Pannexin 1 and Adipose Tissue
Adamson, Samantha, Pharmacology - Graduate School of Arts and Sciences, University of Virginia
Leitinger, Norbert, Department of Pharmacology, University of Virginia
Defective glucose uptake in adipocytes leads to impaired metabolic homeostasis and insulin resistance, hallmarks of type 2 diabetes. Extracellular ATP-derived nucleotides and nucleosides are important regulators of adipocyte function, but the pathway for controlled ATP release from adipocytes is unknown. Here, we investigated whether Pannexin 1 (Panx1) channels control ATP release from adipocytes and contribute to metabolic homeostasis. Our studies show that adipocytes express functional Pannexin 1 (Panx1) channels that can be activated to release ATP by known mechanisms including alpha adrenergic stimulation and caspase-mediated C-terminal cleavage during apoptosis. Further, we identify insulin as a novel activator of Panx1 channels. Pharmacologic inhibition or selective genetic deletion of Panx1 from adipocytes decreased insulin-induced glucose uptake in vitro and in vivo and exacerbated diet-induced insulin resistance in mice. In obese humans, Panx1 expression in adipose tissue is increased and correlates with the degree of insulin resistance. Although in other systems extracellular ATP has been shown to be chemotactic for immune cells such as macrophages, we observed no difference in the level of macrophage infiltration or inflammation in adipose tissue of diet-induced obese, insulin resistant AdipPanx1 KO mice, (mice in which Panx1 was selectively deleted in adipocytes). We also observed that deficiency of the ATP receptor P2Y2 on myeloid cells in mice did not affect glucose intolerance in a model of diet-induced obesity and insulin resistance. However, mice which lack P2Y2 receptors in myeloid cells show decreased crown-like structure formation in perigonadal adipose tissue although the amount of macrophages within the tissue are not different from WT mice. In conclusion, Panx1 channel activity controls metabolic homeostasis in adipocytes, namely through the regulation of insulin-stimulated glucose uptake.
PHD (Doctor of Philosophy)
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