BACKGROUND: The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT). METHODS: Obese and type-2 diabetic women (n = 39, BMI > 35 kg/m2) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-19 levels were then assessed. RESULTS: All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-19 increased in both BPD and LGCP (χ2(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-19 serum levels decreased (P = 0.028). Interestingly, circulating FGF-19 was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01). CONCLUSIONS: Elevated serum FGF-19 levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-19 levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a potential target of FGF-19 during diabetes remission.

Aston Medical Research Institute Aston Medical School Aston University Birmingham UK

Department of Biomedical Sciences University of Westminster London W1W 6UW UK

Derby Teaching Hospitals NHS Foundation Trust Derby UK

Institute of Endocrinology Prague Czech Republic

OB Clinic Prague Czech Republic

School of Science and Technology Nottingham Trent University Nottingham NG11 8NS UK

Warwick Medical School University of Warwick Coventry UK

Warwickshire Institute for the Study of Diabetes Endocrinology and Metabolism NHS Trust Coventry UK

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Gibby JT, Njeru DK, Cvetko ST, Merrill RM, Bikman BT, Gibby WA. Volumetric analysis of central body fat accurately predicts incidence of diabetes and hypertension in adults. BMC Obes. 2015;2:10. doi: 10.1186/s40608-015-0039-3. PubMed DOI PMC

Dennedy MC, Vidal-Puig A. An adipocentric view of the metabolic syndrome and cardiovascular disease. Curr Cardiovasc Risk Rep. 2014;8:379. doi: 10.1007/s12170-014-0379-4. DOI

Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trends Endocrinol Metab. 2012;23(9):435–43. doi: 10.1016/j.tem.2012.06.004. PubMed DOI PMC

Corkey BE, Shirihai O. Metabolic master regulators: sharing information among multiple systems. Trends Endocrinol Metab. 2012;23(12):594–601. doi: 10.1016/j.tem.2012.07.006. PubMed DOI PMC

Yin X, Lanza IR, Swain JM, Sarr MG, Nair KS, Jensen MD. Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J Clin Endocrinol Metab. 2014;99(2):E209–216. doi: 10.1210/jc.2013-3042. PubMed DOI PMC

Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013;17(4):491–506. doi: 10.1016/j.cmet.2013.03.002. PubMed DOI PMC

Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, Han SS, Yoon YS, Yoon G, Choi KM, Ko YG. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia. 2006;49(4):784–91. doi: 10.1007/s00125-006-0170-2. PubMed DOI

Wang T, Si Y, Shirihai OS, Si H, Schultz V, Corkey RF, Hu L, Deeney JT, Guo W, Corkey BE. Respiration in adipocytes is inhibited by reactive oxygen species. Obesity. 2010;18(8):1493–502. doi: 10.1038/oby.2009.456. PubMed DOI PMC

Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, et al. The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem. 2005;280(6):4617–26. doi: 10.1074/jbc.M411863200. PubMed DOI

Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7(1):45–56. doi: 10.1016/j.cmet.2007.10.013. PubMed DOI

Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440(7086):944–8. doi: 10.1038/nature04634. PubMed DOI

Bharadwaj MS, Tyrrell DJ, Leng I, Demons JL, Lyles MF, Carr JJ, Nicklas BJ, Molina AJ. Relationships between mitochondrial content and bioenergetics with obesity, body composition and fat distribution in healthy older adults. BMC Obes. 2015;2:40. doi: 10.1186/s40608-015-0070-4. PubMed DOI PMC

Soronen J, Laurila PP, Naukkarinen J, Surakka I, Ripatti S, Jauhiainen M, Olkkonen VM, Yki-Jarvinen H. Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects. BMC Med Genomics. 2012;5:9. doi: 10.1186/1755-8794-5-9. PubMed DOI PMC

Zhou MC, Min R, Ji JJ, Zhang S, Tong AL, Xu JP, Li ZY, Zhang HB, Li YX. Analysis of association among clinical features and shorter leukocyte telomere length in mitochondrial diabetes with m.3243A > G mitochondrial DNA mutation. BMC Med Genet. 2015;16:92. doi: 10.1186/s12881-015-0238-2. PubMed DOI PMC

