The mitochondrial uncoupling protein from guinea-pig brown adipose tissue. Synchronous increase in structural and functional parameters during cold-adaptation.
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ABSTRACT:
SUBMITTER: Rial E
PROVIDER: S-EPMC1144231 | biostudies-other | 1984 Sep
REPOSITORIES: biostudies-other
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Project description:Acute cold induces beige adipocyte protein marker expression in human subcutaneous white adipose tissue (SC WAT) from both the cold treated and contralateral leg, and the immune system regulates SC WAT beiging in mice. Cold treatment significantly increased the gene expression of the macrophage markers CD68 and 86 in SC WAT. Therefore, we comprehensively investigated the involvement of macrophages in SC WAT beiging in lean and obese humans by immunohistochemistry. Cold treatment significantly increased CD163/CD68 macrophages in SC WAT from the cold treated and contralateral legs of lean and obese subjects, and had similar effects on CD206/CD68 macrophages, whereas the effects on CD86/CD68 macrophages were inconsistent between lean and obese. However, linear regression analysis did not find significant relationships between the change in macrophage numbers and the change in UCP1 protein abundance. A high percentage of CD163 macrophages in SC WAT expressed UCP1, and these UCP1 expressing CD163 macrophages were significantly increased by cold treatment in SC WAT of lean subjects. In conclusion, our results suggest that CD163 macrophages are involved in some aspect of the tissue remodeling that occurs during SC WAT beiging in humans after cold treatment, but they are likely not direct mediators of the beiging process.
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Project description:In response to cold, brown adipose tissue (BAT) increases its metabolic rate and expands its mass to produce heat required for survival, a process known as BAT recruitment. The mechanistic target of rapamycin complex 1 (mTORC1) controls metabolism, cell growth and proliferation, but its role in regulating BAT recruitment in response to chronic cold stimulation is unknown. Here, we show that cold activates mTORC1 in BAT, an effect that depends on the sympathetic nervous system. Adipocyte-specific mTORC1 loss in mice completely blocks cold-induced BAT expansion and severely impairs mitochondrial biogenesis. Accordingly, mTORC1 loss reduces oxygen consumption and causes a severe defect in BAT oxidative metabolism upon cold exposure. Using in vivo metabolic imaging, metabolomics and transcriptomics, we show that mTORC1 deletion impairs glucose and lipid oxidation, an effect linked to a defect in tricarboxylic acid (TCA) cycle activity. These analyses also reveal a severe defect in nucleotide synthesis in the absence of mTORC1. Overall, these findings demonstrate an essential role for mTORC1 in the regulation of BAT recruitment and metabolism in response to cold.
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Project description:After cold exposure, cytochrome c oxidase (COX) activity increased about 2.5-fold within 2 weeks in the brown adipose tissue (BAT) of Djungarian hamsters. The mRNAs for COX subunits I and III and the 12 S rRNA, encoded on mitochondrial DNA (mtDNA), as well as mRNAs for COX subunits IV, Va and mitochondrial transcription factor A, encoded in the nucleus, were unchanged when expressed per unit of total tissue RNA. However, since total tissue RNA doubled per BAT depot, while total DNA remained unchanged, the actual levels of these transcripts were increased within BAT cells. In contrast, the abundance of mRNA for uncoupling protein was increased 10-fold, indicating specific activation of this gene. In addition, the maximal rate of protein synthesis analysed in a faithful in organello system was increased 2.5-fold in mitochondria isolated from BAT after 7 days of cold exposure. We conclude from these data that the biogenesis of thermogenic mitochondria in BAT following cold adaptation is achieved by increasing the overall capacity for synthesis of mitochondrial proteins in both compartments, by increasing their mRNAs as well as the ribosomes needed for their translation. In addition, the translational rate for COX subunits as well as all other proteins encoded on mtDNA is increased. Thus the pool of subunits encoded on mtDNA required for assembly of respiratory chain complexes is provided. By comparison with other models of increased mitochondrial biogenesis, we propose that thyroid hormone (generated within BAT cells by 5'-deiodinase, and induced upon sympathetic stimulation), which is a well known regulator of the biogenesis of mitochondria in many tissues, is also the major effector of these adaptive changes in BAT.
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Project description:Tyrosine hydroxylase (TH) catalyzes the first step in catecholamines synthesis. We studied the impact of reduced TH in brown adipose tissue (BAT) activation. In adult heterozygous (Th+/- ) mice, dopamine and noradrenaline (NA) content in BAT decreased after cold exposure. This reduced catecholaminergic response did not impair cold adaptation, because these mice induced uncoupling protein 1 (UCP-1) and maintained BAT temperature to a similar extent than controls (Th+/+ ). Possible compensatory mechanisms implicated were studied. Prdm16 and Fgf21 expression, key genes in BAT activation, were elevated in Th+/- mice at thermoneutrality from day 18.5 of embryonic life. Likewise, plasma FGF21 and liver Fgf21 mRNA were increased. Analysis of endoplasmic reticulum (ER) stress, a process that triggers elevations in FGF21, showed higher phospho-IRE1, phospho-JNK, and CHOP in BAT of Th+/- mice at thermoneutrality. Also, increased lipolysis in BAT of cold-exposure Th+/- mice was demonstrated by increased phosphorylation of hormone-sensitive lipase (HSL), as well as diacylglycerol (DAG) and FFA content. Overall, these results indicate that the mild effects of Th haploinsufficiency on BAT function are likely due to compensatory mechanisms involving elevations in Fgf21 and Prdm16 and through adaptive changes in the lipid profile.
