Adipocyte heparan sulfate determines type 2 diabetes susceptibility in mice via FGF1-Mediated glucose regulation
Year: 2025
Type: article
Abstract: 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. • Adipocyte heparan sulfate does not impact diet-induced weight gain. • Adipocyte heparan sulfate sulfation compromises glucose regulation and insulin sensitivity under nutrient stress. • Mice with reduced HS sulfation show increased insulin resistance and fatty liver disease in a diet-induced obesity model. • Mechanistically HS sulfation is essential for the glucose-lowering effect of FGF1, a critical paracrine insulin sensitizer in adipose tissue.
Source: Molecular Metabolism
Authors: Chung-Jui Yu, Ariane R. Pessentheiner, Sihao Liu, Sarah Wax, Marissa L. Maciej-Hulme, Chelsea D. Painter, Bastian Ramms, Daniel R. Sandoval, Anthony Quach, Natalie DeForest, G. Michelle Ducasa, Chiara Tognaccini, Caroline Labib, Norah Al-Azzam, Friederike Haumann, Greg Trieger, Patrick Secrest, Amit Majithia, Aaron C. Petrey, Kamil Godula, Annette R. Atkins, Michael Downes, Ronald M. Evans, Philip L.S.M. Gordts
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,270
Funders: American Heart Association, Larry L. Hillblom Foundation, Fondation Leducq, Austrian Science Fund, NOMIS Stiftung, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1886062415, UCSD Biomedical Scientist Career Development Program in Glycoscience, G297113894, Impact of apolipoproteinC-III on lipoprotein-receptor interaction and atherosclerosis regression, LEAN (Leducq Epigenetics of Atherosclerosis Network) Defining and targeting epigenetic pathways in monocytes and macrophages that contribute to cardiovascular disease., G3812021946, HUMAN MILK OLIGOSACCHARIDES AND CARDIOVASCULAR DISEASE, G9000105172, Training in Reproductive Sciences, The Role of Layilin as a Novel Regulator of Platelet Activation and Thromboinflammation
OpenAlex ID: W4414998488