Scharfe C, Lu HH, Neuenburg JK, Allen EA, Li GC, Klopstock T, Cowan TM, Enns GM, Davis RW. Mapping gene associations in human mitochondria using clinical disease phenotypes. PLoS Comput Biol. 2009;5(4):e1000374. doi: 10.1371/journal.pcbi.1000374. PubMed DOI PMC

Loo JH, Trejaut JA, Yen JC, Chen ZS, Ng WM, Huang CY, Hsu KN, Hung KH, Hsiao Y, Wei YH, et al. Mitochondrial DNA association study of type 2 diabetes with or without ischemic stroke in Taiwan. BMC Res Notes. 2014;7:223. doi: 10.1186/1756-0500-7-223. PubMed DOI PMC

Sjostrom L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a prospective controlled intervention study of bariatric surgery. J Int Med. 2013;273(3):219–34. doi: 10.1111/joim.12012. PubMed DOI

Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, Thomas S, Abood B, Nissen SE, Bhatt DL. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–76. doi: 10.1056/NEJMoa1200225. PubMed DOI PMC

Warkentin LM, Majumdar SR, Johnson JA, Agborsangaya CB, Rueda-Clausen CF, Sharma AM, Klarenbach SW, Karmali S, Birch DW, Padwal RS. Weight loss required by the severely obese to achieve clinically important differences in health-related quality of life: two-year prospective cohort study. BMC Med. 2014;12:175. doi: 10.1186/s12916-014-0175-5. PubMed DOI PMC

Yang J, Wang C, Cao G, Yang W, Yu S, Zhai H, Pan Y. Long-term effects of laparoscopic sleeve gastrectomy versus Roux-en-Y gastric bypass for the treatment of Chinese type 2 diabetes mellitus patients with body mass index 28-35 kg/m(2) BMC Surg. 2015;15:88. doi: 10.1186/s12893-015-0074-5. PubMed DOI PMC

Vage V, Sande VA, Mellgren G, Laukeland C, Behme J, Andersen JR. Changes in obesity-related diseases and biochemical variables after laparoscopic sleeve gastrectomy: a two-year follow-up study. BMC Surg. 2014;14:8. doi: 10.1186/1471-2482-14-8. PubMed DOI PMC

Batterham RL, Cummings DE. Mechanisms of diabetes improvement following bariatric/metabolic surgery. Diabetes Care. 2016;39(6):893–901. doi: 10.2337/dc16-0145. PubMed DOI PMC

Kyrou I, Weickert MO, Gharanei S, Randeva HS, Tan BK. Fibroblast growth factors: new insights, new targets in the management of diabetes. Minerva Endocrinol. 2016. Ahead of print. PubMed

Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Perez HE, Sandoval DA, Kohli R, Backhed F, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509(7499):183–8. doi: 10.1038/nature13135. PubMed DOI PMC

Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, Williams PM, Soriano R, Corpuz R, Moffat B, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145(6):2594–603. doi: 10.1210/en.2003-1671. PubMed DOI

Sachdev S, Wang Q, Billington C, Connett J, Ahmed L, Inabnet W, Chua S, Ikramuddin S, Korner J. FGF 19 and bile acids increase following Roux-en-Y gastric bypass but not after medical management in patients with type 2 diabetes. Obes Surg. 2016;26(5):957–65. doi: 10.1007/s11695-015-1834-0. PubMed DOI PMC

Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, Bekker JH, Ghatei MA, Bloom SR, Walters JR, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology. 2012;153(8):3613–9. doi: 10.1210/en.2011-2145. PubMed DOI PMC

Gerhard GS, Styer AM, Wood GC, Roesch SL, Petrick AT, Gabrielsen J, Strodel WE, Still CD, Argyropoulos G. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care. 2013;36(7):1859–64. doi: 10.2337/dc12-2255. PubMed DOI PMC

Jansen PL, van Werven J, Aarts E, Berends F, Janssen I, Stoker J, Schaap FG. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis. 2011;29(1):48–51. doi: 10.1159/000324128. PubMed DOI