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Project description:In thermogenic brown adipose tissue, uncoupling protein 1 (UCP1) catalyzes the dissipation of mitochondrial proton motive force as heat. In a cellular environment of high oxidative capacity such as brown adipose tissue (BAT), mitochondrial uncoupling could also reduce deleterious reactive oxygen species, but the specific involvement of UCP1 in this process is disputed. By comparing brown adipose tissue mitochondria of wild type mice and UCP1-ablated litter mates, we show that UCP1 potently reduces mitochondrial superoxide production after cold acclimation and during fatty acid oxidation. We address the sites of superoxide production and suggest diminished probability of "reverse electron transport" facilitated by uncoupled respiration as the underlying mechanism of reactive oxygen species suppression in BAT. Furthermore, ablation of UCP1 represses the cold-stimulated increase of substrate oxidation normally seen in active BAT, resulting in lower superoxide production, presumably avoiding deleterious oxidative damage. We conclude that UCP1 allows high oxidative capacity without promoting oxidative damage by simultaneously lowering superoxide production.
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Project description:The effect of 'cafeteria diet' on mitochondrial uncoupling protein in brown adipose tissue of rats was examined. 'Cafeteria diet' induced an increase of the 32 kDa uncoupling protein in electrophoresed proteins of brown-fat mitochondria. Use of a cDNA probe corresponding to uncoupling-protein mRNA indicated that this mRNA was increased in rats fed on the 'cafeteria diet'. Nevertheless, this effect was weak compared with that observed in rats adapted to cold.
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Project description:The effect of cold exposure on thermogenic parameters such as mitochondrial protein content, GDP-binding and uncoupling protein (UCP) levels in different mitochondrial fractions from rat brown adipose tissue has been investigated. Rats were exposed from 12 h to 5 days at 4 degrees C, and three mitochondrial fractions were isolated by differential centrifugation: the M1 fraction (1000 g), the M3 fraction (3000 g) and the M15 fraction (15,000 g). Cytochrome c oxidase activity as an index of mitochondrial mass showed an increase during cold exposure. During the first 24 h of cold exposure UCP was incorporated specifically into the M3 and M15 mitochondrial fractions, and thereafter UCP appeared in the heaviest M1 fraction. However, specific GDP binding was increased during the first 24 h in the same way in all subpopulations, and this increase continued up to 72 h of cold exposure. Results suggest that different molecular events are involved during acute and chronic adaptation to cold: during the first 24 h of cold acclimatization, thermogenic activity is increased by an unmasking process of the UCP binding sites in the M1 mitochondrial fraction as UCP levels were constant and GDP binding increased, but in the M3 and M15 fraction the increase in thermogenic activity was completely due to an increase in GDP binding induced by a specific incorporation of UCP targeted to these mitochondria. Thus thermogenic parameters change in a different way in the brown-fat mitochondrial subpopulations during cold acclimatization.
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Project description:Inflammation and endoplasmic reticulum (ER) stress are hallmarks of metabolic syndrome. While these metabolic derangements have been well-investigated in white adipose tissue, their existence and etiology in brown adipose tissue (BAT) are poorly understood. Here, we aimed to investigate ER homeostasis and the inflammatory status and of BAT lacking uncoupling protein-1 (UCP1), a protein required for BAT thermogenesis. H&E staining illustrated lipid accumulation and crown-like structures surrounding adipocytes in BAT of UCP1-/- mice housed at room temperature compared to control mice. Further, immunohistological evaluation of F4/80 and gene expression studies demonstrated BAT macrophage infiltration and robust elevation of pro-inflammatory markers in UCP1-/- BAT. ER stress was also present in BAT of UCP1-/- mice, as evidenced by elevated gene expression and post-translational modifications of unfolded protein response components. After four weeks of thermoneutral housing, UCP1-/- mice did not exhibit elevated BAT inflammation and ER stress gene expression compared to WT mice, but depot expansion persisted. Collectively, we demonstrate that the effects of UCP1 deficiency in BAT are not restricted to mitochondrial uncoupling. We conclude that brown adipose tissue of UCP1-/- mice exhibits pro-inflammatory immune cell infiltration and perturbations in ER homeostasis and that this phenotype is driven by cold exposure rather than lipid accumulation.
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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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