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

Other TitlesIncreased FGF21 expression in BAT of TH heterozygous mice
AuthorsVázquez Pérez, Patricia ; Hernández-Sánchez, Catalina ; Escalona-Garrido, Carmen; Pereira, Laura; Contreras, Cristina; López, Miguel; Balsinde, Jesús ; Pablo, Flora de ; Valverde, Ángela M.
KeywordsAdipose tissue
Brown adipose tissue
Fatty acids
Metabolic disease
Issue Date23-Oct-2018
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Lipid Research 59(12): 2308-2320 (2018)
AbstractTyrosine 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, since these mice induced uncoupling protein-1 (UCP1) 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 coldexposure Th+/- mice was demonstrated by increased phosphorylation of hormone-sensitive lipase (HSL), as well as diacylglycerol (DAG) and free fatty acids (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.
Publisher version (URL)https://doi.org/10.1194/jlr.M085209
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