FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats[S]

The farnesoid X receptor (FXR) is a bile acid activated nuclear receptor. Zucker (fa/fa) rats, harboring a loss of function mutation of the leptin receptor, develop diabetes, insulin resistance, obesity, and liver steatosis. In this study, we investigated the effect of FXR activation by 6-ethyl-chenodeoxycholic acid, (6E-CDCA, 10 mg/kg) on insulin resistance and liver and muscle lipid metabolism in fa/fa rats and compared its activity with rosiglitazone (10 mg/kg) alone or in combination with 6E-CDCA (5 mg/kg each). In comparison to lean (fa/+), fa/fa rats on a normal diet developed insulin resistance and liver steatosis. FXR activation protected against body weight gain and liver and muscle fat deposition and reversed insulin resistance as assessed by insulin responsive substrate-1 phosphorylation on serine 312 in liver and muscles. Activation of FXR reduced liver expression of genes involved in fatty acid synthesis, lipogenesis, and gluconeogenesis. In the muscles, FXR treatment reduced free fatty acid synthesis. Rosiglitazone reduced blood insulin, glucose, triglyceride, free fatty acid, and cholesterol plasma levels but promoted body weight gain (20%) and liver fat deposition. FXR activation reduced high density lipoprotein plasma levels. In summary, FXR administration reversed insulin resistance and correct lipid metabolism abnormalities in an obesity animal model.

• Publication year

  2010

• Venue

  Journal of Lipid Research

• Publication date

  2010-04-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1194/jlr.M001602PMID 19783811PMCID PMC2842143
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Targetting farnesoid-X-receptor: from medicinal chemistry to disease treatment.

  2010cited by this paper
• Bile acids: regulation of synthesis

  2009cited by this paper
• Kupffer cells mediate leptin-induced liver fibrosis.

  2009cited by this paper
• Non-alcoholic steatohepatitis and animal models: understanding the human disease.

  2009cited by this paper
• Farnesoid X receptor agonists in biliary tract disease

  2009cited by this paper
• A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation.

  2009cited by this paper
• Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

  2008cited by this paper
• Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets.

  2008cited by this paper
• Farnesoid X Receptor Induces GLUT4 Expression Through FXR Response Element in the GLUT4 Promoter

  2008cited by this paper
• Animal models of NASH: Getting both pathology and metabolic context right

  2008cited by this paper
• Metformin therapy and clinical uses

  2008cited by this paper
• The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis.

  2008cited by this paper
• Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress.

  2008cited by this paper
• Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.

  2008cited by this paper
• Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice

  2007cited by this paper
• Peroxisome Proliferator-Activated Receptor γ and Adipose Tissue—Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism

  2007cited by this paper
• Targeting farnesoid X receptor for liver and metabolic disorders.

  2007cited by this paper
• Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism.

  2007cited by this paper
• Mechanisms linking obesity to insulin resistance and type 2 diabetes

  2006cited by this paper
• Treatment of non-alcoholic fatty liver disease

  2006cited by this paper
• The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice*

  2006cited by this paper
• The Farnesoid X Receptor Promotes Adipocyte Differentiation and Regulates Adipose Cell Function in Vivo

  2006cited by this paper
• Development of insulin resistance and hyperphagia in Zucker fatty rats.

  2006cited by this paper
• Farnesoid X receptor is essential for normal glucose homeostasis.

  2006cited by this paper
• Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice.

  2006cited by this paper
• Retinoid X receptor heterodimers in the metabolic syndrome.

  2005cited by this paper
• The Farnesoid X Receptor Modulates Hepatic Carbohydrate Metabolism during the Fasting-Refeeding Transition*

  2005cited by this paper
• Retinoid x receptor heterodimers in the metabolic syndrome.

  2005cited by this paper
• Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis

  2005cited by this paper
• Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor.

  2005cited by this paper
• The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis.

  2004cited by this paper
• Prevention of cholesterol gallstone disease by FXR agonists in a mouse model

  2004cited by this paper
• Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR.

  2004cited by this paper
• Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR

  2004cited by this paper
• Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.

  2004cited by this paper
• Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element.

  2002cited by this paper
• Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle*

  2002cited by this paper
• Insulin resistance: a phosphorylation-based uncoupling of insulin signaling.

