Program in Molecular Medicine; Davis Lab
Biochemical Phenomena, Metabolism, and Nutrition | Cell Biology | Cellular and Molecular Physiology | Nutritional and Metabolic Diseases | Physiological Processes
Chronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+ channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposure in vitro or by obesity in vivo lead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+ and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+ is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+ homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity.
physiology, adipocytes, inflammation, obesity, metabolism, insulin resistance
Rights and Permissions
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
bioRxiv 2020.10.28.360008; doi: https://doi.org/10.1101/2020.10.28.360008. Link to preprint on bioRxiv.
Guney E, Arruda AP, Parlakgul G, Cagampan E, Min N, Lee Y, Greene L, Tsaousidou E, Inouye K, Han MS, Davis RJ, Harvard University. (2020). Aberrant Ca2+ homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.10.28.360008. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1847
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.