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. 2021 Jan 18;22(2):906.
doi: 10.3390/ijms22020906.

Overexpression of Adiponectin Receptor 1 Inhibits Brown and Beige Adipose Tissue Activity in Mice

Yu-Jen Chen  1   2 , Chiao-Wei Lin  1   2 , Yu-Ju Peng  2 , Chao-Wei Huang  2 , Yi-Shan Chien  2 , Tzu-Hsuan Huang  2 , Pei-Xin Liao  2 , Wen-Yuan Yang  2 , Mei-Hui Wang  3 , Harry J Mersmann  2 , Shinn-Chih Wu  1   2 , Tai-Yuan Chuang  4 , Yuan-Yu Lin  2 , Wen-Hung Kuo  5 , Shih-Torng Ding  1   2
Affiliations

Overexpression of Adiponectin Receptor 1 Inhibits Brown and Beige Adipose Tissue Activity in Mice

Yu-Jen Chen et al. Int J Mol Sci. .

Abstract

Adult humans and mice possess significant classical brown adipose tissues (BAT) and, upon cold-induction, acquire brown-like adipocytes in certain depots of white adipose tissues (WAT), known as beige adipose tissues or WAT browning/beiging. Activating thermogenic classical BAT or WAT beiging to generate heat limits diet-induced obesity or type-2 diabetes in mice. Adiponectin is a beneficial adipokine resisting diabetes, and causing "healthy obese" by increasing WAT expansion to limit lipotoxicity in other metabolic tissues during high-fat feeding. However, the role of its receptors, especially adiponectin receptor 1 (AdipoR1), on cold-induced thermogenesis in vivo in BAT and in WAT beiging is still elusive. Here, we established a cold-induction procedure in transgenic mice over-expressing AdipoR1 and applied a live 3-D [18F] fluorodeoxyglucose-PET/CT (18F-FDG PET/CT) scanning to measure BAT activity by determining glucose uptake in cold-acclimated transgenic mice. Results showed that cold-acclimated mice over-expressing AdipoR1 had diminished cold-induced glucose uptake, enlarged adipocyte size in BAT and in browned WAT, and reduced surface BAT/body temperature in vivo. Furthermore, decreased gene expression, related to thermogenic Ucp1, BAT-specific markers, BAT-enriched mitochondrial markers, lipolysis and fatty acid oxidation, and increased expression of whitening genes in BAT or in browned subcutaneous inguinal WAT of AdipoR1 mice are congruent with results of PET/CT scanning and surface body temperature in vivo. Moreover, differentiated brown-like beige adipocytes isolated from pre-adipocytes in subcutaneous WAT of transgenic AdipoR1 mice also had similar effects of lowered expression of thermogenic Ucp1, BAT selective markers, and BAT mitochondrial markers. Therefore, this study combines in vitro and in vivo results with live 3-D scanning and reveals one of the many facets of the adiponectin receptors in regulating energy homeostasis, especially in the involvement of cold-induced thermogenesis.

