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 imm… Show more
“…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.…”
Section: Discussionmentioning
confidence: 94%
“…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.…”
Section: Discussionmentioning
confidence: 94%
“…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.…”
Recent studies have shown that adipose tissue is an immunological organ. While inflammation in energy-storing white adipose tissues has been the focus of intense research, the regulatory mechanisms of inflammation in heat-producing brown adipose tissues remain largely unknown. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical regulator of brown adipocyte maturation; the PKA-ASK1-p38 axis facilitates uncoupling protein 1 (UCP1) induction cell-autonomously. Here, we show that ASK1 suppresses an innate immune pathway and contributes to maintenance of brown adipocytes. We report a novel chemical pull-down method for endogenous kinases using analog sensitive kinase allele (ASKA) technology and identify an ASK1 interactor in brown adipocytes, receptor-interacting serine/threonine-protein kinase 2 (RIPK2). ASK1 disrupts the RIPK2 signaling complex and inhibits the NOD-RIPK2 pathway to downregulate the production of inflammatory cytokines. As a potential biological significance, an in vitro model for intercellular regulation suggests that ASK1 facilitates the expression of UCP1 through the suppression of inflammatory cytokine production. In parallel to our previous report on the PKA-ASK1-p38 axis, our work raises the possibility of an auxiliary role of ASK1 in brown adipocyte maintenance through neutralizing the thermogenesis-suppressive effect of the NOD-RIPK2 pathway.
“…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.…”
Section: Discussionmentioning
confidence: 94%
“…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.…”
Section: Discussionmentioning
confidence: 94%
“…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.…”
Recent studies have shown that adipose tissue is an immunological organ. While inflammation in energy-storing white adipose tissues has been the focus of intense research, the regulatory mechanisms of inflammation in heat-producing brown adipose tissues remain largely unknown. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical regulator of brown adipocyte maturation; the PKA-ASK1-p38 axis facilitates uncoupling protein 1 (UCP1) induction cell-autonomously. Here, we show that ASK1 suppresses an innate immune pathway and contributes to maintenance of brown adipocytes. We report a novel chemical pull-down method for endogenous kinases using analog sensitive kinase allele (ASKA) technology and identify an ASK1 interactor in brown adipocytes, receptor-interacting serine/threonine-protein kinase 2 (RIPK2). ASK1 disrupts the RIPK2 signaling complex and inhibits the NOD-RIPK2 pathway to downregulate the production of inflammatory cytokines. As a potential biological significance, an in vitro model for intercellular regulation suggests that ASK1 facilitates the expression of UCP1 through the suppression of inflammatory cytokine production. In parallel to our previous report on the PKA-ASK1-p38 axis, our work raises the possibility of an auxiliary role of ASK1 in brown adipocyte maintenance through neutralizing the thermogenesis-suppressive effect of the NOD-RIPK2 pathway.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.