title: Fibroblast growth factor 21 and thyroid hormone show mutual regulatory dependency but have independent actions in vivo.
abstract: Thyroid hormone (TH) regulates fibroblast growth factor 21 (FGF21) levels in the liver and in the adipose tissue. In contrast, peripheral FGF21 administration leads to decreased circulating levels of TH. These data suggest that FGF21 and TH could interact to regulate metabolism. In the present study, we confirmed that TH regulates adipose and hepatic FGF21 expression and serum levels in mice. We next investigated the influence of TH administration on key serum metabolites, gene expression in the liver and brown adipose tissue, and energy expenditure in FGF21 knockout mice. Surprisingly, we did not observe any significant differences in the effects of TH on FGF21 knockout mice compared with those in wild-type animals, indicating that TH acts independently of FGF21 for the specific outcomes studied. Furthermore, exogenous FGF21 administration to hypothyroid mice led to similar changes in serum and liver lipid metabolites and gene expression in both hypothyroid and euthyroid mice. Thus, it appears that FGF21 and TH have similar actions to decrease serum and liver lipids despite having some divergent regulatory effects. Whereas TH leads to up-regulation in the liver and down-regulation in brown adipose tissue of genes involved in the lipid synthesis pathway (eg, fatty acid synthase (FASN) and SPOT14), FGF21 leads to the opposite changes in expression of these genes. In conclusion, TH and FGF21 act independently on the outcomes studied, despite their ability to regulate each other's circulating levels. Thus, TH and FGF21 may modulate the availability of each other in critical metabolic states.
authors.affiliation: Division of Endocrinology (E.M.D., f.M.F., I.A., E.C.F., J.S.F., A.N.H., E.M.-F.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; and Lilly Research Laboratories (A.K.), Indianapolis, Indiana 46225.
authors.forename: Eleni M
authors.initials: EM
authors.lastname: Domouzoglou
authors.forename: Ffolliott Martin
authors.initials: FM
authors.lastname: Fisher
authors.forename: Inna
authors.initials: I
authors.lastname: Astapova
authors.forename: Elliott C
authors.initials: EC
authors.lastname: Fox
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005346:Fibroblast Growth Factors / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D020249:Hormone Replacement Therapy / Q000009:adverse effects; D006949:Hyperlipidemias / Q000209:etiology / Q000517:prevention & control; D006980:Hyperthyroidism / Q000097:blood / Q000139:chemically induced / Q000378:metabolism; D007037:Hypothyroidism / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D050356:Lipid Metabolism / Q000187:drug effects*; D008082:Lipotropic Agents / Q000009:adverse effects / Q000097:blood / Q000506:poisoning / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D013974:Thyroxine / Q000009:adverse effects / Q000097:blood / Q000506:poisoning / Q000627:therapeutic use*; D014284:Triiodothyronine / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*
chemical_list: D008082:Lipotropic Agents; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D014284:Triiodothyronine; D005346:Fibroblast Growth Factors; D013974:Thyroxine