PMID- 37832793 OWN - NLM STAT- MEDLINE DCOM- 20231106 LR - 20231106 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 217 DP - 2023 Nov TI - Cotadutide improves brown adipose tissue thermogenesis in obese mice. PG - 115852 LID - S0006-2952(23)00443-4 [pii] LID - 10.1016/j.bcp.2023.115852 [doi] AB - We studied the effect of cotadutide, a dual agonist glucagon-like peptide 1 (GLP1)/Glucagon, on interscapular brown adipose tissue (iBAT) remodeling and thermogenesis of obese mice. Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Then, animals were redivided, adding cotadutide treatment: C, CC, HF, and HFC for four additional weeks. The multilocular brown adipocyte structure showed fat conversion (whitening), hypertrophy, and structural disarray in the HF group, which was reverted in cotadutide-treated animals. Cotadutide enhances the body temperature, thermogenesis, and sympathetic innervation (peroxisome proliferator-activated receptor-alpha, beta3 adrenergic receptor, interleukin 6, and uncoupled protein 1), reduces pro-inflammatory markers (disintegrin and metallopeptidase domain, morphogenetic protein 8a, and neuregulin 4), and improves angiogenesis (vascular endothelial growth factor A, and perlecan). In addition, cotadutide enhances lipolysis (perilipin and cell death-inducing DNA fragmentation factor alpha), mitochondrial biogenesis (nuclear respiratory factor 1, transcription factor A mitochondrial, mitochondrial dynamin-like GTPase, and peroxisome proliferator-activated receptor gamma coactivator 1alpha), and mitochondrial fusion/fission (dynamin-related protein 1, mitochondrial fission protein 1, and parkin RBR E3 ubiquitin protein ligase). Cotadutide reduces endoplasmic reticulum stress (activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA-damage inducible), and extracellular matrix markers (lysyl oxidase, collagen type I alpha1, collagen type VI alpha3, matrix metallopeptidases 2 and 9, and hyaluronan synthases 1 and 2). In conclusion, the experimental evidence is compelling in demonstrating cotadutide's thermogenic effect on obese mice's iBAT, contributing to unraveling its action mechanisms and the possible translational benefits. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Spezani, Renata AU - Spezani R AD - Pharmacology Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Marcondes-de-Castro, Ilitch A AU - Marcondes-de-Castro IA AD - Pharmacology Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Marinho, Thatiany S AU - Marinho TS AD - Metabolism Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Reis-Barbosa, Pedro H AU - Reis-Barbosa PH AD - Metabolism Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Cardoso, Luiz E M AU - Cardoso LEM AD - Extracellular Matrix Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Aguila, Marcia B AU - Aguila MB AD - Nutrition Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: mbaguila@uerj.br. FAU - Mandarim-de-Lacerda, Carlos A AU - Mandarim-de-Lacerda CA AD - Pharmacology Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil; Nutrition Section, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: mandarim@uerj.br. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231011 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - QL6A9B13HW (cotadutide) RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 3.6.5.5 (Dynamins) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) SB - IM MH - Mice MH - Animals MH - Male MH - *Adipose Tissue, Brown/metabolism MH - Mice, Obese MH - *Vascular Endothelial Growth Factor A/metabolism MH - Mice, Inbred C57BL MH - Obesity/drug therapy/metabolism MH - Adipocytes, Brown MH - Diet, High-Fat/adverse effects MH - Thermogenesis MH - Dynamins/metabolism MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism OTO - NOTNLM OT - Brown adipose tissue OT - Mitochondria OT - Molecular biology OT - Obesity OT - Thermogenesis COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/10/14 10:43 MHDA- 2023/11/06 06:42 CRDT- 2023/10/13 19:26 PHST- 2023/08/28 00:00 [received] PHST- 2023/10/09 00:00 [revised] PHST- 2023/10/10 00:00 [accepted] PHST- 2023/11/06 06:42 [medline] PHST- 2023/10/14 10:43 [pubmed] PHST- 2023/10/13 19:26 [entrez] AID - S0006-2952(23)00443-4 [pii] AID - 10.1016/j.bcp.2023.115852 [doi] PST - ppublish SO - Biochem Pharmacol. 2023 Nov;217:115852. doi: 10.1016/j.bcp.2023.115852. Epub 2023 Oct 11.