WNT10B mutations in human obesity

Christodoulides, Constantinos; Scarda, Alessandro; Granzotto, Marnie; Milan, Gabriella; Nora, Edoardo Dalla; Keogh, Julia M.; Pergola, Giovanni De; Stirling, Heather; Pannacciulli, Nicola; Sethi, J.; Federspil, Giovanni; Vidal-Puig, António; Farooqi, I. Sadaf; O’Rahilly, Stephen; Vettor, Roberto

doi:10.1007/s00125-006-0144-4

Cited by 128 publications

(88 citation statements)

References 17 publications

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“…Wnt signaling pathways, in particular, have been implicated in the regulation of adiposity and insulin sensitivity in both mice and humans. Although inhibition of Wnt signaling by decreased levels or activity of Wnt10b promotes obesity in mice and has been associated with obesity in humans, activation of Wnt signaling through transgenic overexpression of Wnt10b prevents obesity and improves insulin sensitivity in mice (35,53,54). Modulation of Wnt signaling by the small molecule harmine has also been shown to affect adipocyte differentiation in vitro and insulin sensitivity in vivo (55).…”

Section: Discussionmentioning

confidence: 99%

Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Tremblay¹,

Revett²,

Huard³

et al. 2009

Journal of Biological Chemistry

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Adipocyte-secreted proteins play important roles in metabolic regulation through autocrine, paracrine, and endocrine mechanisms. Using transcriptional profiling, we identified coiled-coil domain containing 80 (Ccdc80; also known as DRO1 and URB) as a novel secreted protein highly expressed in white adipose tissue. In 3T3-L1 cells Ccdc80 is expressed and secreted in a biphasic manner with high levels in postconfluent preadipocytes and terminally differentiated adipocytes. To determine whether Ccdc80 regulates adipocyte differentiation, Ccdc80 expression was manipulated using both knockdown and overexpression approaches. Small hairpin RNA-mediated silencing of Ccdc80 in 3T3-L1 cells inhibits adipocyte differentiation. This phenotype was partially reversed by treating the knockdown cells with Ccdc80-containing conditioned medium from differentiated 3T3-L1 cells. Molecular studies indicate that Ccdc80 is required for the full inhibition of T-cell factor-mediated transcriptional activity, down-regulation of Wnt/␤-catenin target genes during clonal expansion, and the subsequent induction of C/EBP␣ and peroxisome proliferator-activated receptor ␥. Surprisingly, overexpression of Ccdc80 in 3T3-L1 cells also inhibits adipocyte differentiation without affecting the repression of the Wnt/␤-catenin signaling pathway. Taken together, these data suggest that Ccdc80 plays dual roles in adipogenesis by mechanisms that involve at least in part down-regulation of Wnt/␤-catenin signaling and induction of C/EBP␣ and peroxisome proliferator-activated receptor ␥.The metabolic abnormalities associated with obesity underlie the development of insulin resistance and type 2 diabetes (1, 2). The emergence of white adipose tissue as an endocrine organ has refined our understanding of the mechanisms by which adipocytes can affect whole-body energy homeostasis (3). Adipose cells not only serve as lipid storage sites but can also secrete various autocrine, paracrine, and/or endocrine mediators referred to as adipocyte-secreted proteins or adipokines. These secreted proteins can have profound effects on energy balance and insulin sensitivity and are affected by hormonal changes, nutritional status, inflammatory mediators, and/or pharmacological treatments (4, 5). Understanding the full set of secreted proteins present in adipocytes and their regulation and activities might help reveal novel molecular links between obesity and metabolic disorders and potential therapeutic opportunities.Commitment of mesenchymal progenitor cells to the adipocyte lineage involves a complex transcriptional cascade that culminates in the induction of the basic leucine-region zipper proteins C/EBP␣, 2 C/EBP␤, and C/EBP␦, the Krüppel-like transcription factor KLF5, and the nuclear receptor PPAR␥ (6 -8). In the mouse 3T3-L1 cell line (9, 10) initiation of this cascade requires the stimulation of growth-arrested fibroblastlike cells with adipogenic inducers forcing the cells to re-enter the cell cycle allowing transcription of early adipogenic genes (11,12). This clona...

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Section: Discussionmentioning

confidence: 99%

Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Tremblay¹,

Revett²,

Huard³

et al. 2009

Journal of Biological Chemistry

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“…More recently, mutations in the Wnt-10b gene have been described in human obesity (8), and LRP5 polymorphisms have been shown to be significantly associated with obesity phenotypes (14). These observations raise the possibility that manipulating Wnt signaling, such as blocking Cby's activity, may eventually provide means to develop new therapies for obesity and its associated disorders, such as diabetes.…”

Section: Discussionmentioning

confidence: 99%

Chibby Promotes Adipocyte Differentiation through Inhibition of β-Catenin Signaling

