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Prostaglandin E2 Regulates Adipogenesis in a Cilia-Dependent Manner
Background: Adipocytes regulate the body’s energy homeostasis by storing a pool of lipids which can be utilized for energy production in times of low nutrient availability. These adipocytes differentiate from stem-like preadipocytes in a process known as adipogenesis. Expansion of adipose tissue through the generation of new adipocytes, rather than the enlargement of existing adipocytes, is more metabolically favorable and less correlated with the risk of diseases such as diabetes. While adipogenesis has been well characterized in vitro using different natural and synthetic drugs, the physiological factors that trigger this process in vivo are still unclear. Preadipocytes, unlike mature adipocytes, are ciliated, and our lab demonstrated that the loss of the primary cilium in preadipocytes severely inhibits their ability to differentiate. Similarly, we’ve demonstrated that the loss of the ciliary trafficking protein TULP3 in preadipocytes inhibits adipogenesis, implicating ciliary G-protein coupled receptors (GPCRs) as crucial mediators of this process. Of the few receptors that have been shown to localize to preadipocyte primary cilia, only the free fatty acid receptor 4 (FFAR4) has been implicated in the initiation of adipogenesis through a ciliary mechanism. Upon its activation, FFAR4 increases levels of cAMP in the cilium and stimulates adipogenesis.
Aims: I hypothesized that multiple unidentified GPCRs reside in preadipocyte cilia and play a crucial role in regulating physiological adipogenesis via ciliary signaling.
Methods: To identify novel ciliary GPCRs in preadipocytes that may regulate adipose tissue expansion, I compared all known ciliary GPCRs with all GPCRs expressed in preadipocytes. These lists were compiled through a comprehensive literature search and by analyzing published single-nucleus RNA sequencing data, respectively. I used 3T3L1 preadipocytes and primary preadipocytes to screen these GPCR candidates for ciliary localization using immunofluorescence staining and tested their native ligands for activity in adipogenesis.
Results: I identified the prostaglandin E2 (PGE2) receptor EP4 as a novel ciliary GPCR in preadipocytes. The obesity-associated inflammatory lipid species PGE2 prolifically inhibits adipogenesis in both cultured and primary preadipocytes. While PGE2 is known to bind with varying affinity to multiple prostaglandin receptors, loss of the EP4 receptor rescues the antiadipogenic effect of PGE2. More strikingly, loss of ciliary EP4 in a TULP3 knockout or loss of the cilium altogether in a KIF3a knockout completely rescues the anti-adipogenic effects of PGE2. These data suggest that PGE2 inhibits adipogenesis through ciliary EP4.
Conclusion: Ciliary GPCR activity in preadipocytes regulates adipogenesis in both stimulatory and inhibitory ways. Different physiological ligands, such as free fatty acids and prostaglandins, elicit their effects through the primary cilium, alluding to a cilium’s unique ability to act as a transceiver of multiple signals to influence cell fate. Identifying novel ciliary GPCRs in preadipocytes will elucidate additional physiological signals and ciliary mechanisms that influence adipose tissue expansion, energy homeostasis, and overall metabolic health.
Speakers
Mark Lee