While it is known that patients with nonalcoholic fatty liver disease exhibit enhanced insulin secretion, the factor(s) that contribute to this effect are not fully understood especially in nondiabetic subjects. Our aim was to examine crosstalk between a steatotic liver induced by a diet that is deficient in methionine choline (MCD) and pancreatic islets in the absence of diabetes/insulin resistance. Nine-week old male C57BL/6J mice were fed normal chow (CTL) or the MCD diet for 3 weeks followed by evaluation of glucose homeostasis, liver and pancreas pathology and hepatic gene expression by RNA-sequencing. Three weeks of MCD diet caused simple hepatic steatosis with hepatic triglyceride content 2-fold higher in MCD compared to CTL (n=5; p<0.05). Hepatic FGF-21 mRNA, protein and circulating FGF-21 levels were all significantly increased in MCD (129-fold, 8-fold, 5-fold respectively; n=5; p<0.05). Interestingly, while β-cell mass was not significantly altered between groups, insulin secretion as evaluated by ex-vivo GSIS in freshly isolated islets was significantly increased in MCD (5-fold; p<0.05, n=10). Examination of liver samples from patients with or without steatosis mimicked hepatic MCD data in the mouse model. Thus a significant increase in both mRNA and protein FGF-21 were evident in the steatotic group (3-fold, 5-fold respectively; n=6, p<0.05). Furthermore, 3 days treatment of nondiabetic human islets with recombinant FGF-21 protein led to a significant increase in GSIS compared to control (1.5-fold; p<0.05, n=4). FGF-21 treatment of EndoC-βH1 cells revealed significant activation of AKT and ERK1/2 signaling that likely promoted the enhanced insulin secretion. Taken together, liver steatosis significantly increases circulating FGF-21 to promote enhanced insulin secretion via improved signaling in nondiabetic beta cells.
T. Kimura: None. D.F. De Jesus: None. K. Fukuda: None. S. Kahraman: None. K. Shibue: None. K. Orime: None. R. Kulkarni: None.
National Institutes of Health (R01DK067536, R01DK103215)