{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:27:06Z","timestamp":1781584026284,"version":"3.54.5"},"reference-count":57,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T00:00:00Z","timestamp":1701993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ghana Education Trust Fund"},{"name":"Medical Research Council, UK"},{"name":"Chancellor\u2019s scholarship for international students, University of Warwick UK"},{"name":"QR fund, Nottingham Trent University"},{"name":"Open Access Fund from the Nottingham Trent University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Prolonged metformin treatment decreases vitamin B12 (B12) levels, whereas low B12 is associated with dyslipidaemia. Some studies have reported that metformin has no effect on intrahepatic triglyceride (TG) levels. Although AMP-activated protein kinase (AMPK) activation via adiponectin lowers hepatic TG content, its role in B12 deficiency and metformin has not been explored. We investigated whether low B12 impairs the beneficial effect of metformin on hepatic lipid metabolism via the AMPK-adiponectin axis. Methods: HepG2 was cultured using custom-made B12-deficient Eagle\u2019s Minimal Essential Medium (EMEM) in different B12-medium concentrations, followed by a 24-h metformin\/adiponectin treatment. Gene and protein expressions and total intracellular TG were measured, and radiochemical analysis of TG synthesis and seahorse mitochondria stress assay were undertaken. Results: With low B12, total intracellular TG and synthesized radiolabelled TG were increased. Regulators of lipogenesis, cholesterol and genes regulating fatty acids (FAs; TG; and cholesterol biosynthesis were increased. FA oxidation (FAO) and mitochondrial function were decreased, with decreased pAMPK\u03b1 and pACC levels. Following metformin treatment in hepatocytes with low B12, the gene and protein expression of the above targets were not alleviated. However, in the presence of adiponectin, intrahepatic lipid levels with low B12 decreased via upregulated pAMPK\u03b1 and pACC levels. Again, combined adiponectin and metformin treatment ameliorated the low B12 effect and resulted in increased pAMPK\u03b1 and pACC, with a subsequent reduction in lipogenesis, increased FAO and mitochondrion function. Conclusions: Adiponectin co-administration with metformin induced a higher intrahepatic lipid-lowering effect. Overall, we emphasize the potential therapeutic implications for hepatic AMPK activation via adiponectin for a clinical condition associated with B12 deficiency and metformin treatment.<\/jats:p>","DOI":"10.3390\/nu15245046","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T08:47:26Z","timestamp":1702025246000},"page":"5046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Metformin Inefficiency to Lower Lipids in Vitamin B12 Deficient HepG2 Cells Is Alleviated via Adiponectin-AMPK Axis"],"prefix":"10.3390","volume":"15","author":[{"given":"Joseph","family":"Boachie","sequence":"first","affiliation":[{"name":"Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Zammit","sequence":"additional","affiliation":[{"name":"Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9566-2626","authenticated-orcid":false,"given":"Ponnusamy","family":"Saravanan","sequence":"additional","affiliation":[{"name":"Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK"},{"name":"Diabetes Centre, George Eliot Hospital NHS Trust, College Street, Nuneaton CV10 7DJ, UK"},{"name":"Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7HL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2974-3388","authenticated-orcid":false,"given":"Antonysunil","family":"Adaikalakoteswari","sequence":"additional","affiliation":[{"name":"Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK"},{"name":"Department of Bioscience, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/s41366-021-01044-5","article-title":"Geography and equity: Expanding access to obesity medicine diplomate care","volume":"46","author":"Townsend","year":"2022","journal-title":"Int. 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