SUN-665 - Impaired CRF2R Expression and Signaling Pathways in Adipocytes from an Insulin-Resistance Metabolic Syndrome Model

Metabolic syndrome (MetS), a cluster of interrelated metabolic abnormalities, increases the risk of diabetes and cardiovascular disorders, which represent major global health problems. The pathophysiology of MetS is closely associated with insulin resistance and increased fatty acid influx into the cells. In recent years, urocortins have been implicated in metabolic regulation, and the corticotropin-releasing factor receptor type 2/urocortin 2 (CRF2R/Ucn2) system has been identified in metabolic tissues, such as adipose tissue. In this study, we evaluated the response of isolated adipocytes, the principal endocrine cells in adipose tissue, to insulin and Ucn2 in an animal model of MetS. The model was established in Wistar rats by administering a 30% sucrose beverage with chow feeding ad libitum for four months, resulting in a 26% increase in body weight (p < 0.001), a 2-fold increase in adiposity percentage (p < 0.001), and an increase in the Triglyceride-Glucose index (TyG) in MetS rats (p < 0.001). The MetS animals also showed glucose intolerance (p < 0.001) and dyslipidemia (p < 0.001). Likewise, wild-type adipocytes showed a 5-fold higher insulin-stimulated glucose uptake than MetS adipocytes (p < 0.001). In the analysis of proteins involved in the insulin signaling pathway, we observed decreased protein expression of the insulin receptor (p < 0.05) and Akt2 (p < 0.01). Consistent with this, insulin-stimulated Akt-Thr308 phosphorylation was not detected in MetS adipocytes, suggesting impaired insulin signaling. Given that insulin resistance has been associated with increased Ucn2 levels in the blood, particularly in obesity and type 2 diabetes, we next evaluated the effect of Ucn2 on adipocyte signaling. We observed the activation of the lipolytic pathway in wild-type adipocytes following Ucn2 stimulation. Ucn2 promoted the phosphorylation of Akt-Thr308, Akt-Ser473, and HSL-Ser660 (p < 0.05) in wild-type adipocytes. In contrast, Ucn2 failed to induce the phosphorylation of any of these proteins in MetS adipocytes. In wild-type adipocytes, we observed significant endogenous cAMP production induced by Ucn2 (p < 0.01), whereas no such production was detected in MetS adipocytes after Ucn2 stimulation. Consistently, real-time PCR results showed decreased CRF2R mRNA expression (p < 0.01) and protein levels (p < 0.01). Additionally, Ucn2 mRNA expression was reduced (p < 0.05). In conclusion, the CRF2R/Ucn2 system regulates the lipolytic pathway in adipocytes; however, in insulin-resistant MetS adipocytes, this signaling pathway is downregulated. Impaired function of this signaling pathway is directly linked to lipid metabolism and has a strong impact on the pathophysiology of metabolic syndrome, particularly in adipose tissue, suggesting its potential as a promising therapeutic agent.

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