Adipocyte heparan sulfate determines type 2 diabetes susceptibility in mice via FGF1-Mediated glucose regulation

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.