Red blood cell ß-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply.

ABSTRACT

Diet-induced obesity (DIO) represents the major cause for the current obesity epidemic, but the mechanism underlying DIO is unclear. ß-Adrenergic receptors (ß-ARs) play a major role in sympathetic nervous system-mediated (SNS-mediated) diet-induced energy expenditure (EE). Rbc express abundant ß-ARs; however, a potential role for rbc in DIO remains untested. Here, we demonstrated that high-fat, high-caloric diet (HFD) feeding increased both EE and blood O2 content, and the HFD-induced increases in blood O2 level and in body weight gain were negatively correlated. Deficiency of ß-ARs in rbc reduced glycolysis and ATP levels, diminished HFD-induced increases in both blood O2 content and EE, and resulted in DIO. Importantly, specific activation of cAMP signaling in rbc promoted HFD-induced EE and reduced HFD-induced tissue hypoxia independent of obesity. Both HFD and pharmacological activation cAMP signaling in rbc led to increased glycolysis and ATP levels. These results identify a previously unknown role for rbc ß-ARs in mediating the SNS action on HFD-induced EE by increasing O2 supply, and they demonstrate that HFD-induced EE is limited by blood O2 availability and can be augenmented by increased O2 supply.