
David Perkins,
Maria-Luisa Alegre,
Alexander S Banks,
Hao Zhou,
Abdallah Elkhal,
Stefan G Tullius
Affiliations
Markus Quante
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
Jasper Iske
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Institute of Transplant Immunology, Hannover Medical School, Hannover, Lower Saxony, Germany
Timm Heinbokel
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Department of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
Bhavna N Desai
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
Hector Rodriguez Cetina Biefer
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
Yeqi Nian
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China
Felix Krenzien
Department of Visceral, Abdominal and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
Tomohisa Matsunaga
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Department of Urology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
Hirofumi Uehara
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Department of Urology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
Ryoichi Maenosono
Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Department of Urology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
Haruhito Azuma
Department of Urology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
Johann Pratschke
Department of Visceral, Abdominal and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
Christine S Falk
Institute of Transplant Immunology, Hannover Medical School, Hannover, Lower Saxony, Germany
Tammy Lo
Division of Gastrointestinal and General Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Eric Sheu
Division of Gastrointestinal and General Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Ali Tavakkoli
Division of Gastrointestinal and General Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Reza Abdi
Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
David Perkins
Division of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, United States
Maria-Luisa Alegre
Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, United States
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 (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. 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 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. 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. Funding: 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).
