Increased FGF21 in brown adipose tissue of tyrosine hydroxylase heterozygous mice: implications for cold adaptation.

Tyrosine hydroxylase (TH) catalyzes the first step in catecholamines synthesis. We studied the impact of reduced TH in brown adipose tissue (BAT) activation. In adult heterozygous (Th+/- ) mice, dopamine and noradrenaline (NA) content in BAT decreased after cold exposure. This reduced catecholaminergic response did not impair cold adaptation, because these mice induced uncoupling protein 1 (UCP-1) and maintained BAT temperature to a similar extent than controls (Th+/+ ). Possible compensatory mechanisms implicated were studied. Prdm16 and Fgf21 expression, key genes in BAT activation, were elevated in Th+/- mice at thermoneutrality from day 18.5 of embryonic life. Likewise, plasma FGF21 and liver Fgf21 mRNA were increased. Analysis of endoplasmic reticulum (ER) stress, a process that triggers elevations in FGF21, showed higher phospho-IRE1, phospho-JNK, and CHOP in BAT of Th+/- mice at thermoneutrality. Also, increased lipolysis in BAT of cold-exposure Th+/- mice was demonstrated by increased phosphorylation of hormone-sensitive lipase (HSL), as well as diacylglycerol (DAG) and FFA content. Overall, these results indicate that the mild effects of Th haploinsufficiency on BAT function are likely due to compensatory mechanisms involving elevations in Fgf21 and Prdm16 and through adaptive changes in the lipid profile.