GLP-1 receptor agonist, liraglutide, ameliorates hepatosteatosis induced by anti-CD3 antibody in female mice

• Published in: Journal of diabetes and its complications 2017-09, Vol.31 (9), p.1370-1375
• Main Authors: Itoh, Arata, Irie, Junichiro, Tagawa, Hirotsune, Kusumoto, Yukie, Kato, Mari, Kobayashi, Nana, Tanaka, Kumiko, Kikuchi, Rieko, Fujita, Masataka, Nakajima, Yuya, Wu, Yuehong, Yamada, Satoru, Kawai, Toshihide, Ridgway, William M, Itoh, Hiroshi
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - adverse effects; Antidiabetics; CD3 Complex - immunology; CD4-positive T lymphocyte; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Endocrinology & Metabolism; Fatty Liver - drug therapy; Fatty Liver - etiology; Female; GLP-1 receptor agonists; Glucagon-like peptide-1; Glucagon-Like Peptide-1 Receptor - agonists; Glucose; Glucose intolerance; Hepatosteatosis; Insulin resistance; Lipids; Liraglutide - therapeutic use; Lymphocyte Activation - drug effects; Lymphocyte Activation - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; Obesity; Rodents
• ISSN: 1056-8727; 1873-460X
• DOI: 10.1016/j.jdiacomp.2017.05.013

Abstract Aims Hepatosteatosis is mainly induced by obesity and metabolic disorders, but various medications also induce hepatosteatosis. The administration of anti-CD3 antibody was shown to induce hepatosteatosis, but changes in lipid and glucose metabolism remain unclear. We investigated the mechanism of hepatosteatosis induced by anti-CD3 antibody and the effects of glucagon-like peptide-1 (GLP-1) receptor agonist that was recently shown to affect immune function in metabolic disorders. Methods Anti-CD3 antibody was administered to female BALB/c and C.B-17- scid mice with or without reconstitution by naïve CD4-positive splenocytes. Hepatic lipid content, serum lipid profile and glucose tolerance were evaluated. Splenic CD4-positive T lymphocytes were stimulated with the GLP-1R agonist, liraglutide, and cytokine production was measured. The effect of liraglutide on metabolic parameters in vivo was investigated in a T-cell activation-induced hepatosteatosis model. Results The administration of anti-CD3 antibody induced hepatosteatosis, hyperlipidemia, and glucose intolerance. C.B-17- scid mice reconstituted with CD4-positive T lymphocytes developed hepatosteatosis induced by anti-CD3 antibody. Liraglutide suppressed CD4-positive T lymphocyte cytokine expression in vitro and in vivo , and improved hepatosteatosis, glucose tolerance, and insulin sensitivity. Conclusions Liraglutide suppressed the activation of CD4-positive T lymphocytes, and improved hepatosteatosis and metabolic disorders induced by T-cell activation in female mice.