Li¹,

Singh

Mofunanya

et al. 2007

Molecular and Cellular Biology

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The canonical Wnt/␤-catenin signaling pathway plays diverse roles in embryonic development and disease. Activation of this pathway, likely by Wnt-10b, has been shown to inhibit adipogenesis in cultured 3T3-L1 preadipocytes and in mice. Here, we report that the ␤-catenin antagonist Chibby (Cby) is required for adipocyte differentiation. Cby is expressed in adipose tissue in mice, and Cby protein levels increase during adipogenic differentiation of 3T3-L1 cells. Ectopic expression of Cby induces spontaneous differentiation of these cells into mature adipocytes to an extent similar to that of dominant-negative Tcf-4. In contrast, depletion of Cby by RNA interference potently blocks adipogenesis of 3T3-L1 and mouse embryonic stem cells. In support of this, embryonic fibroblasts obtained from Cby-deficient embryos display attenuated differentiation to the adipogenic lineage. Mechanistically, Cby promotes adipocyte differentiation, in part by inhibiting ␤-catenin, since gain or loss of function of Cby influences ␤-catenin signaling in 3T3-L1 cells. Our results therefore establish Cby as a novel proadipogenic factor required for adipocyte differentiation.Adipose tissue plays critical roles in the regulation of energy homeostasis by storing and releasing fuel as a reservoir and by secreting a number of hormones and cytokines as an endocrine organ (37). Excess body fat, or obesity, is a major public health problem, particularly in industrialized countries, increasing the risk of diabetes, cardiovascular diseases and several types of cancers (28, 37). Conversely, lipoatrophy, the lack of adipose tissue, is also associated with diabetes and a number of other metabolic abnormalities (32). Hence, understanding the signaling pathways that govern adipocyte differentiation is necessary to develop comprehensive therapeutic strategies for the prevention and treatment of these disorders.Adipogenesis involves the formation of preadipocytes from mesenchymal progenitor cells and their differentiation into adipocytes (29,33,34). The cellular and molecular mechanisms of adipocyte differentiation have been extensively studied using preadipocyte culture systems, such as 3T3-L1 and 3T3-F442A cell lines (10,31,33,34). In response to hormonal stimuli of adipogenesis, two transcription factors, CCAAT/ enhancer-binding protein ␤ (C/EBP␤) and C/EBP␦, are rapidly and transiently induced. These proteins then stimulate expression of the key adipogenic transcription factors, C/EBP␣ and peroxisome proliferator-activated receptor ␥ (PPAR␥), which act synergistically to induce expression of various adipocyte-specific genes.Intracellular signaling by the Wnt family of secreted glycoproteins regulates cell proliferation, differentiation, and polarity throughout vertebrate embryonic development (27,44,46). ␤-Catenin plays a pivotal role as a transcriptional coactivator in the canonical Wnt pathway (39). In the absence of Wnt signaling, cytoplasmic ␤-catenin becomes phosphorylated by glycogen synthase kinase-3␤ (GSK-3␤) in a complex containing Axin and t...

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“…In one report, using a candidate gene approach, a heterozygous mutation in the WNT10B gene was found in a proband with early onset obesity but not in 600 healthy controls (Christodoulides et al 2006a). Although this clearly suggests a relevant role of WNT signalling molecules in the pathogenesis of obesity in humans, this single mutation does not represent a common mechanism in the large preponderance of subjects suffering from obesity.…”

Section: Wnt Molecules In the Determination Of Preadipocytesmentioning

confidence: 99%

“…In 2006, a pathophysiological role of canonical WNT10B signalling could also be demonstrated in humans. Sequencing the WNT10B gene in two independent populations with more than 200 obese individuals identified a proband with early onset obesity carrying a C256Y mutation in the WNT10B gene, which abrogated the ability of WNT10B to activate the canonical signalling pathway (Christodoulides et al 2006a). As a consequence, adipogenesis is no longer inhibited, which might explain the occurrence of severe obesity.…”

Section: Wnt Molecules In the Determination Of Preadipocytesmentioning

confidence: 99%

Role of WNT pathway in the determination of human mesenchymal stem cells into preadipocytes

Laudes¹

2011

Journal of Molecular Endocrinology

107

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The development of obesity is characterised not only by increased storage of lipids in existing fat cells but also by the generation of new adipocytes from progenitor cells. This process, called adipogenesis, can be divided into two related steps. First, during determination, multipotent mesenchymal stem cells commit to preadipocytes. These cells exhibit similar morphology compared with stem cells; however, they are committed to the adipogenic lineage and are not longer able to transform into osteoblasts, myocytes or chondrocytes. Secondly, during differentiation, preadipocytes become mature fat cells. As in other developmental processes, adipogenesis is tightly regulated at a molecular level by several transcription factors. Within the last decade, it has also become clear how the activity of these transcription factors is coordinated by extracellular signals. In this respect, secreted WNT signalling molecules are particularly important. Several members of the WNT family have been shown to inhibit early steps of adipogenesis. Conversely, endogenous inhibitors of WNT signalling were found to promote generation of adipocytes, indicating a fundamental role of these bioactive peptides in adipogenesis. From a pathophysiological point of view, it is of interest that polymorphisms in genes of the WNT signalling system have been associated with the development of obesity and type 2 diabetes in humans. Moreover, recent findings indicate that certain WNT molecules are involved in the so-called low-grade inflammation of adipose tissue, which is crucial in the development of obesity-associated insulin resistance. These important findings in nutritional and metabolic medicine will be summarised in the present review.

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WNT10B mutations in human obesity

Cited by 128 publications

References 17 publications

Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Chibby Promotes Adipocyte Differentiation through Inhibition of β-Catenin Signaling

Role of WNT pathway in the determination of human mesenchymal stem cells into preadipocytes

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