{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:43:49Z","timestamp":1792784629192,"version":"4.5.0"},"reference-count":46,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019535","name":"Texas Tech University Health Sciences Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019535","id-type":"DOI","asserted-by":"publisher"}]},{"name":"School of Pharmacy, Texas Tech University","id":[{"id":"https:\/\/ror.org\/0405mnx93","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 \u03b2-oxidation without altering lipogenic enzymes (FASN, ACC1, ACLY, ACSS2) or glucose-handling proteins (PDH, GLUT2). These findings suggest a substrate limitation over enhanced \u03b2-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.<\/jats:p>","DOI":"10.1021\/acs.jproteome.6c00404","type":"journal-article","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T20:01:23Z","timestamp":1789329683000},"page":"5418-5429","source":"Crossref","is-referenced-by-count":0,"title":["Semaglutide\nand Tirzepatide Suppress Hepatic Fatty\nAcid Uptake and Fatty Acid \u03b2-Oxidation in High-Fat Diet-Induced\nObesity Mice"],"prefix":"10.1021","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6959-3487","authenticated-orcid":true,"given":"Dhavalkumar","family":"Patel","sequence":"first","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Ewida","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]},{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]},{"name":"Future University in Egypt , , ,","place":["Cairo, Egypt, 12311"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed","family":"Tareq","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Tareq","family":"Aziz","sequence":"additional","affiliation":[{"name":"Texas Tech University , , , ,","place":["Amarillo, Texas, United States, 79106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanth K.","family":"Chelikani","sequence":"additional","affiliation":[{"name":"Texas Tech University , , , ,","place":["Amarillo, Texas, United States, 79106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Bickel","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]},{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5600-4698","authenticated-orcid":true,"given":"Mahmoud Salama","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]},{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Amarillo, Texas, United States, 79106"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"issue":"6","key":"2026100208422004200_cit1","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus Semaglutide\nOnce Weekly in Patients with Type 2 Diabetes","volume":"385","author":"Fri\u0301as","year":"2021","journal-title":"N. Engl. J. Med."},{"issue":"10","key":"2026100208422004200_cit2","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1038\/s41591-022-02026-4","article-title":"Two-year effects of\nsemaglutide in adults with overweight or obesity: the STEP 5 trial","volume":"28","author":"Garvey","year":"2022","journal-title":"Nat. Med."},{"issue":"11","key":"2026100208422004200_cit3","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1056\/NEJMoa2032183","article-title":"Once-Weekly Semaglutide\nin Adults with Overweight or Obesity","volume":"384","author":"Wilding","year":"2021","journal-title":"N. Engl.\nJ. Med."},{"issue":"4","key":"2026100208422004200_cit4","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for Metabolic\nDysfunction-Associated Steatohepatitis with Liver Fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N. Engl. J. Med."},{"issue":"21","key":"2026100208422004200_cit5","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 Trial of Semaglutide\nin Metabolic Dysfunction-Associated Steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N. Engl. J. Med."},{"issue":"4","key":"2026100208422004200_cit6","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.jhep.2011.08.025","article-title":"The interaction of hepatic\nlipid and glucose metabolism in liver diseases","volume":"56","author":"Bechmann","year":"2012","journal-title":"J. Hepatol."