222-LB: Diabetes Induces Liver Inflammation and FGF21 through C-Jun NH2-Terminal Kinase Pathways

Abstract

Fibroblast growth factor 21 (FGF-21) is a hormone that regulates important metabolic pathways. Serum fibroblast FGF-21 levels were significantly higher in obesity and type 2 diabetes mellitus (T2DM). Previously, we have found that the JNK pathway played a critical role in diabetes-induced Kupffer cell activation, and pJNK1 inhibition decreases Kupffer cell activation induced by diabetes. We aim to study the involvement c-Jun NH2-terminal kinase pathways in the regulatory mechanisms of liver inflammation and FGF-21 in diabetes. Type 1 diabetic Akita mice (C57BL/6J-Ins2Akita) and type 2 diabetic Leprdb/db mice (C57BL/6J- Leprdb/db) were used. Leprdb/db-JNK1-/- and Ins2Akita-JNK1-/- mice were produced and used to study the role of pJNK in the regulatory mechanisms of diabetes on liver inflammation and FGF-21. Diabetic mice demonstrated increased ICAM, iNOS, interleukin 1 beta (IL-1β), FGF-21, and FMO3 expression of liver; and tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells; and plasma FGF-21 levels. Ins2Akita-JNK1-/- and Leprdb/db-JNK1-/- mice demonstrated decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver; and ICAM, iNOS, and FMO3 expression in aorta, tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells, plasma IL-6 and TNF-α levels; dipeptidyl peptidase (DPP-4) activity. JNK inhibitor, SP600125, injection into adipose tissue of Leprdb/db mice significantly decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver and serum FGF-21 levels. Altogether, our data suggest that diabetes induces liver inflammation, FGF-21, and insulin resistance through c-Jun NH2-terminal kinase. Disclosure L. Chen: None. Funding National Science Council (MOST 107-2314-B-010-043-MY3)