Increased Hypothalamic Anti-Inflammatory Mediators in Non-Diabetic Insulin Receptor Substrate 2-Deficient Mice

• Main Authors: María Vinaixa, Sandra Canelles, África González-Murillo, Vítor Ferreira, Diana Grajales, Santiago Guerra-Cantera, Ana Campillo-Calatayud, Manuel Ramírez-Orellana, Óscar Yanes, Laura M. Frago, Ángela M. Valverde, Vicente Barrios
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Cells
• Subjects: diabetes; hypothalamus; inflammation; IRS2^−/− mice; PUFA
• Online Access: https://www.mdpi.com/2073-4409/10/8/2085

Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2^−/−) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2^−/− mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2^−/− mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2^−/− mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2^−/− mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2^−/− mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2^−/− mice. Conversely, D IRS2^−/− mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.