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- Title
Aberrant Ca<sup>2+</sup> signaling by IP<sub>3</sub>Rs in adipocytes links inflammation to metabolic dysregulation in obesity.
- Authors
Guney, Ekin; Arruda, Ana Paula; Parlakgul, Günes; Cagampan, Erika; Min, Nina; Lee, Grace Yankun; Greene, Lily; Tsaousidou, Eva; Inouye, Karen; Han, Myoung Sook; Davis, Roger J.; Hotamisligil, Gökhan S.
- Abstract
Insulin resistance from IP3Rs: Dysregulation of Ca2+ homeostasis in adipose tissue is associated with lipid accumulation and obesity. Guney et al. investigated how IP3Rs, ligand-gated channels that release Ca2+ from intracellular stores, are affected by and contribute to the inflammatory responses in adipose tissue that occur during obesity. The abundance and activity of IP3Rs increased in adipocytes exposed to proinflammatory cytokines or in the adipose tissue of mice fed a high-fat diet. Mice lacking IP3R1/2 in adipocytes still gained weight on a high-fat diet but had reduced inflammatory cell infiltration of adipose tissue and did not develop some of the adverse metabolic effects of obesity, such as insulin resistance. Thus, inhibiting IP3Rs in adipose tissue may prevent the development of the metabolic complications associated with obesity. Chronic metabolic inflammation is a key feature of obesity, insulin resistance, and diabetes. Here, we showed that altered regulation of the Ca2+ channel inositol trisphosphate receptor (IP3R) was an adipocyte-intrinsic event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation induced by cytokine exposure in vitro or by obesity in vivo led to increases in the abundance and activity of IP3Rs and in the phosphorylation of the Ca2+-dependent kinase CaMKII in adipocytes in a manner dependent on the kinase JNK. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance, despite the mice exhibiting substantial diet-induced weight gain. Thus, this work suggests that increased IP3R activity is a key link between obesity, inflammation, and insulin resistance. These data also suggest that approaches to target IP3R-mediated Ca2+ homeostasis in adipocytes may offer new therapeutic opportunities against metabolic diseases, especially because GWAS studies also implicate this locus in human obesity.
- Subjects
ADIPOSE tissues; OBESITY; FAT cells; INSULIN resistance; WEIGHT gain; HOMEOSTASIS; INSULIN receptors; METABOLIC disorders
- Publication
Science Signaling, 2021, Vol 14, Issue 713, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abf2059