PMID- 33677937 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20220314 IS - 2093-5978 (Electronic) IS - 2093-596X (Print) IS - 2093-596X (Linking) VI - 36 IP - 1 DP - 2021 Feb TI - Effects of Glucagon-Like Peptide-1 Analogue and Fibroblast Growth Factor 21 Combination on the Atherosclerosis-Related Process in a Type 2 Diabetes Mouse Model. PG - 157-170 LID - 10.3803/EnM.2020.781 [doi] AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) analogues regulate glucose homeostasis and have anti-inflammatory properties, but cause gastrointestinal side effects. The fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism that has poor pharmacokinetic properties, including a short half-life. To overcome these limitations, we investigated the effect of a low-dose combination of a GLP-1 analogue and FGF21 on atherosclerosis-related molecular pathways. METHODS: C57BL/6J mice were fed a high-fat diet for 30 weeks followed by an atherogenic diet for 10 weeks and were divided into four groups: control (saline), liraglutide (0.3 mg/kg/day), FGF21 (5 mg/kg/day), and low-dose combination treatment with liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day) (n=6/group) for 6 weeks. The effects of each treatment on various atherogenesisrelated pathways were assessed. RESULTS: Liraglutide, FGF21, and their low-dose combination significantly reduced atheromatous plaque in aorta, decreased weight, glucose, and leptin levels, and increased adiponectin levels. The combination treatment upregulated the hepatic uncoupling protein-1 (UCP1) and Akt1 mRNAs compared with controls. Matric mentalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were downregulated and phosphorylated Akt (p-Akt) and phosphorylated extracellular signal-regulated kinase (p-ERK) were upregulated in liver of the liraglutide-alone and combination-treatment groups. The combination therapy also significantly decreased the proliferation of vascular smooth muscle cells. Caspase-3 was increased, whereas MMP-9, ICAM-1, p-Akt, and p-ERK1/2 were downregulated in the liraglutide-alone and combination-treatment groups. CONCLUSION: Administration of a low-dose GLP-1 analogue and FGF21 combination exerts beneficial effects on critical pathways related to atherosclerosis, suggesting the synergism of the two compounds. FAU - Kim, Jin Hee AU - Kim JH AD - Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. FAU - Lee, Gha Young AU - Lee GY AD - Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. FAU - Maeng, Hyo Jin AU - Maeng HJ AD - Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. FAU - Kim, Hoyoun AU - Kim H AD - Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. FAU - Bae, Jae Hyun AU - Bae JH AD - Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea. FAU - Kim, Kyoung Min AU - Kim KM AD - Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. FAU - Lim, Soo AU - Lim S AD - Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210224 PL - Korea (South) TA - Endocrinol Metab (Seoul) JT - Endocrinology and metabolism (Seoul, Korea) JID - 101554139 RN - 0 (fibroblast growth factor 21) RN - 62031-54-3 (Fibroblast Growth Factors) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM CIN - Endocrinol Metab (Seoul). 2021 Feb;36(1):57-59. PMID: 33677927 MH - Animals MH - *Atherosclerosis/drug therapy MH - *Diabetes Mellitus, Type 2/drug therapy MH - Fibroblast Growth Factors MH - Glucagon-Like Peptide 1/therapeutic use MH - Mice MH - Mice, Inbred C57BL PMC - PMC7937856 OTO - NOTNLM OT - Atherosclerosis OT - Diabetes mellitus OT - Fibroblast growth factor 21 OT - Glucagon-like peptide 1 OT - Inflammation COIS- CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. EDAT- 2021/03/09 06:00 MHDA- 2022/03/15 06:00 PMCR- 2021/02/01 CRDT- 2021/03/08 00:33 PHST- 2020/07/22 00:00 [received] PHST- 2020/12/04 00:00 [accepted] PHST- 2021/03/08 00:33 [entrez] PHST- 2021/03/09 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/02/01 00:00 [pmc-release] AID - EnM.2020.781 [pii] AID - enm-2020-781 [pii] AID - 10.3803/EnM.2020.781 [doi] PST - ppublish SO - Endocrinol Metab (Seoul). 2021 Feb;36(1):157-170. doi: 10.3803/EnM.2020.781. Epub 2021 Feb 24.