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. 2023 Feb 8;24(4):3412.
doi: 10.3390/ijms24043412.

Increased Aquaporin-7 Expression Is Associated with Changes in Rat Brown Adipose Tissue Whitening in Obesity: Impact of Cold Exposure and Bariatric Surgery

Gema Frühbeck  1   2   3   4 , Leire Méndez-Giménez  1 , Sara Becerril  1   2   3 , Beatriz Ramírez  1   2   3 , Ana Wenting Hernández-Pardos  1 , Javier A Cienfuegos  5 , Víctor Valentí  2   3   5 , Rafael Moncada  2   3   6 , Victoria Catalán  1   2   3 , Javier Gómez-Ambrosi  1   2   3 , Inês V da Silva  7 , Graça Soveral  7 , Amaia Rodríguez  1   2   3
Affiliations

Increased Aquaporin-7 Expression Is Associated with Changes in Rat Brown Adipose Tissue Whitening in Obesity: Impact of Cold Exposure and Bariatric Surgery

Gema Frühbeck et al. Int J Mol Sci. .

Abstract

Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white-like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2, Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4 °C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2, Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy.

Keywords: adipocyte hypertrophy; aquaglyceroporin; lipogenesis; peroxisome proliferator-activated receptor γ; sleeve gastrectomy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Experimental design. The experimental groups are extensively explained in Section 4.1.
Figure 2
Figure 2
Protective effect of cold exposure against BAT whitening by reducing triacylglycerol content. (a) Representative hematoxylin–eosin-stained images of BAT whitening in rats fed either ND or HFD at RT and 1 week after cold exposure (magnification 200×, scale bar = 100 µm). BAT weight (b), cell surface area (CSA) (c), triacylglycerol content (d) and mRNA expression of the lipogenic transcription factor Pparg2 (e) and the effector lipogenic enzymes Mogat2 (f) and Dgat1 (g). The transcript levels in rats fed ND at RT was assumed to be 1. Statistical differences were evaluated by two-way ANOVA or one-way ANOVA followed by Tukey’s post hoc test in case of interaction between factors. a p < 0.05 effect of diet; b p < 0.05 effect of cold exposure; * p < 0.05 vs. rats fed ND.
Figure 3
Figure 3
The expression of AQP7 in BAT is increased during BAT whitening and downregulated by cold exposure. (a) Representative images of AQP7 immunostaining in sections of BAT from rats fed either ND or HFD at RT and 1 week after cold exposure (magnification 400×); negative controls without primary antibody are shown in the upper panels and arrows indicate specific staining of AQP7 in the bottom panels. Gene (b) and protein (c) expression levels of AQP7 in BAT of experimental animals. The transcript and protein levels in rats fed ND at RT were assumed to be 1. Correlation of Aqp7 mRNA and lipogenic factors Pparg2 (d), Mogat2 (e) and Dgat1 (f) mRNA levels. Statistical differences were evaluated by two-way ANOVA. a p < 0.05 effect of diet; b p < 0.05 effect of cold exposure.
Figure 4
Figure 4
Beneficial effect of sleeve gastrectomy on BAT whitening in DIO rats by reducing adipocyte hypertrophy and triacylglycerol content under different thermic conditions. (a) Representative images of BAT whitening after surgical or dietary interventions in animals exposed to different thermic conditions (magnification 200×, scale bar = 100 µm). BAT weight (b), cell surface area (CSA) (c), triacylglycerol content (d) and mRNA expression of lipogenic transcription factor Pparg2 (e) and effector lipogenic enzymes Mogat2 (f) and Dgat1 (g). Transcript levels in rats submitted to sham surgery fed ND at RT was assumed to be 1. Statistical differences were evaluated by three-way ANOVA. a p < 0.05 effect of diet; b p < 0.05 effect of sleeve gastrectomy; c p < 0.05 effect of cold exposure.
Figure 5
Figure 5
AQP7 expression in BAT was repressed after sleeve gastrectomy in DIO rats under both thermic conditions. Gene (a) and protein (b) expression levels of AQP7 in BAT after surgical, dietary and thermic interventions. Correlation of Aqp7 mRNA and lipogenic factors Pparg2 (c), Mogat2 (d) and Dgat1 (e) mRNA levels. Statistical differences were evaluated by two-way ANOVA. a p < 0.05 effect of diet; b p < 0.05 effect of cold exposure; c p < 0.05 effect of cold exposure.
Figure 6
Figure 6
Regulation of Aqp7 gene expression in rat brown adipocytes. Effect of lipolytic (a,b) and lipogenic (c) factors on the mRNA expression of Aqp7 in brown adipocytes. Statistical analysis was assessed by Student’s t test. * p < 0.05; ** p < 0.01 vs. unstimulated cells.
Figure 7
Figure 7
Role of AQP7 in BAT whitening.
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