Transient inflammatory signaling promotes beige adipogenesis

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Science Signaling  24 Apr 2018:
Vol. 11, Issue 527, eaat3192
DOI: 10.1126/scisignal.aat3192


Inflammatory signaling has been implicated in adipose tissue remodeling and metabolism. In this issue of Science Signaling, Babaei et al. report that lipolysis induced by β3-adrenergic signaling triggers transient inflammation that directs progenitor cells toward beige adipogenesis.

Obesity, the condition of adipose tissue overgrowth, is a risk factor for the metabolic syndrome underlying type 2 diabetes, cardiovascular disease, and cancer (1). Adipose tissue expansion is driven by adipocyte progenitor proliferation and by lipid accumulation in differentiated white adipocytes. In response to sympathetic nervous system stimuli, subcutaneous adipose tissue can acquire mitochondria-rich adipocytes. These beige adipocytes that arise in white adipose tissue in response to β3-adrenergic receptor activation are functionally similar to adipocytes in canonical brown adipose tissue, which are specialized to burn lipids through adaptive thermogenesis. In mouse models, brown and beige adipose tissues protect against obesity-induced metabolic dysfunction. Therefore, understanding the mechanisms that activate brown and beige adipogenesis is clinically important.

Adipogenesis is driven by a cascade of growth factors and hormones activating the core transcriptional machinery. Proinflammatory cytokines, which promote lipolysis, have been traditionally considered to antagonize adipocyte differentiation. However, transient low-level inflammation actually stimulates adipogenesis in animal models. For instance, low-dose LPS leads to adipocyte hyperplasia at the administration site (2). In addition, the inflammatory microenvironment and alternatively polarized macrophage accumulation in adipose tissue promote beige adipogenesis (3). Consistent with these results, a transient inflammatory response is essential for healthy expansion of white adipose tissue through adipocyte progenitor recruitment (4). However, the signaling pathways that mediate inflammatory and adipogenic signaling in progenitors have remained unclear. In this issue of Science Signaling, Babaei et al. identify a missing link (5). By genetically and pharmacologically inactivating proteins in cell culture models, they demonstrated a role for Jak1/2-Stat3 signaling in adipogenesis initiation. They showed that Stat3 signaling suppressed the TGFβ-Srf-Smad3 pathway, resulting in preadipocyte commitment to beige adipogenesis. Together, their data suggest that Stat3 signaling cross-talks with the TGFβ pathway in response to transient and lipolysis-dependent inflammation to direct progenitor cell differentiation into beige adipocytes, rather than white adipocytes. This signaling cross-talk is important in that it establishes a new mechanism by which the sympathetic nervous system stimulates adipose tissue beiging.

Babaei et al. found that adipogenesis was triggered by a transient inflammatory wave in response to ATGL-mediated lipolysis induced by β3-agonists (5). The IL-6 family inflammatory cytokines, particularly IL-11, were the essential factors that initiated the signaling. For Stat3 signaling to promote adipogenesis, it had to transiently occur before the expression of core adipogenic transcriptional factors (C/EBPβ and PPARγ). Babaei et al. demonstrated that the TGFβ pathway was a primary target of Stat3 signaling in adipocyte progenitors (5). The effect of Stat3 was mediated by suppressing the expression of Tgfβ3 and Tgfβ1, resulting in decreased TGFβ-Srf-Smad3 signaling. Cytokines of the TGFβ family and their antagonists are produced locally within adipose tissue and control the balance between adipocyte differentiation and fibrosis. Consistent with these findings, TGFβ activity selectively suppresses beige adipogenesis (6). However, Moisan et al. had reported that inhibition of the Jak-Stat pathway enabled beige adipogenesis (7). An apparent explanation for this seeming discrepancy is that Moisan et al. chronically suppressed Jak-Stat signaling, whereas Babaei et al. manipulated it only during adipogenesis initiation (5).

The authors proposed a model whereby a transient proinflammatory wave triggers the proadipogenic Jak-Stat-TGFβ-SMAD3 signaling in progenitor cells (Fig. 1). These effects of the spike in IL-6 family cytokines oppose those of chronic inflammation. Indeed, long-term activation of TGFβ-SMAD signaling in stromal cells inhibits adipogenesis and promotes fibrosis, which exacerbates adipose tissue dysfunction and metabolic disease. The findings of Babaei et al. (5) are consistent with previous reports on the role of Stats in early adipogenic commitment. Indeed, NF-κB, activated by Stat3, plays either a pro- or anti-inflammatory role depending on whether inflammation is acute or chronic. Innate lymphoid cells promote beige adipogenesis through IL-4 and its receptor IL-4Rα, which also signals through Stat3 (8). Transient activation of PDGRFα and PDGRFβ underlies progenitor commitment to beige or white adipogenesis, respectively, whereas constitutive activation of their signaling, which is also mediated by Stats, results in fibrosis (9). Similarly, short-term induction of VEGF-A locally in adipose tissue triggers beiging, whereas a long-term increase in VEGF-A production can cause metabolic disorders (10). VEGF signaling is also transduced in part by Stat3. These reports suggest that various distinct pathways can influence the fate of adipose tissue progenitors by converging on the transient activation of Stat3 (Fig. 1).

Fig. 1 Adipose tissue remodeling in response to inflammatory signaling.

β3-Adrenergic and Stat3 signaling trigger lipolysis in adipose tissue. Lipolytic products initiate local inflammatory reactions mediated by endothelial cells and leukocytes that secrete IL-6 family cytokines that act in a paracrine fashion on adipocyte progenitors. Transient Stat3 signaling blocks the TGFβ pathway and directs progenitors toward adipogenesis. Adipocyte beiging, manifested by accumulation of mitochondria, also relies on transcriptional machinery downstream of β3-adrenergic signaling in preadipocytes, which induces UCP1-dependent thermogenesis. In contrast, chronic inflammation blocks adipogenesis and leads to fibrosis.

Credit: A. Kitterman/Science Signaling

The study raises several questions. It is not clear how transient (as opposed to constant) Jak-Stat3 signaling is achieved in vivo and how continuous beige adipogenesis induction is maintained during postnatal development in subcutaneous adipose tissue. Because beige adipogenesis is not observed in intraperitoneal adipose tissue, it would be interesting to investigate the Jak-Stat–TGFβ–SMAD3 signaling in that depot. Stat3 signaling operates not only in progenitors but also in differentiated adipocytes, where it induces lipolysis and fatty acid oxidation, which should be considered as another mechanistic component in intercellular adipose tissue signaling cross-talk. Currently, the lipolytic products that trigger the transient increase in IL-6 family cytokines remain unknown and it is unclear whether both β3-adrenergic and Stat3 signaling pathways generate the same or distinct lipolytic products. Another uncertainty is the identity of cells with increased COX2 activity that secrete the prostaglandin PGI2, as well as the molecular target through which PGI2 contributes to adipogenic commitment. Endothelial cells are the likely source of PGI2, whereas leukocytes infiltrating adipose tissue are a major source of IL-6 and IL-11 (Fig. 1). Addressing these questions in animal models will help to better understand these signaling pathways and outline new therapeutic strategies to treat obesity and associated diseases.


Funding: M.G.K. is supported by NIH grants 2R01DK088131-06, R01CA195659-01A1, and R21CA216745-01A1, as well as the Bovay Foundation. K.S. is supported by NIH grant R01DK109001.
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