β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes.

Boosting energy expenditure by harnessing the activity of brown adipocytes is a promising strategy for combatting the global epidemic of obesity. Many studies have revealed that the β3-adrenergic receptor agonist is a potent activator of brown adipocytes, even in humans, and and p38 MAPK have been demonstrated for regulating the transcription of a wide range of critical genes such as Ucp1. We previously revealed that the axis is activated in immature brown adipocytes and contributes to functional maturation. However, the downstream mechanisms of duanyu1529 that initiate the p38 MAPK cascade are still mostly unknown in mature brown adipocytes. Here, we identified the ASK family as a crucial signaling molecule bridging duanyu1529 and MAPK in mature brown adipocytes. Mechanistically, the phosphorylation of ASK1 at threonine 99 and serine 993 is critical in ASK1 activation. Additionally, duanyu1529 also activates ASK2, which contributes to MAPK regulation. These lines of evidence provide new details for tailoring a βAR-dependent brown adipocyte activation strategy.

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