C-C chemokine receptor type 5 activation stimulates adipocyte differentiation through ERK-dependent pathway

Obesity is associated with low-grade chronic inflammation, and research has shown that RANTES and CCR5 mRNA levels are notably higher in the visceral adipose tissue of obese individuals compared to lean controls. However, the precise role of CCR5 activation in obesity development is still unclear. This study aims to explore the impact of CCR5 activation on adipogenesis and the underlying regulatory mechanisms. The study used 3T3-F442A preadipocytes and primary preadipocytes from wild-type (WT) and CCR5 knockout (CCR5^-/-) mice to assess the role of CCR5 activation in adipocyte differentiation. To investigate the in vivo effects of CCR5 on obesity, male C57BL/6J WT and CCR5^-/- mice were fed either a normal chow (NC) or a high-fat diet (HFD) for two months. Plasma RANTES levels, fat pad weight, adipocyte size, and adipose CCR5 expression were measured. Treatment with RANTES resulted in increased intracellular triglyceride accumulation and enhanced expression of adipogenic transcription factors such as PPARγ, C/EBPα, and the adipocyte-specific protein aP2 during differentiation. These findings suggest that RANTES facilitates adipocyte differentiation. Moreover, pretreatment with the CCR5 inhibitor maraviroc and the ERK inhibitor PD98059 significantly reduced RANTES-induced adipocyte differentiation. RANTES also promoted differentiation in primary preadipocytes from WT mice, but not from CCR5^-/- mice. In vivo, WT mice on a high-fat diet showed higher plasma RANTES levels and increased adipose CCR5 expression, as well as obesity, whereas these changes were absent in CCR5^-/- mice. The results suggest that CCR5 activation by RANTES enhances adipocyte differentiation via an ERK-dependent pathway, and that CCR5 plays a critical role in the development of obesity.