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Restored TDCA and valine levels imitate the effects of bariatric surgery

  1. Markus Quante
  2. Jasper Iske
  3. Timm Heinbokel
  4. Bhavna N Desai
  5. Hector Rodriguez Cetina Biefer
  6. Yeqi Nian
  7. Felix Krenzien
  8. Tomohisa Matsunaga
  9. Hirofumi Uehara
  10. Ryoichi Maenosono
  11. Haruhito Azuma
  12. Johann Pratschke
  13. Christine S Falk
  14. Tammy Lo
  15. Eric Sheu
  16. Ali Tavakkoli
  17. Reza Abdi
  18. David Perkins
  19. Maria-Luisa Alegre
  20. Alexander S Banks
  21. Hao Zhou
  22. Abdallah Elkhal
  23. Stefan G Tullius  Is a corresponding author
  1. Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, United States
  2. Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Germany
  3. Institute of Transplant Immunology, Hannover Medical School, Germany
  4. Department of Pathology, Charité Universitätsmedizin Berlin, Germany
  5. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, United States
  6. Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Germany
  7. Department of Urology, The Second Xiangya Hospital, Central South University, China
  8. Department of Visceral, Abdominal and Transplantation Surgery, Charité Universitätsmedizin Berlin, Germany
  9. Department of Urology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Japan
  10. Division of Gastrointestinal and General Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, United States
  11. Renal Division, Brigham and Women’s Hospital, Harvard Medical School, United States
  12. Division of Nephrology, Department of Medicine, University of Illinois at Chicago, United States
  13. Department of Medicine, Section of Rheumatology, The University of Chicago, United States
Research Article
Cite this article as: eLife 2021;10:e62928 doi: 10.7554/eLife.62928
6 figures, 1 table and 1 additional file

Figures

Sleeve gastrectomy (SGx) induces significant weight loss independent of the surgical procedure.

C57BL/6 DIO mice (n = 5) underwent SGx or sham surgery, were fasted on the day of surgery, switched to a liquid diet for 2 days and returned to a high-fat diet by day 3. An additional set of C57BL/6 DIO and C57BL/6 lean mice receiving a similar diet served as controls. (A) Body weight was monitored for a course of 2 weeks every 24 hr. (B) Proportional weight loss of C57BL/6 DIO mice undergoing SGx and sham surgery was calculated comparing mean weight loss after 7 and 14 days, respectively. Results are representative of at least three independent experiments. Column plots display mean with standard deviation. Statistical significance was determined using two-way analysis of variance (ANOVA) followed by Turkey’s multiple comparison test with single pooled variance. Asterisks indicate p-values: *p < 0.05, **p < 0.01, and ***p < 0.001. Only significant values are shown (n = 7 animals/group).

Sleeve gastrectomy (SGx) restores systemic taurodeoxycholic acid (TDCA)/valine levels in both diet-induced obese (DIO) mice and obese humans.

Whole blood samples from C57BL/6 DIO mice after SGx and DIO and lean controls were analyzed with a 5500 QTRAP mass spectrometer. Quantitative analysis was performed utilizing MetaboAnalyst 3.0. (A) Heat map of 32 metabolites displayed after hierarchical clustering, p<0.05. (B) Significance analysis of microarrays (SAM) revealed 17 metabolites with significance. (C) Pattern hunter stratified the 25 metabolites with top peaks (mz/rt) according to the order obese-control-SGx. (D) Serum was isolated from patients undergoing SGx pre-operative (Pre-OP) and 3 months after surgery (POM3). TDCA and valine levels were quantified using mass spectrometry and peak are integrated TIC values compared (n = 6). Results are representative of at least three independent experiments. Statistical significance was determined using one-way analysis of variance (ANOVA) and SAM. TDCA/valine TIC values from human samples were compared using paired Student’s t-test. Asterisks indicate p-values: *p < 0.05, **p < 0.01, and ***p < 0.001. Only significant values are shown (n = 6 animals/group, n = 6 patients). All data supporting figures are provided as source data files.

Figure 3 with 1 supplement
Taurodeoxycholic acid (TDCA)/valine treatment induces robust weight loss and ameliorates obesity-related insulin resistance.

C57BL/6 diet-induced obese (DIO) mice received intraperitoneal injections of TDCA (50 mg/kg) and L-valine (200 mg/kg) daily over the course of 2 weeks. (A) Plasma TDCA and valine levels were quantified before and after 14 days of treatment by mass spectrometry (n = 5). (B) Body weight was evaluated for 2 weeks every 24 hr. (B) Column plot of mean body weight comparing sleeve gastrectomies (SGx) and TDCA/valine (T/V)-treated animals at days 0, 7, and 14. (C) Subcutaneous and epididymal fat tissue was removed after 14 days of treatment or SGx and weight was determined. (D) Systemic leptin levels were quantified by ELISA after fasting in control and T/V-treated DIO and lean mice. (E) 2 g/kg glucose was injected following 8 hr of daytime fasting. Blood glucose levels were assessed in blood samples utilizing a blood glucose meter. Results are representative of at least three independent experiments. Column plots display mean with standard deviation. Statistical significance was determined by using one-way analysis of variance (ANOVA). Asterisks indicate p-values: *p < 0.05, **p < 0.01, and ***p < 0.001. Only significant values are shown (n = 5–7 animals/group).

