Transgenic mice expressing dominant-negative
retinoic acid receptor (RAR) α specifically in the liver exhibit
steatohepatitis, which leads to the development of liver
tumors. Although the cause of
steatohepatitis in these mice is unknown, diminished hepatic expression of
insulin-like growth factor-1 suggests that
insulin resistance may be involved. In the present study, we examined the effects of
retinoids on
insulin resistance in mice to gain further insight into the mechanisms responsible for this condition. Dietary administration of
all-trans-retinoic acid (ATRA) significantly improved
insulin sensitivity in C57BL/6J mice, which served as a model for high-fat, high-
fructose diet-induced
nonalcoholic fatty liver disease (
NAFLD). The same effect was observed in genetically
insulin-resistant KK-A(y) mice, occurring in concert with activation of
leptin-signaling pathway
proteins, including
signal transducer and activator of transcription 3 (STAT3) and
Janus kinase 2. However, such an effect was not observed in
leptin-deficient ob/ob mice. ATRA treatment significantly up-regulated
leptin receptor (LEPR) expression in the livers of
NAFLD mice. In agreement with these observations, in vitro experiments showed that in the presence of
leptin, ATRA directly induced LEPR gene expression through RARα, resulting in enhancement of STAT3 and
insulin-induced
insulin receptor substrate 1 phosphorylation. A selective RARα/β agonist,
Am80, also enhanced hepatic LEPR expression and STAT3 phosphorylation and ameliorated
insulin resistance in KK-A(y) mice.
CONCLUSION: