Acute Wnt pathway activation positively regulates leptin gene expression in mature adipocytes

Chen, Zonglan; Shao, Weijuan; Xu, Fen; Liu, Ling; Lin, BinLiang; Wei, Xiaohong; Song, Zhuolun; Lu, Huogen; Fantus, I. George; Weng, Jianping; Jin, Tianru

doi:10.1016/j.cellsig.2014.12.012

Cited by 26 publications

(24 citation statements)

References 65 publications

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Section: Discussionmentioning

confidence: 98%

“…Promoter analyses reveal the presence of an evolutionarily conserved cAMP response element (CRE) within the leptin promoter region of mouse, rat, and human (39)(40)(41). Super gel-shift assay using CREB antibody confirms direct physical interaction between CREB and CRE of the leptin promoter, which is required for Wnt3a-mediated leptin expression in primary and 3T3-L1 adipocytes (40). Furthermore, Soliman and colleagues showed that butyrate can stimulate leptin expression in fully differentiated human adipocytes at the transcriptional level by activating mitogen-activated protein kinase (MAPK) and phospho-CREB signaling in a time-dependent manner (42).…”

Section: Discussionmentioning

confidence: 99%

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Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue

Robichaux

Mei

et al. 2016

Molecular and Cellular Biology

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h Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.O besity has become a severe public health problem, and its prevalence has increased dramatically since the 1970s. In the United States, more than one-third of adults and approximately 17% of children are obese, defined as a body mass index (BMI) of 30 or above. It is projected that by 2030, more than 50% of the U.S. population will be obese (1). This dire outlook led the American Medical Association to officially recognize obesity as a disease. In addition to its direct health problems, obesity is also closely associated with other major human diseases, such as diabetes and cardiovascular diseases (2, 3). Despite its overwhelming prevalence and major health burdens, we know little about the molecular etiology of obesity and even less about its cures. At the physiology level, one major factor leading to the development of obesity is a chronic imbalance of energy homeostasis, which results in the accumulation of the excessive energy intake as fat in tissues, especially in adipocytes.Adipose tissue not only is the main reservoir for fat storage but also is an important endocrine organ that secrets various adiposederived hormones, called adipokines. As one of the most important and widely studied adipokines, leptin plays a critical role in energy balance, mainly by acting on receptors in the arcuate nucleus of the hypothalamus to suppress appetite and to increase energy expenditure (4, 5). While the circulating leptin level is proportional to the total body fat mass in rodents and human, in obese patients a reduced sensitivity to leptin leads to a failure in suppressing food intake despite increased fat stores and blood leptin levels. This apparent condition of leptin resistance is one major driver in developing obesity (6).Recent studies have implicated the involvement of Epac1 (exchange protein directly activated by cyclic AMP [cAMP])-mediated...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue

Robichaux

Mei

et al. 2016

Molecular and Cellular Biology

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“…46 Briefly, epididymal fat pads from the Wistar rats were removed and rinsed with PBS immediately after the animals were killed. The fat tissues were then minced, followed by collagenase digestion (37 °C for 1 h).…”

Section: Methodsmentioning

confidence: 99%

Curcumin represses mouse 3T3-L1 cell adipogenic differentiation via inhibiting miR-17-5p and stimulating the Wnt signalling pathway effector Tcf7l2

et al. 2017

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Understanding mechanisms underlying adipogenic differentiation may lead to the discovery of novel therapeutic targets for obesity. Wnt signalling pathway activation leads to repressed adipogenic differentiation while certain microRNAs may regulate pre-adipocyte proliferation and differentiation. We show here that in mouse white adipose tissue, miR-17-5p level is elevated after high fat diet consumption. miR-17-5p upregulates adipogenic differentiation, as its over-expression increased while its inhibition repressed 3T3-L1 differentiation. The Tcf7l2 gene encodes a key Wnt signalling pathway effector, and its human homologue TCF7L2 is a highly regarded diabetes risk gene. We found that Tcf7l2 is an miR-17-5p target and confirmed the repressive effect of Tcf7l2 on 3T3-L1 adipogenic differentiation. The natural plant polyphenol compound curcumin possesses the body weight lowering effect. We observed that curcumin attenuated miR-17-5p expression and stimulated Tcf7l2 expression in 3T3-L1 cells. These, along with the elevation of miR-17-5p expression in mouse epididymal fat tissue in response to high fat diet consumption, allowed us to suggest that miR-17-5p is among central switches of adipogenic differentiation. It activates adipogenesis via repressing the Wnt signalling pathway effector Tcf7l2, and its own expression is likely nutritionally regulated in health and disease.

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“…Wnt ligands promote the dissociation of this destructive complex and thereby prevent β-catenin from degradation, which results in cytoplasmic β-catenin accumulation and translocation into the nucleus where β-catenin co-activates the T-cell factor (TCF)/lymphoid enhancer factor family of transcription factors to inhibit adipogenesis [28][29][30]. TCF-4, also known as transcription factor 7 like-2, is an important transcription factor that triggers the downstream responsive genes of WNT signaling [31]. Hence, the Wnt/β-catenin signaling pathway, which suppresses adipocyte differentiation, is a molecular adipogenesis switch [29].…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia Altered the Fate of Cardiac Stem Cells to Adipogenesis through Inhibiting the β-Catenin/TCF-4 Pathway

Zhang

Meng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hyperglycemia is an important risk factor for the most severe cardiovascular diseases in patients with diabetes. It has been demonstrated that cardiac stem cells (CSCs) play a pivotal role in the maintenance of cardiac homeostasis and regeneration. However, the mechanism underlying the influence of diabetes on CSCs remains unclear. This study demonstrated that hyperglycemia might promote adipogenesis in CSCs, which induces a decline in myocardial regeneration capability in diabetes. Methods: CSCs were isolated and cultured in high-glucose medium. The levels of β-catenin and TCF-4 in CSCs were determined by immunofluorescence staining and western blot analysis. Adipogenic transcriptional factors and CSCs markers were also examined by flow cytometry and western blot analysis after adipogenesis induction. In addition, Oil Red O staining was performed to investigate lipid droplet formation during adipogenesis induction with or without LiCl, a potent activator of TCF/β-catenin-dependent transcription. Results: High-glucose conditions inhibited nuclear translocation of β-catenin/TCF-4 and promoted adipogenesis in CSCs. After adipogenesis induction, expression of adipogenic transcriptional factors (PPARγ, ADD1, and C/EBPα) were increased (P < 0.01) and that of CSCs markers (c-Kit, Sca-1, MDR-1, and isl-1) were decreased (P< 0.01) in CSCs in the high-glucose group. Furthermore, lipid droplet formation was increased in CSCs cultured with high glucose, while LiCl attenuated lipid droplet formation in these CSCs (P < 0.01). Conclusion: These results demonstrated that hyperglycemia inhibited the β-catenin/TCF-4 pathway and promoted CSCs adipogenesis. Our findings suggest a new opportunity for future interventional strategie for abnormal myocardial regeneration and epicardial fat in patients with diabetes.

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Acute Wnt pathway activation positively regulates leptin gene expression in mature adipocytes

Cited by 26 publications

References 65 publications

Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue

Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue

Curcumin represses mouse 3T3-L1 cell adipogenic differentiation via inhibiting miR-17-5p and stimulating the Wnt signalling pathway effector Tcf7l2

Hyperglycemia Altered the Fate of Cardiac Stem Cells to Adipogenesis through Inhibiting the β-Catenin/TCF-4 Pathway

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