The T3 Receptor β1 Isoform Regulates UCP1 and D2 Deiodinase in Rat Brown Adipocytes

Abstract

Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T 3 . In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T 3 required for UCP1 expression. T 3 actions are mediated by thyroid hormone nuclear T 3 receptors (TR), TR␣ and TR␤. Studies in mice suggest that TR␤ is required for UCP1 induction, whereas TR␣ regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T 3 vs. specific TR␤1 and TR␣1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T 3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nM). GC-1 at low doses (0.2-10 nM) was less potent than T 3 , increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T 3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T 3 , GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T 3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The ␣1-and ␣2-adrenergic D2 responses increased using high T 3 doses. In summary, T 3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TR␤1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T 3 on TR␤1. (Endocrinology 151: 5074 -5083, 2010)

Effects of postnatal bromocriptine injection on thyroid function and prolactinemia of rats at adulthood

“…Thus, one limitation of the current study is that we only evaluated total TSH content in the pituitary. The increase found in BAT UCP-1 mRNA expression may be due to the high plasma T3, since this hormone increased UCP1 (Fain et al, 1997;Martinez de Mena et al, 2010). This result reinforces the notion that a hypermetabolic state is present in late-treated BRO animals.…”

“…The decrease in BAT mRNA UCP-1 expression may be due to the lower level of T3. In fact, it is known that T3, via TRβ1, increases UCP-1 expression (Martinez de Mena et al, 2010). The importance of thyroid hormones in this process is demonstrated by impaired thermogenesis in hypothyroid animals (Christoffolete et al, 2004;Silva, 2011), with decrease in the basal metabolic rate.…”

Differences in the Response of UCP1 mRNA to Hormonal Stimulation Between Rat and Mouse Primary Cultures of Brown Adipocytes

“…It is only when T3 is present that UCP-1 is fully induced in rat adipocytes by adrenergic stimulation. This phenomenon is observed at any time during the differentiation process [28] and is consistent with the enhancement of adrenergic or cAMP induction of UCP-1 expression achieved by T3 in rats [6] and in floating or cultured rat brown adipocytes [47,48].…”

Thyroid hormone status affects expression of daily torpor and gene transcription in Djungarian hamsters (Phodopus sungorus)

“…T3 could also have posttranscriptional regulatory effects at the protein level. In rat cell cultures high doses of T3 reduced DIO2 activity, but not dio2 transcription (Martinez de Mena et al, 2010). Surprisingly dio3 was nearly undetectable in all three tissues, and intracellular deactivation of T3 via DIO3 seems to play no role.…”