Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis

Abstract

The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as 3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGF signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGF signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by 3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.

Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages

“…It has also been shown that AT development and remodeling are critically dependent on inflammatory signaling early in postnatal life (85). Most recently, β 3 adrenergic stimulation of lipolysis has been shown to trigger IL-6/JAK/STAT3 signaling and promote beige adipocyte development (36). Our findings on the role of AKG/ PAF/IL-6/STAT3 signaling in BeAT development are in line with these recent findings and confirm that BeAT development in the infant requires transient inflammatory signaling (86).…”

“…MitoTracker Green and Red staining of mitochondria confirmed that they were functional (Figure 3 Figure 3E). The level of NADH-DH activity reflects mitochondrial respiration (35), which is increased in beige adipocytes (36). In the presence of ATMs, AKG treatment increased Ucp1 transcription in 3T3-L1 adipocytes ( Figure 3F).…”

“…AKGs caused a moderate TNF-α secretion from ATMs (Supplemental Figure 13J), which, however, did not affect BeAT gene transcription ( Figure 5F). IL-6 can act through STAT3 (36). Ucp1, Ppargc1a, Cidea, Cox7a1, Dio2, and Tmem26 have binding sites for STAT3 and STATs upstream of their promoters ( Figure 5G).…”

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

“…Expression of constitutively active STAT3 (C-STAT3) has been shown to restore BAT differentiation of Tyk2−/− preadipocytes and reverse the obese phenotype in Tyk2−/− mice [155]. A recent report showed that transient activation of the JAK family of kinases and STAT3 signaling in the context of β-adrenergic tissue remodeling increased the potential for thermogenic adipocyte differentiation i.e., browning [156]. Although these data suggest that there is a role for STAT3 in adipose tissue browning, the authors also point-out that this is only in the case of transient inflammation but not chronic inflammation.…”

METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m 6 A‐YTHDF2–dependent manner

“…Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays an important role in a variety of physiologic processes including development, hematopoiesis, inflammation, and lipid metabolism progress (10)(11)(12)(13)(14). The JAK family of receptor-associated tyrosine kinases act as primary transducers of multiple cytokine receptors and mediate a variety of their effects through the phosphorylation of the transcription factor STATs (12,(15)(16)(17)(18)(19). JAK/STAT pathway also participates in adipocyte differentiation (14), and of the 7 known STATs, only STAT3 and STAT5 have been reported to positively affect adipogenesis (20)(21)(22)(23)(24)(25)(26)(27)(28).…”