Prostaglandin F2α Inhibits Adipogenesis Via an Autocrine‐Mediated Interleukin‐11/Glycoprotein 130/STAT1‐Dependent Signaling Cascade

Abstract

Prostaglandin F2α (PGF2α) is a potent inhibitor of adipocyte differentiation in vitro, that has also recently been implicated in the regulation of the adipogenic process in vivo, by opposing adipose tissue accretion and the subsequent development of obesity and its attendant metabolic consequences. In previous studies, we have demonstrated that PGF2α inhibits adipocyte differentiation by means of a calcium-dependent signaling pathway that is critically dependent upon the activity of the calcineurin phosphatase. In the current study, we have now extended these findings to further elucidate the mechanism by which the PGF2α/calcineurin-pathway inhibits the adipogenic process. We now report that the IL-11 cytokine, a member of the gp130 cytokine co-receptor-related family, is a downstream transcriptional target of this pathway in 3T3-L1 preadipocytes and is actively secreted in differentiating cells in response to PGF2α stimulation. Using a combined shRNA and dominant-negative receptor mutant approach, we provide evidence that IL-11/gp130-signaling is required to mediate the inhibitory effects of PGF2α on adipogenesis. Moreover, by taking advantage of a well-characterized panel of chimeric gp130 mutant receptors, we demonstrate that gp130 signaling is sufficient to inhibit adipocyte differentiation and specifically requires the activation of the STAT1 transcription factor. Conversely, we find that depleting endogenous STAT1 levels rescues adipogenesis in the presence of both IL-11/gp130 signaling and PGF2α. Collectively, our findings support a model in which PGF2α inhibits adipocyte differentiation by means of an IL-11 mediated autocrine negative feedback loop, that acts via gp130 to block adipogenesis through the essential actions of the STAT1 transcription factor.

Abnormal Mammary Development in 129:STAT1-Null Mice is Stroma-Dependent

“…This consideration raises the question of whether the metabolic capacity of the 129: Stat1-null MFP is modified, and whether this property is affected by the altered profile of microenvironmental cytokines. Certainly STAT1 is crucial for adipocyte function where it mediates IFNγ-regulated lipolysis in adipocytes [56] and the effects of prostaglandins on their differentiation [57]. At the same time we found that both the cytokine profile and mitogenic capacity of CM could be restored by exogenous PDOM.…”

Suppression of adipocyte differentiation and lipid accumulation by stearidonic acid (SDA) in 3T3-L1 cells

“…These results indicate that SDA consumption will be expected to confer the health benefits associated with the consumption of EPA, but not DHA. While the exact molecular mechanisms by which SDA decreases gene transcription is not apparent from this study, the downstream biosynthesis of lipid-derived eicosanoids via its conversion to EPA may be a potential mechanism through which gene transcription effects could be modulated [ 25 , 62 , 63 ].…”

Molecular Mechanism of Stem Cell Differentiation into Adipocytes and Adipocyte Differentiation of Malignant Tumor

“…Early adipocyte differentiation of 3T3-L1 cells was inhibited by STAT1 agonist interferon γ . Loss of STAT1 in 3T3-L1 cells can rescue the inhibition of adipocyte differentiation caused by prostaglandin factor 2 α [ 70 ]. Other studies have found that STAT1 is required for adipose differentiation, and STAT1 overexpression in C3H10T1/2 cells can prevent the inhibition of lipid differentiation caused by B-cell lymphoma-6 knockdown [ 71 ].…”