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

Abstract

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 β 3 -adrenergic receptor agonist is a potent activator of brown adipocytes, even in humans, and PKA 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 PKA-ASK1-p38 axis is activated in immature brown adipocytes and contributes to functional maturation. However, the downstream mechanisms of PKA 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 PKA and MAPK in mature brown adipocytes. Mechanistically, the phosphorylation of ASK1 at threonine 99 and serine 993 is critical in PKA-dependent ASK1 activation. Additionally, PKA also activates ASK2, which contributes to MAPK regulation. These lines of evidence provide new details for tailoring a βAR-dependent brown adipocyte activation strategy.

ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes

“…Alternatively, our results may point out the existence of latent beneficial aspect of ASK1 upregulation through tuning the NOD-RIPK2 pathway under obesity. As a potential relevant finding to this assumption, we previously demonstrated that global Ask1 knockout mice showed impaired glucose clearance compared to wild-type mice under high-fat diet treatment, and the phenotype was more robust in severely obese animals 20 . Unexpectedly, however, adipocyte-specific Ask1 knockout mice exhibited comparable glucose clearance with wild-type 20 , which denies the potential influence of ASK1 on blood glucose level under obesity through downregulating the pro-inflammatory NOD-RIPK2 pathway in adipocytes.…”

“…As a potential relevant finding to this assumption, we previously demonstrated that global Ask1 knockout mice showed impaired glucose clearance compared to wild-type mice under high-fat diet treatment, and the phenotype was more robust in severely obese animals 20 . Unexpectedly, however, adipocyte-specific Ask1 knockout mice exhibited comparable glucose clearance with wild-type 20 , which denies the potential influence of ASK1 on blood glucose level under obesity through downregulating the pro-inflammatory NOD-RIPK2 pathway in adipocytes. Nevertheless, considering the confounding example of body weight in the phenotype of Ask1 knockout mice and complexity of obesity-induced inflammatory response in vivo, we should keep in mind that negative regulation of the NOD-RIPK2 pathway by ASK1 in brown adipocytes may contribute to unidentified whole-body phenotype in some obesity-associated situation.…”

“…We have previously reported apoptosis signal-regulating kinase 1 (ASK1) 18 as a critical regulator of thermogenesis; under β-adrenergic receptor stimulation, protein kinase A (PKA) activates the ASK1-p38 MAPK axis to induce brown adipocyte-specific genes 19,20 . Here, we show that ASK1 suppresses the NOD-RIPK2 pathway in brown adipocytes.…”