  2001cited by this paper
• The role of TNFalpha and TNF receptors in obesity and insulin resistance.

  1999cited by this paper
• The role of TNFα and TNF receptors in obesity and insulin resistance

  1999cited by this paper
• A Molecular Basis for Insulin Resistance

  1997cited by this paper
• Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1.

  1995cited by this paper
• Tumor necrosis factor alpha inhibits signaling from the insulin receptor.

  1994cited by this paper
• On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance

  year unknowncited by this paper

• Effects of the FXR agonist GW4064 on metabolic disorders in db/db mice

  2026cites this paper
• Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease.

  2025cites this paper
• Insights into Clinical Trials for Drugs Targeting MASLD: Progress, Challenges, and Future Directions

  2025cites this paper
• Machine learning-based association between mixed metal exposure in early pregnancy and gestational diabetes mellitus: Mediating role of bile acid metabolism.

  2025cites this paper
• The Vicious Circle of Metabolic Dysfunction-Associated Steatotic Liver Disease When Micronutrient Deficiency Drives Microbial Imbalance and Liver Injury

  2025cites this paper
• Nuclear receptors as therapeutic targets in metabolic and cardiovascular disorders

  2025cites this paper
• Dietary chenodeoxycholic acid inclusion improves carbohydrate utilisation and inflammation of largemouth bass (Micropterus salmoides) partly mediated by the activation of farnesoid X receptor

  2025cites this paper
• Gut Microbiota and Exercise: Probiotics to Modify the Composition and Roles of the Gut Microbiota in the Context of 3P Medicine

  2025cites this paper
• Gut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD

  2025cites this paper
• The gut microbiota-bile acid axis: a crucial regulator of immune function and metabolic health

  2025cites this paper
• Obeticholic Acid and Other Farnesoid-X-Receptor (FXR) Agonists in the Treatment of Liver Disorders

  2025cites this paper
• From Nuclear Receptor Regulation to Spleen Activating and Accumulation Resolving Therapy: A Review of Traditional Chinese Medicine Against Diabetes and Inflammation

  2025cites this paper
• Attenuation of chlorpyrifos-induced liver injury, oxidative stress and inflammation by selenium nanoparticles via SIRT1/FXR/Nrf2 signaling pathway modulation

  2025cites this paper
• Advances of pharmacological therapies in lipodystrophy syndromes: current evidence and future directions

  2025cites this paper
• Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders

  2025cites this paper
• Cyclodextrins as Modulators of Gut Microbiota: Pharmaceutical Applications and Impact on Intestinal Health

  2025cites this paper
• DMF, an activator of Nrf2, could mitigate cholic-acid-induced liver damage in high-fat diet

  2025cites this paper
• Upregulation of Nrf2/HO-1 signaling and farnesoid X receptor and attenuation of oxidative stress and inflammation mediate the protective effect of sitagliptin against diabetic nephropathy in rats.

  2025cites this paper
• Gut microbiota in MAFLD: therapeutic and diagnostic implications

  2024cites this paper
• Galangin attenuates chlorpyrifos-induced kidney injury by mitigating oxidative stress and inflammation and upregulating Nrf2 and farnesoid-X-receptor in rats.

  2024cites this paper
• Gut–Liver–Pancreas Axis Crosstalk in Health and Disease: From the Role of Microbial Metabolites to Innovative Microbiota Manipulating Strategies

  2024cites this paper
• The bile-gut axis and metabolic consequences of cholecystectomy.

  2024cites this paper
• BAR502/fibrate conjugates: synthesis, biological evaluation and metabolic profile

  2024cites this paper
• Butylparaben induces glycolipid metabolic disorders in mice via disruption of gut microbiota and FXR signaling.

  2024cites this paper
• Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness with Liver Fat Among Older Adults.

  2024cites this paper
• The hepatokine orosomucoid 2 mediates beneficial metabolic effects of bile acids.

  2024cites this paper
• Chronic sucralose consumption inhibits farnesoid X receptor signaling and perturbs lipid and cholesterol homeostasis in the mouse livers, potentially by altering gut microbiota functions.