},{"issue":"10","key":"2026100208422004200_cit7","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1136\/gut.2010.222844","article-title":"Hepatic\nfatty acid translocase CD36 upregulation is associated with insulin\nresistance, hyperinsulinaemia and increased steatosis in non-alcoholic\nsteatohepatitis and chronic hepatitis C","volume":"60","author":"Miquilena-Colina","year":"2011","journal-title":"Gut"},{"issue":"2","key":"2026100208422004200_cit8","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1210\/en.2015-1866","article-title":"Hepatocyte-Specific\nDisruption of CD36 Attenuates Fatty Liver and Improves Insulin Sensitivity\nin HFD-Fed Mice","volume":"157","author":"Wilson","year":"2016","journal-title":"Endocrinology"},{"issue":"1","key":"2026100208422004200_cit9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1432-1033.1997.00001.x","article-title":"The mitochondrial carnitine palmitoyltransferase system.\nFrom concept to molecular analysis","volume":"244","author":"McGarry","year":"1997","journal-title":"Eur. J.\nBiochem."},{"issue":"2","key":"2026100208422004200_cit10","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqz046","article-title":"CPT1A-mediated Fat\nOxidation, Mechanisms, and Therapeutic Potential","volume":"161","author":"Schlaepfer","year":"2020","journal-title":"Endocrinology"},{"issue":"1","key":"2026100208422004200_cit11","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/j.2040-4603.2014.tb00548.x","article-title":"Energy metabolism\nin the liver","volume":"4","author":"Rui","year":"2014","journal-title":"Compr. Physiol."},{"key":"2026100208422004200_cit12","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2025.107706","article-title":"Dual inhibition of hepatic ACLY and ACSS2:\nA synergistic approach to combat NAFLD through lipogenesis reduction\nand mitochondrial enhancement","volume":"215","author":"Zhang","year":"2025","journal-title":"Pharmacol. Res."},{"issue":"2","key":"2026100208422004200_cit13","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/apt.15316","article-title":"Effect of semaglutide\non liver enzymes and markers of inflammation in subjects with type\n2 diabetes and\/or obesity","volume":"50","author":"Newsome","year":"2019","journal-title":"Aliment. Pharmacol.\nTher."},{"issue":"6","key":"2026100208422004200_cit14","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1016\/j.jhep.2023.07.033","article-title":"Incretins (GLP-1 receptor agonists and dual\/triple\nagonists) and the liver","volume":"79","author":"Newsome","year":"2023","journal-title":"J. Hepatol."},{"issue":"12","key":"2026100208422004200_cit15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI146353","article-title":"GIPR agonism mediates\nweight-independent insulin sensitization by tirzepatide in obese mice","volume":"131","author":"Samms","year":"2021","journal-title":"J. Clin. Invest."},{"issue":"1","key":"2026100208422004200_cit16","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/oby.2004.20","article-title":"Evaluation of a quantitative magnetic\nresonance method for mouse whole body composition analysis","volume":"12","author":"Tinsley","year":"2004","journal-title":"Obes. Res."},{"issue":"4","key":"2026100208422004200_cit17","doi-asserted-by":"publisher","first-page":"2343","DOI":"10.1021\/cr3003533","article-title":"Protein analysis by\nshotgun\/bottom-up proteomics","volume":"113","author":"Zhang","year":"2013","journal-title":"Chem. Rev."},{"issue":"6928","key":"2026100208422004200_cit18","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/nature01511","article-title":"Mass spectrometry-based\nproteomics","volume":"422","author":"Aebersold","year":"2003","journal-title":"Nature"},{"key":"2026100208422004200_cit19","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1002\/cpt.70131","article-title":"Advances in Incretin-Based\nTherapies for MAFLD: Mechanisms and Clinical Evidence","volume":"119","author":"Dong","year":"2025","journal-title":"Clin. Pharmacol. Ther."},{"issue":"8","key":"2026100208422004200_cit20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2025.101472","article-title":"Consistent improvements\nin liver histology across subgroups in a post hoc analysis of the\nSYNERGY-NASH trial with tirzepatide","volume":"7","author":"Hartman","year":"2025","journal-title":"JHEP Rep."},{"issue":"10","key":"2026100208422004200_cit21","doi-asserted-by":"publisher","first-page":"2147","DOI":"10.1002\/oby.20811","article-title":"Variations in body weight,\nfood intake and body composition after long-term high-fat diet feeding\nin C57BL\/6J mice","volume":"22","author":"Yang","year":"2014","journal-title":"Obesity"},{"key":"2026100208422004200_cit22","doi-asserted-by":"publisher","DOI":"10.1111\/obr.70039","article-title":"CD36 and Its Role in\nObesity","author":"Garcia","year":"2025","journal-title":"Obes. Rev."