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. 2017 Mar 23;8:179.
doi: 10.3389/fphys.2017.00179. eCollection 2017.

Metabolic Response of Visceral White Adipose Tissue of Obese Mice Exposed for 5 Days to Human Room Temperature Compared to Mouse Thermoneutrality

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Free PMC article

Metabolic Response of Visceral White Adipose Tissue of Obese Mice Exposed for 5 Days to Human Room Temperature Compared to Mouse Thermoneutrality

Inge van der Stelt et al. Front Physiol. .
Free PMC article

Abstract

Housing of laboratory mice at room temperature (22°C) might be considered a constant cold stress, which induces a thermogenic program in brown adipose tissue (BAT). However, the early adaptive response of white adipose tissue (WAT), the fat storage organ of the body, to a change from thermoneutrality to room temperature is not known. This was investigated here for various WAT depots, focusing on epididymal WAT (eWAT), widely used as reference depot. Male adult diet-induced obese (DIO) C57BL/6JOlaHsd mice housed at thermoneutrality (29°C), were for 5 days either switched to room temperature (22°C) or remained at thermoneutrality. Energy metabolism was continuously measured using indirect calorimetry. At the end of the study, serum metabolomics and WAT transcriptomics were performed. We confirmed activation of the thermogenic program in 22°C housed mice. Body weight and total fat mass were reduced. Whole body energy expenditure (EE) was increased, with a higher fatty acid to carbohydrate oxidation ratio and increased serum acylcarnitine levels, while energy intake was not significantly different between the two groups. Transcriptome analysis of eWAT identified tissue remodeling and inflammation as the most affected processes. Expression of pro-inflammatory M1 macrophage-related genes, and M1 over M2 macrophage ratio were decreased, which might be linked to an increased insulin sensitivity. Markers of thermogenesis were not altered in eWAT. Decreased expression of tryptophan hydroxylase 2 (Tph2) and cholecystokinin (Cck) might represent altered neuroendocrine signaling. eWAT itself does not show increased fatty acid oxidation. The three measured WATs, epididymal, mesenteric, and retroperitoneal, showed mainly similar responses; reduced inflammation (s100a8), decreased carbohydrate oxidation, and no or small differences in fatty acid oxidation. However, Ucp1 was only expressed and increased in rWAT in 22°C housed mice. Cck expression was decreased in the three WATs, significantly in eWAT and rWAT, in contrast to Tph2, which was decreased in eWAT while not expressed in mWAT and rWAT. Our data show that tissue remodeling, inflammation and neuroendocrine signaling are early responses in WAT to a moderate decrease in environmental temperature.

Keywords: indirect calorimetry; serum metabolomics; thermogenesis; thermoneutrality; transcriptomics; visceral white adipose tissue.

Figures

Figure 1
Figure 1
Relative gene expression of genes involved in adaptive thermogenesis in brown adipose tissue (BAT). Thermoneutral housed mice were switched to 22°C for 5 days (n = 12) vs. control thermoneutral (29°C) housed mice. Full gene names are listed in Supplementary Table 1. Data is presented as mean ± SEM (n = 7–11). Significant different values of the 22°C housed mice compared to the 29°C housed mice are indicated with **p < 0.01, and ***p < 0.001.
Figure 2
Figure 2
Body weight, body composition, food intake and fecal energy loss at 29°C or after switching to 22°C. (A) Body weight, (B) total lean mass, (C) total fat mass, (D) epididymal white adipose tissue weight, (E) retroperitoneal white adipose tissue weight, (F) adiposity; fat mass as percentage of body weight, (G) food intake, averaged per hour and differentiated between the inactive light phase and active dark phase, (H) fecal energy loss. All data was collected in the same set of mice, before and after the temperature switch. Data is presented as mean ± SEM (n = 12). Significant different values of the 22°C housed mice compared to the control 29°C housed mice are indicated with *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 3
Figure 3
Energy balance of mice housed at 29°C or 22°C. (A) 24 h Respiratory exchange ratio (RER), (B) average RER, (C) 24 h energy expenditure (EE), (D) average EE, (E) 24 h physical activity (n = 8), (F) average physical activity (n = 8) for mice fed a high fat diet housed at thermoneutrality (black) or 22°C (gray lines, white bars). Values are displayed for both inactive light phase and active dark phase (gray area). Data shown is calculated from the last 24 h in the indirect calorimetry system and is presented as mean ± SEM (n = 12), unless stated otherwise. Significant different values of the 22°C housed mice compared to the 29°C housed mice are indicated with *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 4
Figure 4
Transcriptomics of epididymal white adipose tissue. (A) Differential expression of processes between 29°C and 22°C housed mice (n = 10). Processes are ranked based on known functions of all genes with significant false discovery rate adjusted p-values. (B) Expression of key genes for the top 2 differential expressed processes, processes involved in metabolism, and the 2 genes with the highest fold change (FC). Expression of the control 29°C group has been set at 1. Underlined genes are key markers for the assigned processes. Genes are ranked based on FC, bold numbers indicate significantly different transcript levels between the 22°C vs. control 29°C housed mice and are assigned with *p < 0.05, **p < 0.01, and ***p < 0.001. See Supplementary Table 2 for gene names, systematic names, and full p-values.
Figure 5
Figure 5
Relative expression of Cck and Tph2 in white adipose tissues at 29°C or 22°C ambient temperature. (A) Cck gene expression in white adipose tissue of epididymal (eWAT), mesenteric (mWAT), and retroperitoneal (rWAT) origin, as measured by RT-qPCR (n = 7–10), (B) Representative samples of CCK protein levels in eWAT as measured by Western blot and normalized using β-Actin (n = 11–12), (C) Tph2 gene expression as measured by RT-qPCR (n = 8–10). Cck: cholecystokinin; Tph2, tryptophan hydroxylase 2. Data is presented as mean ± SEM. N.q., not quantifiable. Significant different values of the 22°C housed mice (white bar) compared to the control 29°C housed mice (black bar) are indicated with *p < 0.05, **p < 0.01.
Figure 6
Figure 6
Gene expression in white adipose tissue (WAT) depots of mice housed at either 29°C or 22°C. Relative gene expression of (A) s100 calcium binding protein A8 (s100a8), (B) glycogen synthase 2 (Gys2), (C) pyruvate dehydrogenase kinase, isoenzyme 4 (Pdk4), (D) carnitine palmitoyltransferase 1a (Cpt1a), (E) fatty acid synthase (Fasn), (F) acyl-coenzyme A dehydrogenase long chain (Acadl), and (G) uncoupling protein 1 (Ucp1), of the 22°C vs. the 29°C housed mice in epididymal WAT (eWAT), mesenteric WAT (mWAT) and retroperitoneal WAT (rWAT). Data is presented as mean ± SEM (n = 4–10). Significant different values of the 22°C housed mice (white bar) compared to the 29°C housed mice (black bar) are indicated with *p < 0.05, **p < 0.01, and ***p < 0.001.

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