Haluzikova D, Lacinova Z, Kavalkova P, Drapalova J, Krizova J, Bartlova M, Mraz M, Petr T, Vitek L, Kasalicky M, et al. Laparoscopic sleeve gastrectomy differentially affects serum concentrations of FGF-19 and FGF-21 in morbidly obese subjects. Obesity. 2013;21(7):1335–42. doi: 10.1002/oby.20208. PubMed DOI

Ryan KK, Kohli R, Gutierrez-Aguilar R, Gaitonde SG, Woods SC, Seeley RJ. Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology. 2013;154(1):9–15. doi: 10.1210/en.2012-1891. PubMed DOI PMC

Morton GJ, Matsen ME, Bracy DP, Meek TH, Nguyen HT, Stefanovski D, Bergman RN, Wasserman DH, Schwartz MW. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Investig. 2013;123(11):4799–808. doi: 10.1172/JCI70710. PubMed DOI PMC

Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143(5):1741–7. doi: 10.1210/endo.143.5.8850. PubMed DOI

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9. doi: 10.1007/BF00280883. PubMed DOI

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502. PubMed

Hsieh CJ, Weng SW, Liou CW, Lin TK, Chen JB, Tiao MM, Hung YT, Chen IY, Huang WT, Wang PW. Tissue-specific differences in mitochondrial DNA content in type 2 diabetes. Diabetes Res Clin Pract. 2011;92(1):106–10. doi: 10.1016/j.diabres.2011.01.010. PubMed DOI

Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001;1(4):515–25. doi: 10.1016/S1534-5807(01)00055-7. PubMed DOI

Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004;15(11):5001–11. doi: 10.1091/mbc.E04-04-0294. PubMed DOI PMC

Molina AJ, Wikstrom JD, Stiles L, Las G, Mohamed H, Elorza A, Walzer G, Twig G, Katz S, Corkey BE, et al. Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes. 2009;58(10):2303–15. doi: 10.2337/db07-1781. PubMed DOI PMC

Las G, Serada SB, Wikstrom JD, Twig G, Shirihai OS. Fatty acids suppress autophagic turnover in beta-cells. J Biol Chem. 2011;286(49):42534–44. doi: 10.1074/jbc.M111.242412. PubMed DOI PMC

Brookheart RT, Michel CI, Schaffer JE. As a matter of fat. Cell Metab. 2009;10(1):9–12. doi: 10.1016/j.cmet.2009.03.011. PubMed DOI PMC

Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51(10):2944–50. doi: 10.2337/diabetes.51.10.2944. PubMed DOI

Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, et al. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem. 2003;278(19):17190–7. doi: 10.1074/jbc.M212754200. PubMed DOI

Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433–46. doi: 10.1038/sj.emboj.7601963. PubMed DOI PMC

Vila M, Ruiz O, Belmonte M, Riesco M, Barcelo A, Perez G, Moreiro J, Salinas R. Changes in lipid profile and insulin resistance in obese patients after Scopinaro biliopancreatic diversion. Obes Surg. 2009;19(3):299–306. doi: 10.1007/s11695-008-9790-6. PubMed DOI

Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra MC, Goubern M, Surwit R, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000;26(4):435–9. doi: 10.1038/82565. PubMed DOI

Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21(2):159–65. doi: 10.1038/nm.3760. PubMed DOI PMC

Wu X, Ge H, Lemon B, Weiszmann J, Gupte J, Hawkins N, Li X, Tang J, Lindberg R, Li Y. Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice. Proc Natl Acad Sci U S A. 2009;106(34):14379–84. doi: 10.1073/pnas.0907812106. PubMed DOI PMC

Reiche M, Bachmann A, Lossner U, Bluher M, Stumvoll M, Fasshauer M. Fibroblast growth factor 19 serum levels: relation to renal function and metabolic parameters. Horm Metab Res. 2010;42(3):178–81. doi: 10.1055/s-0029-1243249. PubMed DOI

Mraz M, Lacinova Z, Kavalkova P, Haluzikova D, Trachta P, Drapalova J, Hanusova V, Haluzik M. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment. Physiol Res. 2011;60(4):627–36. PubMed

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