},{"issue":"12","key":"2026100208422004200_cit23","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.2337\/db07-0907","article-title":"Increased Hepatic CD36\nExpression Contributes to Dyslipidemia Associated With Diet-Induced\nObesity","volume":"56","author":"Koonen","year":"2007","journal-title":"Diabetes"},{"issue":"11","key":"2026100208422004200_cit24","doi-asserted-by":"publisher","first-page":"2988","DOI":"10.1194\/jlr.M037812","article-title":"CD36 deletion reduces\nVLDL secretion, modulates liver prostaglandins, and exacerbates hepatic\nsteatosis in ob\/ob mice","volume":"54","author":"Nassir","year":"2013","journal-title":"J. Lipid Res."},{"issue":"4","key":"2026100208422004200_cit25","doi-asserted-by":"publisher","first-page":"281","DOI":"10.18632\/aging.100652","article-title":"Increased hepatic CD36\nexpression with age is associated with enhanced susceptibility to\nnonalcoholic fatty liver disease","volume":"6","author":"Sheedfar","year":"2014","journal-title":"Aging"},{"key":"2026100208422004200_cit26","doi-asserted-by":"publisher","DOI":"10.34133\/research.1001","article-title":"EVA1A Regulates Hepatic Lipid Homeostasis by\nModulating CD36 Expression and Its Palmitoylation","volume":"8","author":"Yang","year":"2025","journal-title":"Research"},{"key":"2026100208422004200_cit27","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2024.155914","article-title":"O-GlcNAcylation promotes\nthe progression of nonalcoholic fatty liver disease by upregulating\nthe expression and function of CD36","volume":"156","author":"Zhu","year":"2024","journal-title":"Metabolism"},{"issue":"2","key":"2026100208422004200_cit28","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.bbagrm.2018.12.009","article-title":"Epigenetic regulation\nof carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet","volume":"1862","author":"Moody","year":"2019","journal-title":"Biochim. Biophys. Acta, Gene Regul. Mech."},{"issue":"8","key":"2026100208422004200_cit29","doi-asserted-by":"publisher","DOI":"10.1038\/nutd.2011.11","article-title":"Long-term effects of\nhigh-fat or high-carbohydrate diets on glucose tolerance in mice with\nheterozygous carnitine palmitoyltransferase-1a deficiency","volume":"1","author":"Nyman","year":"2011","journal-title":"Nutr. Diabetes"},{"issue":"4","key":"2026100208422004200_cit30","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.cmet.2019.09.003","article-title":"Dietary Sugars Alter\nHepatic Fatty Acid Oxidation via Transcriptional and Post-translational\nModifications of Mitochondrial Proteins","volume":"30","author":"Softic","year":"2019","journal-title":"Cell\nMetab."},{"key":"2026100208422004200_cit31","doi-asserted-by":"publisher","DOI":"10.1038\/srep10222","article-title":"Chronic inflammation\naggravates metabolic disorders of hepatic fatty acids in high-fat\ndiet-induced obese mice","volume":"5","author":"Zhao","year":"2015","journal-title":"Sci. Rep."},{"issue":"4","key":"2026100208422004200_cit32","doi-asserted-by":"publisher","DOI":"10.3390\/cimb47040285","article-title":"The Expanding\nRole of GLP-1 Receptor Agonists: Advancing Clinical Outcomes in Metabolic\nand Mental Health","volume":"47","author":"Al Qassab","year":"2025","journal-title":"Curr. Issues Mol. Biol."},{"issue":"6","key":"2026100208422004200_cit33","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2025.101761","article-title":"Tirzepatide, a dual GIP\/GLP-1 receptor agonist,\nalleviates metabolic dysfunction-associated steatotic liver disease\nby reducing the expression of CD36 and OBP2A","volume":"12","author":"Li","year":"2025","journal-title":"Genes Dis."},{"key":"2026100208422004200_cit34","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1046130","article-title":"Semaglutide ameliorates\nmetabolism and hepatic outcomes in an NAFLD mouse model","volume":"13","author":"Niu","year":"2022","journal-title":"Front. Endocrinol."