Metabolomic analysis shows differential hepatic effects of T(2) and T(3) in rats after short-term feeding with high fat diet

Nonalcoholic fatty liver disease (NAFLD) is a major health problem worldwide, and is often associated with lipotoxic injury, defective mitochondrial function, and insulin resistance. Thyroid hormones (THs) are important regulators of hepatic lipid metabolism. Among the THs, diiodothyronine (T(2)) and triiodothyronine (T(3)) have shown promising results in lowering hepatic fat content in various models of NAFLD. In this study, we used a targeted metabolomics approach to investigate the differential effects of T(2) and T(3) on the early metabolic adaptation in the livers of rats fed high fat diet (HFD), a period when hepatosteatosis is reversible. Our results showed that both T(2) and T(3) strongly induced autophagy and intra-hepatic acylcarnitine flux but prevented the generation of sphingolipid/ceramides in animals fed HFD. Interestingly, although both T(2) and T(3) decreased hepatic fat content, only T(2) was able to rescue the impairment in AKT and MAPK/ERK pathways caused by HFD. In summary, we have identified and characterized the effects of T(2) and T(3) on hepatic metabolism during short-term exposure to HFD. These findings illuminate the common and divergent metabolic pathways by T(2) and T(3) that also may be important in the prevention and treatment of NAFLD.