Detection of brown adipose tissue in rats with acute cold stimulation using quantitative susceptibility mapping.
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ABSTRACT:
SUBMITTER: Zhu C
PROVIDER: S-EPMC10476742 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Detection of brown adipose tissue in rats with acute cold stimulation using quantitative susceptibility mapping.
Zhu Cuiling C Guo Yihao Y Si Wenbin W Zhong Qiaoling Q Mei Yingjie Y Feng Yanqiu Y Zhang Xiaodong X
Chinese medical journal 20230905 17
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Project description:Brown adipose tissue (BAT) plays an important role in regulation of energy expenditure while adapting to a cold environment. BAT thermogenesis depends on uncoupling protein 1 (UCP1), which is expressed in the inner mitochondrial membranes of BAT. Gene expression profiles induced by cold exposure in BAT have been studied, but the metabolomic biological pathway that contributes to the activation of thermogenesis in BAT remains unclear. In this study, we comprehensively compared the relative levels of metabolites between the BAT of rats kept at room temperature (22?°C) and of those exposed to a cold temperature (4?°C) for 48?h using capillary electrophoresis (CE) time-of-flight mass spectrometry (TOFMS) and liquid chromatography (LC)-TOFMS. We identified 218 metabolites (137 cations and 81 anions) by CE-TOFMS and detected 81 metabolites (47 positive and 34 negative) by LC-TOFMS in BAT. We found that cold exposure highly influenced the BAT metabolome. We showed that the cold environment lead to lower levels of glycolysis and gluconeogenesis intermediates and higher levels of the tricarboxylic acid (TCA) cycle metabolites, fatty acids, and acyl-carnitine metabolites than control conditions in the BAT of rats. These results indicate that glycolysis and ?-oxidation of fatty acids in BAT are positive biological pathways that contribute to the activation of thermogenesis by cold exposure, thereby facilitating the generation of heat by UCP1. These data provide useful information for understanding the basal metabolic functions of BAT thermogenesis in rats in response to cold exposure.
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Project description:Cold exposure imposes a metabolic challenge to mammals that is met by a coordinated response in different tissues to prevent hypothermia. This study reports a transcriptomic analysis in brown adipose tissue (BAT), white adipose (WAT) and liver of mice in response to 24 h cold exposure at 8°C. Expression of 1895 genes were significantly (P<0.05) up- or down-regulated more than two fold by cold exposure in all tissues but only 5 of these genes were shared by all three tissues, and only 19, 14 and 134 genes were common between WAT and BAT, WAT and liver, and BAT and liver, respectively. We confirmed using qRT-PCR, the increased expression of a number of characteristic BAT genes during cold exposure. In both BAT and the liver, the most common direction of change in gene expression was suppression (496 genes in BAT and 590 genes in liver). Gene ontology analysis revealed for the first time significant (P<0.05) down regulation in response to cold, of genes involved in oxidoreductase activity, lipid metabolic processes and protease inhibitor activity, in both BAT and liver, but not WAT. The results reveal an unexpected importance of down regulation of cytochrome P450 gene expression and apolipoprotein, in both BAT and liver, but not WAT, in response to cold exposure. Pathway analysis suggests a model in which down regulation of the nuclear transcription factors HNF4α and PPARα in both BAT and liver may orchestrate the down regulation of genes involved in lipoprotein and steroid metabolism as well as Phase I enzymes belonging to the cytochrome P450 group in response to cold stress in mice. We propose that the response to cold stress involves decreased gene expression in a range of cellular processes in order to maximise pathways involved in heat production.
