Prostaglandin E2-EP4 signaling suppresses adipocyte differentiation in mouse embryonic fibroblasts via an autocrine mechanism

Abstract

Adipogenesis is a crucial aspect in controlling body fat mass ( 1, 2 ). Acquisition of the mature adipocyte phenotype is a highly regulated process in which mesenchymal stem cells (MSC) undergo differentiation, resulting in both an increase in size and number of mature adipocytes in adipose tissue. Adipose tissue is important not only for energy storage but also as an endocrine organ that regulates energy homeostasis by secreting various adipokines, such as cytokines, chemokines, growth factors, and lipid mediators ( 3 ). The presence of receptors for adipokines in preadipocytes and adipocytes has been shown, suggesting that secreted adipokines have autocrine effects and regulate their own differentiation and functions ( 4 ). Although it has been shown that a number of factors, including adipokines, regulate adipogenesis in various settings, most of the evidence comes from supraphysiological or pharmacological doses of these molecules to elicit a response. Hence, their physiological signifi cance in local milieu has not been established.Prostaglandins (PG) are arachidonate metabolites synthesized by the action of cyclooxygenase (COX) as the rate-limiting enzyme. COX has been shown to exist as two isomers, COX-1 and COX-2. PGs exert a wide range of actions through their binding to plasma membrane receptors ( 5, 6 ). For instance, PGF 2 ␣ exerts its actions via specifi c interactions with the prostanoid FP receptor, which activates phopholipase C, resulting in phophatidylinositol breakdown ( 7 ). In contrast, PGE 2 exerts action through its Abstract The prostaglandin (PG) receptors EP4 and FP have the potential to exert negative effects on adipogenesis, but the exact contribution of endogenous PG-driven receptor signaling to this process is not fully understood. In this study, we employed an adipocyte differentiation system from mouse embryonic fi broblasts (MEF) and compared the effects of each PG receptor-defi ciency on adipocyte differentiation.

Prostaglandins as PPARγModulators in Adipogenesis

“…Finally, we found that mPGES-1 is responsible for the production of PGE 2 in adipocytes [60]. This result is consistent with results showing that treatment of mouse embryonic fibroblast (MEF) cells with PGE 2 for the first two days of adipocyte differentiation is enough to suppress adipocyte differentiation, with reduced expression of the PPAR γ 2 gene and reduced accumulation of intracellular lipids [43]. …”

“…PGF 2 α and PGE 2 suppress the differentiation of adipocytes and exert their functions as antiadipogenic agents exert by acting through their specific FP [37–41] and EP4 [42, 43] receptors, respectively. …”

“…In MEF cells prepared from EP4 receptor gene-knock-out mice, adipocyte differentiation is elevated, and no more enhancement of adipocyte differentiation is observed following treatment with indomethacin. Thus, PGE 2 -EP4 receptor signaling suppresses the early phase of adipocyte differentiation in MEF cells [43]. …”

Synergistic Suppression of Early Phase of Adipogenesis by Microsomal PGE Synthase-1 (PTGES1)-Produced PGE2 and Aldo-Keto Reductase 1B3-Produced PGF2α

“…Moreover, PGF 2α induces the production of anti-adipogenic PGE 2 and PGF 2α by triggering the PTGFR receptor/MEK/ERK cascade in 3T3-L1 cells [18]. PGE 2 also enhances the production of anti-adipogenic PGE 2 and PGF 2α in mouse embryonic fibroblasts [20].…”

“…PGI 2 is involved in the activation of preadipocytes to adipocytes through PGI 2 receptor [14], [15]. In contrast, PGF 2α and PGE 2 suppress the progression of adipogenesis [17], [18], [19], [20]. PGF 2α is synthesized by AKR1B3 in adipocytes and represses the early phase of adipogenesis by engaging the PTGFR receptor [17].…”