Abstract
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.
Highlights
Growing evidence suggests that adipose tissue is an immunological organ
We have previously generated Ask1ASKA knock-in mice harboring an analog sensitive kinase allele (ASKA) of Ask[1] and demonstrated that primary cells from Ask1ASKA knock-in mice showed expression and activation levels of apoptosis signal-regulating kinase 1 (ASK1) comparable to those from wild-type mice[23]
The dissociation constant for the first phase (KD1) of 1NA-PP1-L1 or 1NA-PP1-L2 vs. as-ASK1 kinase domain (KD) was calculated as KD1 = 2.06 × 1 0−6 [M] or 2.23 × 10−6 [M], respectively, implying that this affinity is within a suitable range for pull-down and for the subsequent elution step (Fig. 1a)
Summary
Growing evidence suggests that adipose tissue is an immunological organ. While adipose tissue has long been merely regarded as a lipid-storing organ, it is widely recognized that adipose tissue expresses various receptors for cytokines and chemokines and responds to proinflammatory mediators secreted by itself[1,2]. Cold-induced UCP1 induction was suppressed in adipose tissue from obese mice[8]. These recent studies suggest that obesity-induced inflammation leads to dysfunction of brown adipocytes through the reduction of UCP1 and other thermogenic markers. In addition to the role in immune cells, the NOD-RIPK2 pathway is implicated in adipose inflammation and affects the physiology of adipocytes. NOD1 activation in white adipocytes induces insulin resistance and lipolysis[13,14,15] and suppresses adipocyte differentiation with attenuated expression of adipocyte markers and lipid a ccumulation[16]. NOD1 activation in brown adipocytes leads to suppression of brown adipocyte markers, including U CP117 These lines of evidence suggest that the inflammatory NOD-RIPK2 pathway in adipocytes suppresses the differentiation of adipocytes
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