Figure 3—figure supplement 1
Effect of taurodeoxycholic acid (TDCA), valine, and the combinatorial treatment with TDCA and valine are shown.

C57BL/6 diet-induced obese (DIO) mice received daily, intraperitoneal injections of TDCA (50 mg/kg), L-valine (200 mg/kg), or both over the course of 30 days and weight loss was monitored. Results are representative of at least three independent experiments (mean ± standard deviation [n = 5 animals/group]).

Taurodeoxycholic acid (TDCA)/valine treatment induces weight loss through altered feeding behavior in the absence of reduced energy expenditure.

Twelve DIO mice (control = 6, treatment = 6) were placed into the Columbus Instruments’ Comprehensive Lab Animal Monitoring System (CLAMS) for 6 days. Time graphs represent hourly averages throughout the experiment. Shaded regions represent the 12 hr dark photoperiod. After 1 day of acclimation (not shown), injections of TDCA/valine were performed at 2 p.m. for 5 days. This experiment monitored (A) cumulative energy intake (B) hourly food intake, (C) energy expenditure, (D) locomotor activity, (E) respiratory exchange ratio, and (F) energy balance (energy intake minus energy expenditure). Results are representative of at least three independent experiments. Statistical significance was determined by analysis of variance (ANOVA) using total mass as the covariate. Error bars represent SEM. Asterisks indicate p-values: *p < 0.05, **p < 0.01. Only significant values are shown (n = 6 animals/group).

Taurodeoxycholic acid (TDCA)/valine treatment acts through suppression of hypothalamic melanin-concentrating hormone (MCH) levels.

(A) Lean and diet-induced obese (DIO) mice were treated daily with either PBS or T and V. Two groups of T and V-treated DIO mice were subjected to 12 hr fasting before tissue procurement. After 2 weeks, all mice were sacrificed, hypothalamus tissue dissected, and RNA levels of POMC, CART, NPY, AgRP, and MCH measured by real-time PCR (RT-PCR). (B) DIO mice were subjected to daily intraperitoneal (i.p.) injection of T and V, oral administration of MCH receptor one inhibitor (MCHR1-I), or a combined treatment of both, T and V + MCHR1-I for a course of 2 weeks. Body weight and food consumption was measured and expressed as a contingency plot displaying total weight, percentage of starting weight, and food consumption per mouse. (C) DIO rats were subjected to combined i.p. TDCA/valine injection and intracerebral administration of recombinant MCH and weight loss was monitored for 2 weeks. Results are representative of at least three independent experiments. Column plots display mean with standard deviation. Statistical significance was determined using one-way analysis of variance (ANOVA). Asterisks indicate p-values: *p < 0.05, **p < 0.01, and ***p < 0.001. Only significant values are shown (n = 5–7 animals/group).

Flowchart of neuropeptide-mediated appetite regulation and taurodeoxycholic acid (TDCA)/valine interaction.

Fasting promotes the release of melanin-concentrating hormone (MCH) communicated through various endocrinological pathways. During fasting, fat cells decrease the secretion of leptin while a compromised hepatic gluconeogenesis dampens the pancreatic insulin secretion. Within the stomach in turn, an augmented amount of ghrelin is released. All three pathways lead to an activation of AGRP and NPY releasing neurons within the nucleus arcuatus while inhibitory pro-opiomelanocortin (POMC) neurons are impeded. Subsequently AGRP and NPY neurons promote the activation of MCH releasing neurons located in the hypothalamus that are directly stimulating appetite and food intake.

Tables

Key resources table
Reagent type
(species) or resource
DesignationSource or referenceIdentifiersAdditional information
Strain, strain background (Mus musculus)Diet-induced obese (DIO) C57BL/6 miceTaconicB6-M
Strain, strain background (Mus musculus)Lean C57BL/6 miceTaconicDIO-B6-M
Strain, strain background (Rattus norvegicus)Wistar ratsCharles River003
Peptide, recombinant proteinRecombinant MCHCayman ChemicalID: 24462
Commercial assay or kitDirect-zol RNA MiniPrep kitZymo ResearchID: 205311
Commercial assay or kitReverse transcriptase QuantiTech RT KitQiagenID: R2061
Commercial assay or kitSYBR Green master mixApplied BiosystemsID: 4309155
Chemical compound, drugMCHR1-ITakeda
Chemical compound, drugTDCASigma-AldrichID: T0875-25G
Chemical compound, drugValineSigma-AldrichID: V0513-25G
Software, algorithmGraphPad Prism softwareSan Diego, CASCR_002798
Software, algorithmMetaboAnalyst 3.0Genome CanadaSCR 015539
OtherGlucoseSigma-AldrichID: 50-99-7
OtherHFD D12492Research Diets IncID: 50-99-712492

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