  2024cites this paper
• Regulation Mechanism and Potential Value of Active Substances in Spices in Alcohol–Liver–Intestine Axis Health

  2024cites this paper
• Evidence and Mechanism of Bile Acid-Mediated Gut-Brain Axis in Anxiety and Depression.

  2024cites this paper
• Genetic estimation of fat traits in sheep and association of its NR1H4 gene polymorphisms with tail fat deposition

  2024cites this paper
• The Gut Microbiota Involvement in the Panorama of Muscular Dystrophy Pathogenesis

  2024cites this paper
• Simvastatin mitigates diabetic nephropathy by upregulating farnesoid X receptor and Nrf2/HO-1 signaling and attenuating oxidative stress and inflammation in rats.

  2024cites this paper
• New Insights on the potential therapeutic effects of glibenclamide and Obeticholic acid against Alloxan-Induced diabetes mellitus in rat model.

  2024cites this paper
• Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

  2024cites this paper
• The direct and gut microbiota-mediated effects of dietary bile acids on the improvement of gut barriers in largemouth bass (Micropterus salmoides)

  2023cites this paper
• Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness with Liver Fat Among Older Adults

  2023cites this paper
• An Integrated Approach to Skeletal Muscle Health in Aging

  2023cites this paper
• Regulon analysis identifies protective FXR and CREB5 in proximal tubules in early diabetic kidney disease

  2023cites this paper
• Management of metabolic-associated fatty liver disease: The diabetology perspective

  2023cites this paper
• Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics

  2023cites this paper
• Microbes, metabolites and muscle: Is the gut–muscle axis a plausible therapeutic target in Duchenne muscular dystrophy?

  2023cites this paper
• Farnesoid X receptor is inhibited after ileum transposition in diabetic rats: its hypoglycemic effect

  2023cites this paper
• Prolonged antibiotic exposure during adolescence dysregulates liver metabolism and promotes adiposity in mice.

  2023cites this paper
• Obeticholic Acid—A Pharmacological and Clinical Review

  2023cites this paper
• The diverse roles of macrophages in metabolic inflammation and its resolution

  2023influential citation
• The oral microbiome in the pathophysiology of cardiovascular disease

  2023cites this paper
• Elucidating the glucose‐lowering effect of the bile acid sequestrant sevelamer

  2023cites this paper
• Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

  2023cites this paper
• Effects of Lipophagy on Atherosclerosis

  2023cites this paper
• The growth-promoting and lipid-lowering effects of berberine are associated with the regulation of intestinal bacteria and bile acid profiles in yellow catfish (Pelteobagrus fulvidraco)

  2023cites this paper
• FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

  2023cites this paper
• The 16α-hydroxylated Bile Acid, Pythocholic Acid Decreases Food Intake and Increases Oleoylethanolamide in Male Mice

  2023cites this paper
• Emerging Therapies and Therapeutic Targets for Composite Liver Disease: NASH.

  2023cites this paper
• Bile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets

  2023cites this paper
• THE CONNECTION BETWEEN BILE ACIDS AND TYPE 2 DIABETES MELLITUS - A REVIEW.

  2023cites this paper
• Safety, tolerability, pharmacokinetics and pharmacodynamics of a novel farnesoid X receptor (FXR) agonist-TQA3526 in healthy Chinese volunteers: a double-blind, randomized, placebo-controlled, dose-escalation, food effect phase I study

  2023cites this paper
• Gut microbiome determines therapeutic effects of OCA on NAFLD by modulating bile acid metabolism

  2023cites this paper
• Bile acids-gut microbiota crosstalk contributes to the improvement of type 2 diabetes mellitus

  2022cites this paper
• Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

  2022cites this paper
• The python-derived 16α-hydroxylated bile acid, pythocholic acid decreases food intake and increases jejunal fatty acid ethanolamides in mice

  2022cites this paper
• Gastrodia elata Blume extract improves high-fat diet-induced type 2 diabetes by regulating gut microbiota and bile acid profile

  2022cites this paper
• Role of brain-gut-muscle axis in human health and energy homeostasis

  2022influential citation
• The gut microbiome: a core regulator of metabolism

  2022cites this paper
• Selective Photoaffinity Probe for Monitoring Farnesoid X Receptor Expression in Cultured Cells.

