apyrase and Hyperinsulinism

Chronic inflammation is known to promote metabolic dysregulation in obesity and type 2 diabetes. Although the precise origin of the unchecked inflammatory response in obesity is unclear, it is known that overproduction of proinflammatory cytokines by innate immune cells affects metabolism. For example, TNF-α contributes to the inability of cells to respond to insulin and to the increase in levels of insulin. Whether this hyperinsulinemia itself is part of a feedback loop that affects the progression of chronic adipose inflammation is unknown. In this article, we show that regulatory T cells (Tregs) express the insulin receptor, and that high levels of insulin impair the ability of Tregs to suppress inflammatory responses via effects on the AKT/mTOR signaling pathway. Insulin activated AKT signaling in Tregs, leading to inhibition of both IL-10 production and the ability of Tregs to suppress the production of TNF-α by macrophages in a contact-independent manner. The effect of insulin on Treg suppression was limited to IL-10 production and it did not alter the expression of other proteins associated with Treg function, including CTLA-4, CD39, and TGF-β. In a model of diet-induced obesity, Tregs from the visceral adipose tissue of hyperinsulinemic, obese mice showed a similar specific decrease in IL-10 production, as well as a parallel increase in production of IFN-γ. These data suggest that hyperinsulinemia may contribute to the development of obesity-associated inflammation via a previously unknown effect of insulin on the IL-10-mediated function of Tregs.

Topics: Animals; Antigens, CD; Apyrase; Cells, Cultured; CTLA-4 Antigen; Epithelial Cells; Epithelium; Hyperinsulinism; Inflammation; Insulin; Interferon-gamma; Interleukin-10; Intra-Abdominal Fat; Macrophages; Mice; Mice, Inbred C57BL; Obesity; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Signal Transduction; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Extracellular nucleotides are important mediators of inflammatory responses and could also impact metabolic homeostasis. Type 2 purinergic (P2) receptors bind extracellular nucleotides and are expressed by major peripheral tissues responsible for glucose homeostasis. CD39/ENTPD1 is the dominant vascular and immune cell ectoenzyme that hydrolyzes extracellular nucleotides to regulate purinergic signaling.. We have studied Cd39/Entpd1-null mice to determine whether any associated changes in extracellular nucleotide concentrations influence glucose homeostasis.. Cd39/Entpd1-null mice have impaired glucose tolerance and decreased insulin sensitivity with significantly higher plasma insulin levels. Hyperinsulinemic-euglycemic clamp studies indicate altered hepatic glucose metabolism. These effects are mimicked in vivo by injection into wild-type mice of either exogenous ATP or an ecto-ATPase inhibitor, ARL-67156, and by exposure of hepatocytes to extracellular nucleotides in vitro. Increased serum interleukin-1beta, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha levels are observed in Cd39/Entpd1-null mice in keeping with a proinflammatory phenotype. Impaired insulin sensitivity is accompanied by increased activation of hepatic c-Jun NH(2)-terminal kinase/stress-activated protein kinase in Cd39/Entpd1 mice after injection of ATP in vivo. This results in decreased tyrosine phosphorylation of insulin receptor substrate-2 with impeded insulin signaling.. CD39/Entpd1 is a modulator of extracellular nucleotide signaling and also influences metabolism. Deletion of Cd39/Entpd1 both directly and indirectly impacts insulin regulation and hepatic glucose metabolism. Extracellular nucleotides serve as "metabolokines," indicating further links between inflammation and associated metabolic derangements.

Topics: Adenosine Triphosphate; Adipose Tissue, Brown; Animals; Antigens, CD; Apyrase; Blood Glucose; Cells, Cultured; Cytokines; Energy Metabolism; Glucose Clamp Technique; Hepatocytes; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; JNK Mitogen-Activated Protein Kinases; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Oxygen Consumption; Pancreas; Phosphoproteins; Phosphorylation; Signal Transduction