Keywords: PET/CT scintigraphy; adiponectin; adiponectin receptor 1; beige adipose tissue; brown adipose tissue; cold-induced thermogenesis; uncoupling protein 1 (UCP1).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Body profiles of AdipoR1 mice upon cold exposure. (A) Wild-type (WT) and transgenic adiponectin receptor 1 (AdipoR1) mice of both sexes, male (M) and female (F), were housed in a cold-room (8–10 °C) for two weeks, i.e., 14 d. (B) Percentage of adipose tissue weights was expressed per unit body weights in WT or AdipoR1 mice. Subcutaneous inguinal white adipose tissues (iWAT), gonadal/epididymal white adipose tissues (gWAT), classical interscapular brown adipose tissues (BAT), and suprascapular white adipose tissues (supWAT) were harvested and weighted. (C) AdipoR1 mice had increased food intake (averaged g of feed per mouse per d/g of mouse body weights) while losing more body weight than WT mice. (D) AdipoR1 mice had significant body weight changes with enhanced body weight losses. Body weight changes were calculated and compared with each previous time point as percentage (%). Data were presented as means ± SEM (n = 3–8 for each group). * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001.
Figure 2
Figure 2
Inhibited cold-induced thermogenesis in vivo in classical brown and beige adipose depots of AdipoR1 mice. After two-week cold acclimation, WT and transgenic AdipoR1 mice were anesthetized and evaluated for cold-induced thermogenesis by live positron emission tomography/computed tomography (PET/CT) scanning. Timeline and procedures were described in Figure 1. Radiotracer of 18F-fluorodeoxyglucose (18F-FDG) was injected into the tail-vein to evaluate cold-enhanced glucose uptake in vivo. Asterisks (*) indicate classical iBAT and hashmarks (#) and plus signs (+) indicate supWAT and iWAT (potential depots for WAT browning or beiging), respectively. Procedures in different groups of mice were repeated at least twice. 3D-constructed videos are displayed in the Supplementary Materials.
Figure 3
Figure 3
Increased adipocyte size in classical brown and beige adipose depots of AdipoR1 mice. Cold-acclimated WT and transgenic AdipoR1 mice were evaluated for the morphology of brown and beige adipose tissues. Timeline and procedures were described in Figure 1. Classical iBAT and iWAT (the potential white adipose depot for browning or beiging) in WT and AdipoR1 female mice (A) at room temperature or (B) in cold environments were harvested, fixed, sectioned, and evaluated for histology by hematoxylin and eosin (H&E) staining. Scale bar: 100 μm for 20×, 50 μm for 40× microscope.
Figure 4
Figure 4
Reduced surface BAT depot temperature and surface body temperature of AdipoR1 mice. WT and transgenic AdipoR1 mice were evaluated for surface body temperature, (A) by infrared thermometer both at room temperature (RT) and after cold induction, and (B) by infrared camera after cold induction. Timeline and procedures were described in Figure 1. Measurements of surface body temperature (abdomen region) and surface depot temperature of BAT in (A) and infrared images from the thermographic surface temperature analysis in (B) in WT and AdipoR1 mice were both quantified and expressed as means ± SEM (n ≥ 8 for each group). * p ≤ 0.05; *** p ≤ 0.001.
Figure 5
Figure 5
Female mice showed increased expression of adiponectin receptors and enhanced brown-adipocyte markers in classical brown and beige adipose depots after cold exposure. (A) Indicated adipose depots of male and female WT mice after cold acclimation were determined for expression of adiponectin receptors, including adiponectin receptor 1 (Adipor1), adiponectin receptor 2 (Adipor2), and T-cadherin (Cdh13/Tcad). (B) Comparison of expression of adiponectin receptors and adiponectin (Adipoq) between male and female WT mice was determined in iBAT, iWAT, supWAT, and gWAT, respectively. (C) Indicated adipose depots in male or female WT mice after cold acclimation were determined for expression of brown adipocyte (WAT browning/beiging) markers. Timeline and procedures were described in Figure 1. Classical iBAT, iWAT, supWAT (both of potential white adipose depots for browning or beiging) and gWAT in male and female WT mice were harvested, extracted and measured to evaluate adiponectin and its receptors and cold-induced thermogenic related genes (n = 3–8 for each group). Data were presented as relative means (normalized to β-actin in arbitrary units, AU) ± SEM. * p ≤ 0.05; **p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001.
Figure 6
Figure 6
Increased expression of adiponectin receptor 1 and decreased expression of T-cadherin in classical brown or beige adipose depots of AdipoR1 mice after cold exposure. Indicated adipose depots of WT and AdipoR1 female mice after cold acclimation were determined for expression of adiponectin (Adipoq) and adiponectin receptors, including adiponectin receptor 1 (Adipor1), adiponectin receptor 2 (Adipor2), and T-cadherin (Cdh13/Tcad). Timeline and procedures were described in Figure 1. Classical iBAT, iWAT, supWAT (both of potential white adipose depots for browning or beiging), and gWAT in WT and AdipoR1 female mice were harvested, extracted, and measured to evaluate expression of adiponectin and its receptors (n = 3–8 for each group). Data were presented as relative means (normalized to β-actin in arbitrary units, AU) ± SEM. * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001.
Figure 7
Figure 7
Reduced BAT thermogenic and mitochondrial markers in classical brown and beige adipose depots of AdipoR1 mice before and after cold-stimulation. Expression of brown adipocyte markers and BAT-enriched mitochondrial markers was evaluated in indicated adipose tissues of WT and AdipoR1 female mice, both (A) at room temperature (RT) before and (B) following the cold exposure at 10 °C. Timeline and procedures were described in Figure 1. Classical iBAT, iWAT, supWAT (both of potential white adipose depots for browning or beiging), and gWAT in WT and AdipoR1 female mice were harvested, extracted, and measured to evaluate cold-induced thermogenic related genes at RT or after cold acclimation (n = 3–8 for each group). Data were presented as relative means (normalized to β-actin in arbitrary units, AU) ± SEM. * p ≤ 0.05; ** p ≤ 0.01.
Figure 8
Figure 8
Reduced expression of glucose uptake, lipolysis, and fatty acid oxidation in classical brown and beige adipose depots of AdipoR1 mice after cold-stimulation. Gene expression related to (A) glucose uptake, (B) lipolysis, (C) fatty acid transport, (D) fatty acid oxidation, and (E) fatty acid synthesis was evaluated in indicated adipose tissues of WT and AdipoR1 female mice following cold exposure. Timeline and procedures were described in Figure 1. Classical iBAT and iWAT (the potential white adipose depot for browning or beiging) in WT and AdipoR1 female mice were harvested, extracted, and measured to evaluate adipose metabolism genes (n = 3–8 for each group). Data were presented as relative means (normalized to β-actin in arbitrary units, AU) ± SEM. * p ≤ 0.05; ** p ≤ 0.01.
Figure 9
Figure 9
Reduced BAT markers (browning/beiging) and enhanced WAT markers (whitening) in classical brown and beige adipose depots of AdipoR1 mice after cold-stimulation. Expression of (A) brown and (B) white adipocyte markers was evaluated in indicated adipose tissues of WT and AdipoR1 female mice following cold exposure. Timeline and procedures were described in Figure 1. Classical iBAT and iWAT (the potential white adipose depot for browning or beiging), in WT and AdipoR1 female mice, were harvested, extracted, and measured to evaluate selective markers for brown or white adipocytes (n = 3–8 for each group). Data were presented as relative means (normalized to β-actin in arbitrary units, AU) ± SEM. * p ≤ 0.05; ** p ≤ 0.01.
Figure 10
Figure 10
Decreased BAT thermogenic and mitochondrial markers in differentiated beige adipocytes from iWAT of AdipoR1 mice. Expression of (A) brown adipocyte markers and (B) BAT-enriched mitochondrial markers was evaluated by qPCR. Pre-adipocytes in the stromal/vascular fraction of subcutaneous iWAT (the potential depot for WAT browning or beiging) were derived from WT or transgenic AdipoR1 mice (n = 3) and differentiated into mature beige adipocytes with or without a synergistic browning agent of PPARγ, rosiglitazone (Rosi). Data were presented as relative means (normalized to β-actin in arbitrary units, AU) ± SEM. * p ≤ 0.05.
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