Semaglutide and Tirzepatide Suppress Hepatic Fatty Acid Uptake and Fatty Acid β-Oxidation in High-Fat Diet-Induced Obesity Mice.
4 affiliations
- 1Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas79106, United States.
- 2Brain Drug Discovery Center, Texas Tech University Health Sciences Center, Amarillo, Texas79106, United States.
- 3Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311Cairo, Egypt.
- 4School of Veterinary Medicine, Texas Tech University, Amarillo, Texas79106, United States.
Abstract
Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists show high efficacy in treating obesity and metabolic dysfunction-associated liver diseases, conditions that collectively represent one of the most challenging One Health crises of our time. However, their hepatic molecular mechanisms remain poorly understood. This study defined targeted hepatic proteomic signatures associated semaglutide (GLP-1 agonist) and tirzepatide (dual GLP-1/GIP) in diet-induced obese (DIO) male C57BL/6J mice using an liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted-proteomics approach and validated using western blotting. After 18 weeks of high-fat diet (HFD), obese mice received once-daily subcutaneous semaglutide (10 nmol/kg), tirzepatide (3 nmol/kg), or vehicle for 4 weeks. Tirzepatide produced greater systemic efficacy (24.6% body weight and 30.3% fat mass reduction, preserved lean mass, improved glucose homeostasis), yet both drugs yielded overlapping targeted hepatic proteomic signatures despite different receptor pharmacology. Both drugs significantly downregulated CD36 and CPT1A fatty acid importers for β-oxidation without altering lipogenic enzymes (FASN, ACC1, ACLY, ACSS2) or glucose-handling proteins (PDH, GLUT2). These findings suggest a substrate limitation over enhanced β-oxidation or broad lipogenesis-suppression, suggesting GLP-1 receptor activation is sufficient for the core liver response and GIP co-agonism mainly augments extrahepatic effects. From a One Health proteomics perspective, CD36/CPT1A anchored targeted proteomic signature provides a mechanistically informed benchmark for evaluating novel GLP-1 and non-GLP-1 investigational therapeutics.
Related
- Cutaneous Adverse Events Associated with Semaglutide, Liraglutide and Tirzepatide: A Systematic Review
- Atypical Anorexia Nervosa Developed in a Patient with Severe Obesity and Type 2 Diabetes Following Sleeve Gastrectomy and Postoperative Treatment with Semaglutide and Tirzepatide
- Changes in Eating Behavior and Food Preferences After Semaglutide or Tirzepatide Initiation: A Prospective Observational Pilot Study
- New-Onset Heart Failure in Patients with Obesity using Tirzepatide or Semaglutide
- Neuropsychiatric association of tirzepatide and semaglutide in obesity with and without type 2 diabetes
BibTeX
@article{patel2026semaglutide,
title = {{Semaglutide and Tirzepatide Suppress Hepatic Fatty Acid Uptake and Fatty Acid β-Oxidation in High-Fat Diet-Induced Obesity Mice.}},
author = {Dhavalkumar Patel and Heba Ewida and Syed Tareq and Md Tareq Aziz and Prasanth K Chelikani and Ulrich Bickel and Mahmoud Salama Ahmed},
journal = {Journal of proteome research},
year = {2026},
month = oct,
doi = {10.1021/acs.jproteome.6c00404},
url = {https://europepmc.org/article/MED/42918120},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Semaglutide and Tirzepatide Suppress Hepatic Fatty Acid Uptake and Fatty Acid β-Oxidation in High-Fat Diet-Induced Obesity Mice.
AU - Dhavalkumar Patel
AU - Heba Ewida
AU - Syed Tareq
AU - Md Tareq Aziz
AU - Prasanth K Chelikani
AU - Ulrich Bickel
AU - Mahmoud Salama Ahmed
PY - 2026
DA - 2026/10/01
JO - Journal of proteome research
DO - 10.1021/acs.jproteome.6c00404
UR - https://europepmc.org/article/MED/42918120
AB - Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists show high efficacy in treating obesity and metabolic dysfunction-associated liver diseases, conditions that collectively represent one of the most challenging One Health crises of our time. However, their hepatic molecular mechanisms remain poorly understood. This study defined targeted hepatic proteomic signatures associated semaglutide (GLP-1 agonist) and tirzepatide (dual GLP-1/GIP) in diet-induced obese (DIO) male C57BL/6J mice using an liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted-proteomics approach and validated using western blotting. After 18 weeks of high-fat diet (HFD), obese mice received once-daily subcutaneous semaglutide (10 nmol/kg), tirzepatide (3 nmol/kg), or vehicle for 4 weeks. Tirzepatide produced greater systemic efficacy (24.6% body weight and 30.3% fat mass reduction, preserved lean mass, improved glucose homeostasis), yet both drugs yielded overlapping targeted hepatic proteomic signatures despite different receptor pharmacology. Both drugs significantly downregulated CD36 and CPT1A fatty acid importers for β-oxidation without altering lipogenic enzymes (FASN, ACC1, ACLY, ACSS2) or glucose-handling proteins (PDH, GLUT2). These findings suggest a substrate limitation over enhanced β-oxidation or broad lipogenesis-suppression, suggesting GLP-1 receptor activation is sufficient for the core liver response and GIP co-agonism mainly augments extrahepatic effects. From a One Health proteomics perspective, CD36/CPT1A anchored targeted proteomic signature provides a mechanistically informed benchmark for evaluating novel GLP-1 and non-GLP-1 investigational therapeutics.
SN - 1535-3893
SN - 1535-3907
ER -