  2022cites this paper
• Versatile Triad Alliance: Bile Acid, Taurine and Microbiota

  2022cites this paper
• Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis.

  2022cites this paper
• Gut Microbiome and Metabolites, the Future Direction of Diagnosis and Treatment of Atherosclerosis?

  2022cites this paper
• Recent advances on FXR-targeting therapeutics.

  2022cites this paper
• Obeticholic acid inhibits hepatic fatty acid uptake independent of FXR in mouse.

  2022cites this paper
• Targeting bile acid signaling for the treatment of liver diseases: From bench to bed.

  2022cites this paper
• Gut Microbiota Dysbiosis: Triggers, Consequences, Diagnostic and Therapeutic Options

  2022cites this paper
• Ozonated Olive Oil Alleviates Hepatic Steatosis in Obese Zucker (fa/fa) Rats.

  2022cites this paper
• Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease

  2022cites this paper
• Targeting gut microbial bile salt hydrolase (BSH) by diet supplements: new insights into dietary modulation of human health.

  2022cites this paper
• Membrane polarization in non-neuronal cells as a potential mechanism of metabolic disruption by depolarizing insecticides.

  2022cites this paper
• In Silico Development of Combinatorial Therapeutic Approaches Targeting Key Signaling Pathways in Metabolic Syndrome

  2022cites this paper
• Pharmacological Dose-Effect Profiles of Various Concentrations of Humanised Primary Bile Acid in Encapsulated Cells

  2022cites this paper
• Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice

  2022cites this paper
• Proglumide Reverses Nonalcoholic Steatohepatitis by Interaction with the Farnesoid X Receptor and Altering the Microbiome

  2022cites this paper
• Vertical sleeve gastrectomy confers metabolic improvements by reducing intestinal bile acids and lipid absorption in mice

  2021cites this paper
• Diammonium Glycyrrhizinate Ameliorates Obesity Through Modulation of Gut Microbiota-Conjugated BAs-FXR Signaling

  2021cites this paper
• FXR, a Key Regulator of Lipid Metabolism, Is Inhibited by ER Stress-Mediated Activation of JNK and p38 MAPK in Large Yellow Croakers (Larimichthys crocea) Fed High Fat Diets

  2021cites this paper
• Discovery of a novel and orally active Farnesoid X receptor agonist for the protection of acetaminophen‐induced hepatotoxicity

  2021cites this paper
• Atorvastatin protects against liver and vascular damage in a model of diet induced steatohepatitis by resetting FXR and GPBAR1 signaling

  2021cites this paper
• Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer

  2021cites this paper
• The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

  2021cites this paper
• Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis.

  2021cites this paper
• Deoxycholic Acid and Risks of Cardiovascular Events, ESKD, and Mortality in CKD: The CRIC Study

  2021cites this paper
• The RNA binding protein human antigen R is a gatekeeper of liver homeostasis

  2021cites this paper
• A review on gut microbiota: a central factor in the pathophysiology of obesity

  2021cites this paper
• Obeticholic acid ameliorates obesity and hepatic steatosis by activating brown fat

  2021cites this paper
• Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities

  2021cites this paper
• Bile Acids, Their Receptors, and the Gut Microbiota.

  2021cites this paper
• Brown Rice Inhibits Development of Nonalcoholic Fatty Liver Disease in Obese Zucker (fa/fa) Rats by Increasing Lipid Oxidation Via Activation of Retinoic Acid Synthesis.

  2021cites this paper
• Abnormal Metabolism in the Progression of Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: Mechanistic Insights to Chemoprevention

  2021cites this paper
• Intestinal Flora is a Key Factor in Insulin Resistance and Contributes to the Development of Polycystic Ovary Syndrome

  2021cites this paper
• Therapeutic Approaches for Nonalcoholic Steatohepatitis ( NASH )

  2021cites this paper
• Combined treatment with FABP4 inhibitor ameliorates rosiglitazone‐induced liver steatosis in obese diabetic db/db mice

  2021cites this paper
• Current and Emerging Approaches for Hepatic Fibrosis Treatment

  2021cites this paper
• Modeling Diet-Induced NAFLD and NASH in Rats: A Comprehensive Review

  2021cites this paper