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Project description:1. A group of male Sprague-Dawley rats (5-6 weeks old) was cold-acclimated at 4 degrees C for 4 weeks. Warm-acclimated controls remained at 24 degrees C. Total protein content of brown adipose tissue (BAT) increased more than 3-fold and total uncoupling protein (UCP) content increased more than 6-fold upon cold-acclimation. The concentration of UCP in isolated BAT mitochondria almost doubled. 2. Specific ATPase activity of the non-thermogenic BAT mitochondria (from warm-acclimated controls) was low and increased about 6-fold on addition of 1 microM-Ca2+, which raised free Ca2+ levels (measured by Fura-2) in the incubation media from 1.32 +/- 0.28 microM (mean +/- S.E.M.) to 2.29 +/- 0.39 microM [at which the Ca(2+)-binding ATPase-inhibitor protein (CaBI) is inactivated]. Correspondingly, the specific ATP synthetase activity of the non-thermogenic BAT mitochondria was high and was decreased by 74% by addition of 1 microM-Ca2+. 3. In contrast, specific ATPase activity of thermogenic BAT mitochondria (from cold-acclimated rats) was 5 times that of the control group, and addition of Ca2+ had only a small stimulatory response. Correspondingly, the specific ATP synthetase activity of the thermogenic BAT mitochondria was low, and the decrease by Ca2+ was small, albeit significant. 4. Extracts of BAT mitochondria from both groups of animals contained significant amounts of the ATPase-inhibitor protein of Pullman and Monroy (PMI) as well as of CaBI, as shown by gel electrophoresis. Kinetic studies of inhibition of mitochondrial ATPase activity showed that PMI activity was unaltered in extracts from the thermogenic BAT mitochondria, whereas CaBI activity was slightly but significantly increased. 5. The presence of active ATPase-inhibitor proteins in BAT mitochondria was shown for the first time. We conclude that uncoupling of oxidative phosphorylation occurs in thermogenic BAT mitochondria, even in the presence of the ATPase-inhibitor proteins.
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Project description:The cultured brown adipocytes can oxidize glucose in vitro, but it is still not fully clear whether brown adipose tissue (BAT) could completely oxidize glucose in vivo. Although positron emission tomography (PET) with 18 F-fluorodeoxyglucose (18 F-FDG) showed a high level of glucose uptake in the activated BAT, the non-metabolizable 18 F-FDG cannot fully demonstrate intracellular glucose metabolism. Through in vivo [U-13 C]glucose tracing, here we show that chronic cold exposure dramatically activates glucose oxidation in BAT and the browning/beiging subcutaneous white adipose tissue (sWAT). Specifically, chronic cold exposure enhances glucose flux into the mitochondrial TCA cycle. Metabolic flux analysis models that β3-adrenergic receptor (β3-AR) agonist significantly enhances the flux of mitochondrial pyruvate uptake through mitochondrial pyruvate carrier (MPC) in the differentiated primary brown adipocytes. Furthermore, in vivo MPC inhibition blocks cold-induced glucose oxidation and impairs body temperature maintenance in mice. Together, mitochondrial pyruvate uptake and oxidation serve an important energy source in the chronic cold exposure activated BAT and beige adipose tissue, which supports a role for glucose oxidation in brown fat thermogenesis.
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Project description:Thermogenesis via fatty acid-induced uncoupled mitochondrial respiration is the primary function of brown adipose tissue (BAT). In response to changes in ambient temperatures, the weight and specific gravity of BAT change, depending on the quantity of lipid droplets stored in brown adipocytes (BA). Such conditions should result in the reconstruction of connective tissue skeletons, especially of collagen fiber networks, although the mechanisms have not been clarified. This study showed that, within 4 hr of exposing mice to a cold environment, collagen fibers in the extracellular matrix (ECM) of BAT became discontinuous, twisted, emancipated, and curtailed. Surprisingly, the structure of collagen fibers returned to normal after the mice were kept at room temperature for 19 hr, indicating that the alterations in collagen fiber structures are physiological processes association with adaptation to cold environments. These dynamic changes in connective tissue skeletons were not observed in white adipose tissues, suggesting that they are unique to BAT. Interestingly, the vascular permeability of BAT was also augmented by exposure to cold. Collectively, these findings indicate that dynamic changes in ECM collagen fibers provide high flexibility to BAT, enabling the adjustment of tissue structures and the regulation of vascular permeability, resulting in adaptation to changes in ambient temperatures.
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Project description:Postmenopausal women exhibit a higher prevalence of obesity due to decreased energy expenditure and increased food intake compared to their premenopausal counterparts. Brown adipose tissue (BAT) plays a key role in energy homeostasis, thus providing us with appealing therapeutic targets in obesity. However, how BAT proteomes are altered in response to low levels of estrogen remains unclear. To better understand the underlying mechanisms between the postmenopausal state and BAT proteomic changes, our study aimed to investigate the effect of ovariectomy on the BAT proteome. In this study, eight-week-old female Sprague Dawley rats were randomly allocated into bilateral ovariectomy (Ovx) and sham operation (Sham) groups. Mass spectrometry was used for proteomics assay and Ingenuity Pathway Analysis was applied to examine the differentially regulated proteins. Of the 1,412 identified proteins, 18 proteins were significantly upregulated, whereas 36 proteins were significantly downregulated in the Ovx group as compared to the Sham group. Our findings demonstrate that the proteins involved in BAT morphology, the browning of white adipose tissue, and metabolic substrates for thermogenesis were regulated by ovariectomy. The dysregulation of proteins by ovariectomy might be related to the disruption of BAT function in the postmenopausal status. Understanding how BAT proteomes are altered in response to ovariectomy may illuminate novel therapeutic strategies for the management of postmenopausal weight gain in the future.
