Trends in Molecular Medicine
Volume 10, Issue 9, September 2004, Pages 434-439
Journal home page for Trends in Molecular Medicine

CIDE-A, a novel link between brown adipose tissue and obesity

https://doi.org/10.1016/j.molmed.2004.07.005Get rights and content

Brown adipose tissue (BAT) is the major site of adaptive thermogenesis in rodents. The thermogenic activity of BAT is mediated by uncoupling proteins (Ucp1). Impaired BAT activity is believed to have an important role in the development of obesity. However, direct evidence linking BAT to obesity is scarce. Cidea, which was initially identified as a result of its sequence similarity to the apoptotic DNA fragmentation factor, is highly expressed in BAT. Mice that are deficient for Cidea showed an increase in energy expenditure and are resistant to high-fat diet-induced obesity and diabetes. Although the precise mechanism by which Cidea regulates energy homeostasis is not yet clear, Cidea appears to interact with Ucp1 in mammalian cells and inhibits its uncoupling activity when co-expressed in yeast. Therefore, Cidea offers a new option to explore the linkage between BAT and obesity.

Section snippets

Brown and white adipose tissues

Adipose tissue can be characterized into white adipose tissue (WAT) and BAT, according to their color and distinct function. BAT derives its color from extensive vascularization and densely packed mitochondria. The blood vessels and individual brown adipocytes are directly innervated by sympathetic nerve endings, which regulate adaptive thermogenesis through the release of norepinephrine and other neurotransmitters. BAT structures around the interscapular region become obvious during

Thermogenic activity of uncoupling proteins in BAT

The biochemical mechanisms that are involved in cold-induced thermogenesis in BAT require an acute upregulation of Ucp1 activity, which confers brown adipocytes the ability to uncouple ATP production from proton transport and dissipate the energy as heat [15]. The structure of Ucp1 is highly homologous to that of two other mitochondrial carriers, the ADP–ATP carrier (AAC) and the phosphate carrier (PiC), and acts as a dimer [16]. Ucp1 contains six transmembrane domains and is localized to the

Regulation of thermogenic activity in BAT

Thermogenic activity and lipid metabolism in brown adipocytes is under complex neurohormonal control, with insulin and catecholamines secreted from sympathetic nerves being the two most important regulatory factors 2, 41. Insulin binding to its receptor on the surface of adipocytes simultaneously stimulates lipogenesis and inhibits lipolysis [42]. The effect of catecholamines and the signaling mechanisms underlying the hormonal effects have been extensively studied. Brown adipocytes express a

BAT and obesity

Much of what is known about the functional relevance of BAT and thermogenesis in obesity has been obtained from studies using transgenic mouse lines that express mutant Ucp1 proteins or other proteins that could alter thermogenic activity. Mice expressing a diphtheria toxin transgene that is specifically targeted to BAT (Ucp–DTA) exhibited BAT atrophy, sensitivity to cold and became obese [44]. The development of obesity in these transgenic mice was linked to hyperphagia and severe leptin

The role of Cidea in the regulation of thermogenesis and energy expenditure

The CIDE (cell-death-inducing DFF45-like effector) protein family includes three members (Cidea, Cideb and Fsp27) in mice [6]. Their human orthologs have been identified 6, 59. The overexpression of Cidea or Cideb in various cell lines induced caspase-independent cell death 6, 7. Structural analysis suggested that the N-terminal region of Cideb consists of a novel protein–protein interaction interface [60]. In addition to high levels of expression in BAT, lower levels of Cidea mRNA were

Concluding remarks

Although the precise mechanism whereby Cidea regulates energy expenditure in BAT remains to be characterized in detail, it is clear that Cidea has an important role in the development of obesity and diabetes in rodents. Because Cidea is a relatively new discovery that is involved in the regulation of energy homeostasis and the development of obesity, questions remain that require further in vivo and in vitro analysis: what is the detailed mechanism by which Cidea regulates Ucp1 activity; and

Acknowledgements

We thank Dr Bor Luen Tang for critical comments of the manuscript and Fuxiang Yu, Zhong Li, Jing Ye, Zhihong Zhou and other members of our laboratories for their help with manuscript preparations. We apologize for not citing other relevant articles owing to space limitation. S.C.L. and P.L. are supported by grants from the Hong Kong research grant council (HKUST6141/03M to S.C.L. and HKUST 6277/03M to P.L.).

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      Furthermore Dio2 is centrally involved in the conversion of thyroxine (T4) to triiothyronine (T3), thereby driving Ucp1 gene expression [32]. An increase in EE partly depends on Ucp activity [33–35]; Ucp1 has been shown to uncouple adenosine triphosphate production from the respiratory chain in the inner mitochondrial membrane, thereby initiating energy loss via heat production [23,27,35,36]. As reported previously, the observed increase in EE in our RALA-CD mice could be driven by up-regulation of the Sirt3–Pgc1–Ucp axis [25,28] as well as of the Dio2–T3–Ucp pathway [28,37] as summarized in Figure 5.

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      Previous biochemical studies showed that all CIDE-containing proteins are involved in apoptosis. However, several current studies including a knock-out mouse study showed that CIDE-A, CIDE-B, and CIDE-3 localize to lipid droplets and the endoplasmic reticulum and are involved in lipid metabolism [12–15]. Because the disruption of lipid metabolism results in development of metabolic disorders such as diabetes, obesity and cardiovascular diseases, CIDE-containing proteins have been suggested as novel targets for therapeutic intervention of metabolic disorders.

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