Targeting FXR and FGF19 to Treat Metabolic Diseases—Lessons Learned From Bariatric Surgery

Bariatric surgery procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective interventions available for sustained weight loss and improved glucose metabolism. Bariatric surgery alters the enterohepatic bile acid circulation, resulting in increased plasma bile levels as well as altered bile acid composition. While it remains unclear why both VSG and RYGB can alter bile acids, it is possible that these changes are important mediators of the effects of surgery. Moreover, a molecular target of bile acid synthesis, the bile acid–activated transcription factor FXR, is essential for the positive effects of VSG on weight loss and glycemic control. This Perspective examines the relationship and sequence of events between altered bile acid levels and composition, FXR signaling, and gut microbiota after bariatric surgery. We hypothesize that although bile acids and FXR signaling are potent mediators of metabolic function, unidentified downstream targets are the main mediators behind the benefits of weight-loss surgery. One of these targets, the gut-derived peptide FGF15/19, is a potential molecular and therapeutic marker to explain the positive metabolic effects of bariatric surgery. Focusing research efforts on identifying these complex molecular mechanisms will provide new opportunities for therapeutic strategies to treat obesity and metabolic dysfunction.

[1]  F. Gonzalez,et al.  Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism , 2018, Hepatology.

[2]  J. Trotter,et al.  NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial , 2018, The Lancet.

[3]  S. Kliewer,et al.  FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. , 2017, Cell metabolism.

[4]  D. Freyssenet,et al.  Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice , 2017, Nature Medicine.

[5]  F. Gonzalez,et al.  Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism , 2017, The Journal of Biological Chemistry.

[6]  Deepak L. Bhatt,et al.  Bariatric Surgery versus Intensive Medical Therapy for Diabetes — 5‐Year Outcomes , 2017, The New England journal of medicine.

[7]  S. Ikramuddin,et al.  Bile Acids Increase Independently From Hypocaloric Restriction After Bariatric Surgery , 2016, Annals of surgery.

[8]  F. Bäckhed,et al.  Microbiota-induced obesity requires farnesoid X receptor , 2016, Gut.

[9]  William H. Bisson,et al.  Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction , 2015, Nature Communications.

[10]  R. Ley,et al.  TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice , 2015, Gut.

[11]  F. Mottaghy,et al.  The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity. , 2015, Cell metabolism.

[12]  N. Abumrad,et al.  Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery , 2015, Nature Communications.

[13]  G. Shulman,et al.  FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis , 2015, Nature Communications.

[14]  D. Rajpal,et al.  Effect of Roux-en-Y Gastric Bypass Surgery on Bile Acid Metabolism in Normal and Obese Diabetic Rats , 2015, PloS one.

[15]  B. Neuschwander‐Tetri,et al.  Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial , 2015, The Lancet.

[16]  J. Holst,et al.  Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations. , 2015, The Journal of clinical endocrinology and metabolism.

[17]  D. Huson,et al.  Effects of Surgical and Dietary Weight Loss Therapy for Obesity on Gut Microbiota Composition and Nutrient Absorption , 2015, BioMed research international.

[18]  R. Haeusler,et al.  Temporal changes in bile acid levels and 12α-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes , 2015, International Journal of Obesity.

[19]  D. Brenner,et al.  Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance , 2015, Nature Medicine.

[20]  I. Albert,et al.  Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. , 2015, The Journal of clinical investigation.

[21]  M. Bueter,et al.  The physiology of altered eating behaviour after Roux‐en‐Y gastric bypass , 2014, Experimental physiology.

[22]  T. Arora,et al.  Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19. , 2014, Cancer research.

[23]  V. Tremaroli,et al.  FXR is a molecular target for the effects of vertical sleeve gastrectomy , 2014, Nature.

[24]  R. Bergman,et al.  FGF19 action in the brain induces insulin-independent glucose lowering. , 2013, The Journal of clinical investigation.

[25]  B. Aronow,et al.  Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner , 2013, Obesity.

[26]  M. Horowitz,et al.  Effects of rectal administration of taurocholic acid on glucagon‐like peptide‐1 and peptide YY secretion in healthy humans , 2013, Diabetes, obesity & metabolism.

[27]  S. Woods,et al.  A surgical model in male obese rats uncovers protective effects of bile acids post-bariatric surgery. , 2013, Endocrinology.

[28]  W. D. de Vos,et al.  Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women , 2012, Gut.

[29]  N. Nagelkerke,et al.  Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers , 2012, Diabetologia.

[30]  J. H. Bekker,et al.  The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. , 2012, Endocrinology.

[31]  F. Gonzalez,et al.  Bile Acids Acutely Stimulate Insulin Secretion of Mouse β-Cells via Farnesoid X Receptor Activation and KATP Channel Inhibition , 2012, Diabetes.

[32]  F. Bäckhed,et al.  Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. , 2013, Cell metabolism.

[33]  K. Yoshinari,et al.  Fibroblast growth factor 19 treatment ameliorates disruption of hepatic lipid metabolism in farnesoid X receptor (Fxr)-null mice. , 2011, Biological & pharmaceutical bulletin.

[34]  M. Orešič,et al.  Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity , 2011, Diabetes.

[35]  S. Kliewer,et al.  FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. , 2011, Cell metabolism.

[36]  S. Kliewer,et al.  FGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen Synthesis , 2011, Science.

[37]  A. Peterson,et al.  FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways , 2011, PloS one.

[38]  L. Adorini,et al.  Functional Characterization of the Semisynthetic Bile Acid Derivative INT-767, a Dual Farnesoid X Receptor and TGR5 Agonist , 2010, Molecular Pharmacology.

[39]  S. Woods,et al.  Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[40]  B. Lemon,et al.  Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19) , 2010, Proceedings of the National Academy of Sciences.

[41]  H. Itoh,et al.  Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. , 2009, Metabolism: clinical and experimental.

[42]  J. Holst,et al.  Serum Bile Acids Are Higher in Humans With Prior Gastric Bypass: Potential Contribution to Improved Glucose and Lipid Metabolism , 2009, Obesity.

[43]  B. Lemon,et al.  Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice , 2009, Proceedings of the National Academy of Sciences.

[44]  W. Mckeehan,et al.  FGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet–Induced Fatty Liver , 2007, Diabetes.

[45]  Folkert Kuipers,et al.  The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice* , 2006, Journal of Biological Chemistry.

[46]  Timothy M Willson,et al.  Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Soriano,et al.  Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. , 2004, Endocrinology.

[48]  D. French,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Transgenic Mice Expressing Human Fibroblast Growth Factor-19 Display Increased Metabolic Rate and Decreased Adiposity , 2022 .

[49]  Masahiro Tohkin,et al.  Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis , 2000, Cell.

[50]  G. Bray,et al.  Suppression of appetite by bile acids. , 1968, Lancet.

[51]  R. Haeusler,et al.  Temporal changes in bile acid levels and 12α-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes , 2015, International Journal of Obesity.

[52]  S. Woods,et al.  Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. , 2013, Endocrinology.