Thursday, April 3, 2025
4/3/2025
Adenosine receptors and metacolic homeostasis - Project Summary/Abstract White adipose tissue (WAT) is a key regulator of whole-body energy balance. During feeding WAT enters an anabolic state facilitated by insulin by storing non-esterified fatty acids (NEFA) in triglycerides (TG). During fasting WAT enters a catabolic state facilitated by catecholamines and releases NEFA from TG. During pathogenic insulin resistance, excessive NEFA accumulates in blood (lipotoxicity) and stimulates excessive hepatic glucose production. There is a growing awareness that many of the defects in metabolism seen in obese and prediabetic patients occur not under fasted conditions, but in the postprandial state of one to four hours following a meal. Indeed, elevated postprandial NEFA partitioning to non-adipose tissues clearly occurs in these patients and is strongly implicated in the induction of peripheral insulin resistance. Our novel preliminary data shows that food intake causes a switch from A1R to another adenosine receptor, Gs-coupled A2B receptor (A2BR), resulting in increased A2BR and decreased A1R expression and function. The changes in adenosine receptor expression from A1 to A2B reverse adenosine action. This switch in adenosine signaling reveals that adenosine functions as a feedback metabolite to oppose dominant hormonal signals: opposing catecholamines during fasting via A1R inhibition of lipolysis, and opposing insulin in response to feeding via A2BR stimulation of lipolysis. Obesity shifts the adenosine receptor balance toward A2BR expression characteristic of feeding and this shift provides an explanation for the known obesity-induced impairment in postprandial NEFA storage. This proposal undertakes a rigorous and comprehensive examination of how A2B adenosine receptor (A2BR) signaling changes between fasted and postprandial conditions and the functional consequences of genetic deletion or pharmacological manipulation of A2BR signaling. We will also determine how food intake promotes adenosine signaling via A2BR in fat during the postprandial period.
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