Feeding desensitizes A1 adenosine receptors in adipose through FOXO1-mediated transcriptional regulation

Abstract

Adipose tissue is a critical regulator of energy balance that must rapidly shift its metabolism between fasting and feeding to maintain homeostasis. Adenosine has been characterized as an important regulator of adipocyte metabolism primarily through its actions on A1 adenosine receptors (A1R). We sought to understand the role A1R plays in adipocytes during fasting and feeding to regulate glucose and lipid metabolism by using an inducible, adiponectin-Cre with Adora1 floxed mice (FAdora1−/−), where F designates a fat-specific deletion. Fadora1−/− mice had impairments in the suppression of lipolysis by insulin on normal chow and impaired glucose tolerance on high-fat diet. FAdora1−/− mice also exhibited a higher lipolytic response to isoproterenol than WT controls when fasted, but not after a 4-hour refeeding period. We found that FOXO1 binds to the A1R promoter in adipocytes. Upon feeding, signaling along the insulin-Akt-FOXO1 axis leads to a rapid downregulation of A1R transcript and desensitization of adipocytes to A1R agonism. Obesity also desensitizes adipocyte A1R, and this is accompanied by a disruption of cyclical changes in A1R transcription between fasting and refeeding. We propose that FOXO1 drives high A1R expression under fasted conditions to limit excess lipolysis during stress and augment insulin action upon feeding. Subsequent downregulation of A1R under fed conditions facilitates reentrance into the catabolic state upon fasting.

Attenuation of the Severity of Acute Respiratory Distress Syndrome by Pomiferin through Blocking Inflammation and Oxidative Stress in an AKT/Foxo1 Pathway-Dependent Manner

“…Then, the activated immune system further generates reactive oxygen species (ROS) and cytokines which can further give rise to worsening lung injury [12]. AKT/Foxo1 signaling pathway possesses multiple regulators as well as effectors including glucose, insulin, cytokines, and growth factors, displaying significant functions in cell survival, metabolism, inflammation, and oxidative stress [13][14][15][16]. Previous studies have demonstrated that changes in AKT activity levels in macrophages show significant impacts on polarization and activation of macrophages via regulating Foxo1 activity during ARDS [17,18].…”