Abstract 516: Pharmacological Inhibition of Phosphatase and Tensin Homolog Ameliorates Adipose Tissue Inflammation and Increases Splenic Regulatory B and T Cells in Rats With Metabolic Syndrome

Abstract

Objectives: B cells have emerged as a critical player in innate and adaptive immune responses. However, little is known about the role of B cells in obesity- and/or stress-induced immune responses. We previously reported that restraint stress exacerbates cardiac and adipose tissue pathology via β-adrenergic signaling in rats with metabolic syndrome (MetS). Phosphatidylinositol 3’-kinase (PI3K)/Akt pathway regulates interleukin-10 production by B cells. Phosphatase and tensin homolog (PTEN) is a lipid/protein phosphatase that can negatively regulate PI3K/Akt pathway. To identify the possible role of PI3K signaling in stress-induced immune responses in metabolic disorders, we now examined the effects of restraint stress and PTEN inhibition on B and T cell subsets in rats with MetS. Methods: We used DahlS.Z- Lepr fa / Lepr fa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as an animal model of MetS. Rats were exposed to restraint stress (restraint cage, 2 h/day) for 2 wk from 9 wk of age with or without daily administration of the PTEN inhibitor bisperoxovanadium-pic [bpV(pic), 0.2 mg/kg, i.p.]. Age-matched homozygous lean littermates of DS/obese rats (DahlS.Z- Lepr + / Lepr + rats) served as controls. Results: Treatment with bpV (pic) attenuated hypertension in DS/obese rats under restraint stress. This agent also reduced subcutaneous fat mass and alleviated adipocyte hypertrophy and inflammation in subcutaneous adipose tissue as well as tended to suppress epididymal adipose tissue inflammation in such rats. Flow cytometric analysis showed that regulatory B (Breg) cells were increased and B-1 cells, which attenuate inflammation and insulin resistance, tended to be increased by bpV (pic) in the spleen of DS/obese rats subjected to restrain stress. In addition, bpV (pic) treatment led to an increase in splenic regulatory T (Treg) cells and downregulation of CD8 + T cells in epididymal adipose tissue of stressed rats. Conclusions: PTEN inhibition with bpV (pic) attenuated subcutaneous adipose tissue inflammation as well as increased splenic Breg and Treg cells in DS/obese rats under restraint stress. Pharmacological inhibition of negative regulator of PI3K may represent a therapeutic approach for the treatment of MetS.