| S-EPMC8964325 | biostudies-literature
Project description:Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) methods can non-invasively assess brown adipose tissue (BAT) structure and function. Recently, MRI and MRS have been proposed as a means to differentiate BAT from white adipose tissue (WAT) and to extract morphological and functional information on BAT inaccessible by other means. Specifically, proton MR (1H) techniques, such as proton density fat fraction mapping, diffusion imaging, and intermolecular multiple quantum coherence imaging, have been employed to access BAT microstructure; MR thermometry, relaxometry, and MRI and MRS with 31P, 2H, 13C, and 129Xe have shown to provide complementary information on BAT function. The purpose of the present review is to provide a comprehensive overview of MR imaging and spectroscopy techniques used to detect BAT in rodents and in humans. The present work discusses common challenges of current methods and provides an outlook on possible future directions of using MRI and MRS in BAT studies.
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Project description:The cultured brown adipocytes can oxidize glucose in vitro, but it is still not fully clear whether brown adipose tissue (BAT) could completely oxidize glucose in vivo. Although positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) showed a high level of glucose uptake in the activated BAT, the non-metabolizable 18F-FDG cannot fully demonstrate intracellular glucose metabolism. Through in vivo [U-13C]glucose tracing, here we show that chronic cold exposure dramatically activates glucose oxidation in BAT and the browning/beiging subcutaneous white adipose tissue (sWAT). Specifically, chronic cold exposure enhances glucose flux into the mitochondrial TCA cycle. Metabolic flux analysis models that ?3-adrenergic receptor (?3-AR) agonist significantly enhances the flux of mitochondrial pyruvate uptake through mitochondrial pyruvate carrier (MPC) in the differentiated primary brown adipocytes. Furthermore, in vivo MPC inhibition blocks cold-induced glucose oxidation, and impairs body temperature maintenance in mice. Together, mitochondrial pyruvate uptake and oxidation serves an important energy source in the chronic cold exposure activated BAT and beige adipose tissue, which supports a role for glucose oxidation in brown fat thermogenesis.
| S-SCDT-EMBOR-2020-50085V1 | biostudies-other
Project description:In rodents, brown adipose tissue (BAT) plays an important role in producing heat to defend against the cold and can metabolize large amounts of dietary fatty acids (DFA). The role of BAT in DFA metabolism in humans is unknown. Here we show that mild cold stimulation (18 °C) results in a significantly greater fractional DFA extraction by BAT relative to skeletal muscle and white adipose tissue in non-cold-acclimated men given a standard liquid meal containing the long-chain fatty acid PET tracer, 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid (18FTHA). However, the net contribution of BAT to systemic DFA clearance is comparatively small. Despite a 4-week cold acclimation increasing BAT oxidative metabolism 2.6-fold, BAT DFA uptake does not increase further. These findings show that cold-stimulated BAT can contribute to the clearance of DFA from circulation but its contribution is not as significant as the heart, liver, skeletal muscles or white adipose tissues.
| S-EPMC5290270 | biostudies-literature
Project description:Brown adipocytes store metabolic energy as triglycerides (TGs) in lipid droplets (LDs). Fatty acids released from brown adipocyte LDs by lipolysis are thought to activate and fuel UCP1-mediated thermogenesis. Here, we test this hypothesis by preventing fatty acid storage in murine brown adipocytes through brown adipose tissue (BAT)-specific deletions of the TG synthesis enzymes DGAT1 and DGAT2 (BA-DGAT KO). Despite the absence of TGs in brown adipocytes, BAT is functional, and BA-DGAT-KO mice maintain euthermia during acute or chronic cold exposure. As apparent adaptations to the lack of TG, brown adipocytes of BA-DGAT-KO mice appear to use circulating glucose and fatty acids, and stored glycogen, to fuel thermogenesis. Moreover, BA-DGAT-KO mice are resistant to diet-induced glucose intolerance, likely because of increased glucose disposal by BAT. We conclude that TGs in BAT are dispensable for its contribution to cold-induced thermogenesis, at least when other fuel sources are available.
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