Figure 4. Pathways regulating D2 expression and thyroid hormone signaling.

In D2-expressing cells, such as brown adipocytes, stimulation of D2 expression increases local T3 production, resulting in increased saturation of T3 receptors. This increase can be mediated by norepinephrine (NE) stimulation of β-adrenergic receptors (βARs), such as occurs during cold stimulation, or by bile acid–mediated (BA–mediated) stimulation of GPBAR1 (also known a TGR5). Both of these pathways activate cAMP production and stimulate Dio2 transcription. In brown fat, cAMP also promotes VDU1 expression, amplifying D2 induction via deubiquitination. Other signaling pathways can decrease D2 activity, resulting in relative local hypothyroidism. For example, the Hedgehog cascade decreases D2 activity by promoting WSB-1 expression and thus D2 ubiquitination, presumably via the Gli cascade. rT3, reverse T3; SHH, sonic hedgehog.