Prostaglandin E2 inhibits adipogenesis through the cilia-dependent activation of ROCK2.

Abstract

Functional adipose tissue is essential for maintaining systemic metabolic homeostasis. Dysfunctional adipose tissue, characterized by increased fibrosis, hypoxia, and chronic inflammation, is often associated with obesity and promotes the onset of metabolic disease such as type 2 diabetes. During nutrient excess, adipose tissue function can be preserved by the generation of new adipocytes from adipocyte stem cells, illustrating the importance of identifying the physiological regulators of adipogenesis. Here, we discover a cilia-localized signaling pathway through which the pro-inflammatory lipid metabolite prostaglandin E2 (PGE2) suppresses adipogenesis. We demonstrate that PGE2 specifically signals through the E-type prostaglandin receptor 4 (EP4) localized to the primary cilium of adipocyte stem cells. Activation of ciliary EP4 initiates a cAMP-independent signaling cascade that activates the Rho-associated protein kinase 2 (ROCK2) resulting in the retention of actin stress fibers that prevent adipogenesis. These findings uncover a compartmentalized regulatory mechanism of adipogenesis by which primary cilia alter whole-cell physiology, cell fate, and ultimately adipose tissue expansion in response to an inflammatory hormone, offering insight into how chronic inflammation may contribute to adipose tissue dysfunction and metabolic disease progression.