Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice.

UNLABELLED: 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/ß agonist, Am80, also enhanced hepatic LEPR expression and STAT3 phosphorylation and ameliorated insulin resistance in KK-A(y) mice. CONCLUSION: We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhanced insulin sensitivity in two mouse models of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance.

Value of the serum thyroglobulin level for diagnosing neck compression in postmortem cases.

To investigate the relationship between blood thyroglobulin (Tg) levels and neck compression, the Tg levels of right cardiac blood were measured using a chemiluminescence immunoassay in 256 autopsy cases. There were 11 cases in which neck compression was confirmed based on autopsy findings and other information, in which the mean Tg level was 3155 ng/mL (range: 179-16,500 ng/mL). In the remaining cases, the mean Tg level was 4160 ng/mL (range: 0.3-139,000 ng/mL). There was no significant difference between the mean Tg levels of the two groups. In a comparison between the case groups with Tg levels of ≥200 ng/mL and <200 ng/mL, it was found that the frequency of neck compression was significantly higher (P < 0.05) in the ≥200 ng/mL group. The frequency of high Tg levels (≥200 ng/mL) was increased among the cases in which death was caused by neck compression or asphyxia. In a comparison of the median Tg values of right heart blood, left heart blood, whole blood, and femoral venous blood, the median Tg values of whole blood and right heart blood were shown to be about 10 times higher than those of left heart blood and peripheral blood. It is said that high postmortem blood Tg levels are caused by mechanical compression of the thyroid gland. However, high Tg levels were detected in the half of the cases without neck compression. Therefore, neck compression should be diagnosed carefully based on autopsy findings and other information.