},{"issue":"4","key":"2026100208422004200_cit35","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1007\/s42000-024-00541-2","article-title":"Animal studies on glucagon-like\npeptide-1 receptor agonists and related polyagonists in nonalcoholic\nfatty liver disease","volume":"23","author":"Tsiampali","year":"2024","journal-title":"Hormones"},{"issue":"5","key":"2026100208422004200_cit36","doi-asserted-by":"publisher","first-page":"2844","DOI":"10.1111\/dom.16294","article-title":"Tirzepatide reduces body weight by increasing\nfat utilization via the central nervous system-adipose tissue axis\nin male mice","volume":"27","author":"Zhang","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"2026100208422004200_cit37","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2025.1659233","article-title":"Distinct effects of\nsemaglutide and tirzepatide on metabolic and inflammatory gene expression\nin brown adipose tissue of mice fed a high-fat, high-fructose diet","volume":"12","author":"Ma","year":"2025","journal-title":"Front. Nutr."},{"issue":"7","key":"2026100208422004200_cit38","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.89020","article-title":"Effects\nof Tirzepatide on Skeletal Muscle Mass in Adults: A Systematic Review","volume":"17","author":"Hidalgo Ramos","year":"2025","journal-title":"Cureus"},{"issue":"1","key":"2026100208422004200_cit39","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1056\/NEJMoa2416394","article-title":"Tirzepatide as Compared\nwith Semaglutide for the Treatment of Obesity","volume":"393","author":"Aronne","year":"2025","journal-title":"N. Engl. J. Med."},{"issue":"17","key":"2026100208422004200_cit40","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.140532","article-title":"Tirzepatide is an imbalanced\nand biased dual GIP and GLP-1 receptor agonist","volume":"5","author":"Willard","year":"2020","journal-title":"JCI Insight"},{"key":"2026100208422004200_cit41","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00649","article-title":"Future Perspectives\non GLP-1 Receptor Agonists and GLP-1\/glucagon Receptor Co-agonists\nin the Treatment of NAFLD","volume":"9","author":"Seghieri","year":"2018","journal-title":"Front. Endocrinol."},{"issue":"1","key":"2026100208422004200_cit42","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1056\/NEJMoa2416394","article-title":"Tirzepatide\nas Compared\nwith Semaglutide for the Treatment of Obesity","volume":"393","author":"Aronne","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"2026100208422004200_cit43","unstructured":"EliLillyandCompany.\n          . Lilly\u2019s Tirzepatide was Superior to Placebo for MASH Resolution, News Release. Feb 6, 2024. https:\/\/investor.lilly.com\/news-releases\/news-release-details\/lillys-tirzepatide-was-superior-placebo-mash-resolution-and-more."},{"key":"2026100208422004200_cit44","unstructured":"FDA.\n          . FDA Approves\nTreatment for Serious Liver Disease Known as \u201cMASH\u201d, Aug 15, 2025. https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fda-approves-treatment-serious-liver-disease-known-mash."},{"issue":"1","key":"2026100208422004200_cit45","doi-asserted-by":"publisher","DOI":"10.1002\/pdi3.9","article-title":"The association\nof soluble cluster\nof differentiation 36 with metabolic diseases: A potential biomarker\nand therapeutic target","volume":"1","author":"Li","year":"2023","journal-title":"Pediatr. Discovery"},{"key":"2026100208422004200_cit46","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.1039614","article-title":"Circulating soluble\nCD36 as a novel biomarker for progression and prognosis of HBV-related\nliver diseases","volume":"13","author":"Cai","year":"2022","journal-title":"Front. Microbiol."}],"container-title":["Journal of Proteome Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jproteome.6c00404","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/10\/5418\/68493597\/acs.jproteome.6c00404.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/10\/5418\/68493597\/acs.jproteome.6c00404.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:10:42Z","timestamp":1790946642000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jprobs\/article\/25\/10\/5418\/5429002\/Semaglutide-and-Tirzepatide-Suppress-Hepatic-Fatty"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,13]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,13]]},"published-print":{"date-parts":[[2026,10,2]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jproteome.6c00404","relation":{},"ISSN":["1535-3893","1535-3907"],"issn-type":[{"value":"1535-3893","type":"print"},{"value":"1535-3907","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,13]]}}}