Trends in Molecular Medicine
CIDE-A, a novel link between brown adipose tissue 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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Cited by (52)
Preclinical in vivo imaging for brown adipose tissue
2020, Life SciencesMolecular cloning, genomic organization, chromosome mapping, tissues expression pattern and identification of a novel splicing variant of porcine CIDEb gene
2016, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The region where porcine CIDEb is located contains some quantitative trait loci (QTLs) for fat deposition, highlighting the possible role of CIDEb in fat metabolism in pigs. Some reports have suggested that CIDEa and CIDEc might regulate lipid metabolism in diabetic individuals, and in mice these genes play a role in thermogenesis and lipolysis [6,7,9,11]. Furthermore, Zhao et al. suggested that the CIDEs genes might serve as novel targets for therapeutic interventions to manage obesity [17].
Mitochondrial proteolysis: Its emerging roles in stress responses
2015, Biochimica et Biophysica Acta - General SubjectsR-α lipoic acid γ-cyclodextrin complex increases energy expenditure: A 4-month feeding study in mice
2014, NutritionCitation Excerpt :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.
Molecular basis for homo-dimerization of the CIDE domain revealed by the crystal structure of the CIDE-N domain of FSP27
2013, Biochemical and Biophysical Research CommunicationsCitation Excerpt :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.