Red blood cell β-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply
Eun Ran Kim, Shengjie Fan, Dmitry Akhmedov, Kaiqi Sun, Hoyong Lim, William O’Brien, Yuanzhong Xu, Leandra R. Mangieri, Yaming Zhu, Cheng-Chi Lee, Yeonseok Chung, Yang Xia, Yong Xu, Feng Li, Kai Sun, Rebecca Berdeaux, Qingchun Tong
Eun Ran Kim, Shengjie Fan, Dmitry Akhmedov, Kaiqi Sun, Hoyong Lim, William O’Brien, Yuanzhong Xu, Leandra R. Mangieri, Yaming Zhu, Cheng-Chi Lee, Yeonseok Chung, Yang Xia, Yong Xu, Feng Li, Kai Sun, Rebecca Berdeaux, Qingchun Tong
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Research Article Endocrinology Metabolism

Red blood cell β-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. β-Adrenergic receptors (β-ARs) play a major role in sympathetic nervous system–mediated (SNS-mediated) diet-induced energy expenditure (EE). Rbc express abundant β-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 β-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 β-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.

Authors

Eun Ran Kim, Shengjie Fan, Dmitry Akhmedov, Kaiqi Sun, Hoyong Lim, William O’Brien, Yuanzhong Xu, Leandra R. Mangieri, Yaming Zhu, Cheng-Chi Lee, Yeonseok Chung, Yang Xia, Yong Xu, Feng Li, Kai Sun, Rebecca Berdeaux, Qingchun Tong

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Figure 2

Rbc β-ARs are required for HFD-induced EE and increases in O2 content.

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Rbc β-ARs are required for HFD-induced EE and increases in O2 content. M...
Male β-less mice (i.e., lacking all 3 β-adrenergic receptors) on the FVB background and WT FVB mice with similar ages were used for this study. (A–C) Eight- to 10-week-old control and β-less male mice (n = 6–9/group) received s.c. injection of saline or isopreteneronol (Iso) (1 mg/kg, bw), and O2 consumption (A), changes in blood O2 content (B), and changes in O2 saturation (C) were measured within 3.5 hrs of drug administration. (D–K) BM transplantation (BMT) was performed by injecting BM from β-less mice to lethal dose–irradiated controls (K→W mice) or to β-less mice (K→K) or by injecting BM from controls to lethal dose–irradiated controls (W→W mice). All mice used were young males (12–16 weeks of age, n = 5–6/group) and measured for weekly body weight (D), O2 consumption (E), food intake (F), changes in blood O2 contents (G), changes in O2 saturation (H), and total Hb (I) 3 days before and 5 weeks after HFD. (J and K) Measurements of rbc ATP (J) and 2,3-DPG (K) in the indicated 3 groups of mice 5 weeks after HFD (n = 8–10/group). The data presented in J and K were samples combined from 2 BMT experiments. All data are presented as mean ± SEM; *P < 0.05, ***P < 0.005 by 2-way ANOVA tests in A and D–F; 1-way ANOVA tests in G and H; and unpaired Student’s t tests in B and C and J and K.