27-hydroxycholesterol is a regulatory oxysterol in adipocytes

Obesity is frequently associated with elevated serum cholesterol and 27-hydroxycholesterol (27HC), a metabolite recently identified as a key link between hypercholesterolemia and increased cancer risk. 27HC exerts pathophysiological effects via estrogen receptor (ER)- and liver X receptor (LXR)-mediated pathways. Adipocytes respond to both ER and LXR signaling and exhibit cholesterol dysregulation in obesity, particularly when hypertrophic or dysfunctional. Adipocytes express CYP27A1, enabling 27HC synthesis from cholesterol, and CYP27A1 is upregulated in adipocytes from individuals with obesity. Here we investigated the direct effects of 27HC on adipocyte function to explore how circulating 27HC levels modify adipocyte metabolism. Using differentiated 3 T3-L1 adipocytes, we show that 27HC modulates cellular homeostasis by reducing triglyceride accumulation, enhancing basal lipolysis, upregulating cholesterol efflux, and increasing insulin-stimulated glucose uptake. Conversely, inhibiting the CYP27A1 pathway increases production of 4β-HC and 7α-HC, which promote proinflammatory interleukin-6 secretion and lipogenesis, respectively. These findings suggest that the CYP27A1-27HC axis in adipocytes acts as a regulatory mechanism to limit the production of proinflammatory and lipogenic oxysterols. 27HC likely serves as an intracrine regulator of adipocyte metabolism, and its dysregulation may contribute to adipocyte dysfunction in obesity.