Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial
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Aims/hypothesis Systemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients, suggesting FGF21 resistance. We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity (DIO).Methods Type 2 diabetes mellitus patients (n = 24) on diet and/or metformin were randomised (using a table of random numbers) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone (45 mg/day) and exenatide (10 μg twice daily) for 12 months in an open label parallel study at the Baylor Clinic.Results Twenty-one patients completed the entire study and were included in the analysis. Pioglitazone treatment (n = 10) reduced hepatic fat as assessed by magnetic resonance spectroscopy, despite a significant increase in body weight (Δ = 3.7 kg); plasma FGF21 levels did not change (1.9 ± 0.6 to 2.2 ± 0.6 ng/ml [mean ± SEM]). However, combined pioglitazone and exenatide therapy (n = 11) was associated with a significant reduction of FGF21 levels (2.3 ± 0.5 to 1.1 ± 0.3 ng/ml) and a greater decrease in hepatic fat. Besides weight gain observed in the pioglitazone-treated patients, lower extremity oedema was observed as a side effect in two of the ten patients. Three patients who received pioglitazone and exenatide combination therapy complained of significant nausea that was self-limiting and did not require them to leave the study. In DIO mice, exendin-4 for 4 weeks significantly reduced hepatic triacylglycerol content, decreased hepatic FGF21 protein and mRNA, and enhanced phosphorylation of hepatic AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, although no significant difference in weight and body fat was observed. Hepatic FGF21 correlated inversely with hepatic AMPK phosphorylation Conclusions/interpretation In type 2 diabetes mellitus, combined pioglitazone and exenatide therapy is associated with a reduction in plasma FGF21 levels, as well as a greater decrease in hepatic fat than that achieved with pioglitazone therapy. In DIO mice, exendin-4 treatment reduces hepatic triacylglycerol and FGF21 protein, and enhances hepatic AMPK phosphorylation, suggesting an improvement of hepatic FGF21 resistance.Trial registration number ClinicalTrials.gov NCT 01432405.
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The effect of GLP-1RA on hepatic steatosis was observed in several mice models, with a decrease after exenatide or liraglutide treatment.
“The effect of GLP-1RA on hepatic steatosis was observed in several mice models (including leptin-deficient ob/ob mice, leptin receptor-deficient db/db mice, and high-fat diet (HFD) fed mice that showed a decrease after exenatide treatment [160,161,162] or liraglutide [163].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [162]
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- Authors
- Samson, S. L., Sathyanarayana, P., Jogi, M., Gonzalez, E. V., Gutierrez, A., Krishnamurthy, R., Muthupillai, R., Chan, L., & Bajaj, M.
- Affiliations
- Baylor College of Medicine (US)
- Baylor St. Luke's Medical Center (US)
- Corresponding author
- Bajaj, M.
- Venue
- Diabetologia
- Published
- 2011-09-29
- Volume
- 54
- Issue
- 12
- Pages
- 3093-3100
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC3658171
- OpenAlex
- W2040507318
- Cited by
- 110
- References
- 21
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 9 · 2019: 6 · 2018: 7 · 2017: 6 · 2016: 12 · 2015: 15 · 2014: 14 · 2013: 8 · 2012: 8
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- American Diabetes Association Research Foundation
- Eli Lilly and Company
- Amylin Pharmaceuticals
- National Institutes of Health
- National Heart, Lung, and Blood Institute (T32HL066991, HL-51586, R01HL051586)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079638)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- exenatide, FGF21, FGF21 resistance, non-alcoholic fatty liver disease, type 2 diabetes, pioglitazone, exendin-4, hepatic steatosis, AMPK, acetyl-CoA carboxylase, combination therapy, diet-induced obesity
- MeSH terms
- Pioglitazone, Exenatide, Adult, Aged, Animals, Body Weight, Diabetes Mellitus, Type 2, Disease Models, Animal, Drug Therapy, Combination, Edema, Fatty Liver, Female, Fibroblast Growth Factors, Humans, Hypoglycemic Agents, Liver, Male, Metformin, Middle Aged, Nausea, Obesity, Peptides, Venoms, Lower Extremity, Thiazolidinediones, Mice, Non-alcoholic Fatty Liver Disease
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