Search

Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. WhileTH and FGF21 display overlapping actionswhen administered, including reductions in serum lipids, according to the current models these hormones act independently in vivo. Inthisstudy, we examined mechanismsof regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRß-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRß. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRß1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WTand Fgf21 -knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in the Fgf21-/-K background and we observe no effect of the Fgf27-knockout background on serum triglycerides and glucose. Our findings indicate that T3 regulates the genes involved in classical hepatic metabolic responses independently of FGF21. [ABSTRACT FROM AUTHOR]