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Cytokines Promote Wnt Signaling and Inflammation and Impair the Normal Differentiation and Lipid Accumulation in 3T3-L1 Preadipocytes

Published on Apr 7, 2006in Journal of Biological Chemistry
· DOI :10.1074/jbc.M512077200
Birgit Gustafson19
Estimated H-index: 19
,
Ulf Smith83
Estimated H-index: 83
Cite
Abstract
Abstract Obesity with enlarged fat cells is associated with high local concentrations of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) in the adipose tissue. We examined the effects of this inflammatory state on 3T3-L1 preadipocyte development and differentiation to mature adipose cells. Both IL-6 and TNFα impaired the normal differentiation pattern and lipid accumulation. However, IL-6 allowed a normal early induction of differentiation with inhibition of Wnt10b and Pref-1, whereas expression of CCAAT/enhancer-binding protein α, in contrast to peroxisome proliferator-activated receptor γ, was markedly reduced. TNFα also allowed a normal early induction of differentiation, whereas the terminal differentiation to adipose cells was completely prevented. However, both cytokines induced an inflammatory phenotype of the cells but with different profiles. Remarkably, both IL-6 and TNFα maintained and augmented the canonical Wnt signaling associated with low axin and high low density lipoprotein receptor-related protein (LRD), Dishevelled, and β-catenin levels. TNFα, but not IL-6, activated Wnt10b expression, whereas IL-6 increased the apparent phosphorylation of Dishevelled. Thus, both IL-6 and TNFα prevent the normal development of preadipocytes to fully differentiated adipose cells and, instead, promote an inflammatory phenotype of the adipocytes. These results provide an explanation as to why obesity and diabetes are associated with both local and systemic inflammation, insulin resistance, and ectopic lipid accumulation.
  • References (48)
  • Citations (186)
Cite
References48
Newest
Qi Qun Tang30
Estimated H-index: 30
,
Mads Grønborg11
Estimated H-index: 11
(Johns Hopkins University)
+ 4 AuthorsM Daniellane63
Estimated H-index: 63
(Johns Hopkins University)
CCAAT enhancer-binding protein (C/EBP)β, C/EBPα, and peroxisome proliferator activated receptor (PPAR)γ act in a cascade where C/EBPβ activates expression of C/EBPα and PPARγ, which then function as pleiotropic activators of genes that produce the adipocyte phenotype. When growth-arrested 3T3-L1 preadipocytes are induced to differentiate, C/EBPβ is rapidly expressed but still lacks DNA-binding activity. After a long (14-hour) lag, glycogen synthase kinase 3β enters the nucleus, which correlates ...
Published on Jun 24, 2005in Journal of Biological Chemistry
Jennifer A. Kennell9
Estimated H-index: 9
(UM: University of Michigan),
Ormond A. MacDougald59
Estimated H-index: 59
(UM: University of Michigan)
Abstract Wnt signaling has been reported to block apoptosis and regulate differentiation of mesenchymal progenitors through inhibition of glycogen synthase kinase 3 and stabilization of β-catenin. The effects of Wnt in preadipocytes may be mediated through Frizzled (Fz) 1 and/or Fz2 as these Wnt receptors are expressed in preadipocytes and their expression declines upon induction of differentiation. We ectopically expressed constitutively active chimeras between Wnt8 and Fz1 or Fz2 in preadipocy...
Published on Jan 21, 2005in Science41.04
Atsunori Fukuhara26
Estimated H-index: 26
(Osaka University),
Morihiro Matsuda45
Estimated H-index: 45
(Osaka University)
+ 19 AuthorsHiroko Murakami15
Estimated H-index: 15
Fat tissue produces a variety of secreted proteins (adipocytokines) with important roles in metabolism. We isolated a newly identified adipocytokine, visfatin, that is highly enriched in the visceral fat of both humans and mice and whose expression level in plasma increases during the development of obesity. Visfatin corresponds to a protein identified previously as pre–B cell colony-enhancing factor (PBEF), a 52-kilodalton cytokine expressed in lymphocytes. Visfatin exerted insulin-mimetic effe...
Published on Jan 1, 2005in Critical Reviews in Biochemistry and Molecular Biology6.07
Otto Tc1
Estimated H-index: 1
(JHUSOM: Johns Hopkins University School of Medicine),
Lane1
Estimated H-index: 1
(JHUSOM: Johns Hopkins University School of Medicine)
ABSTRACTCell culture models have been developed to study commitment and subsequent differentiation of preadipocytes into adipocytes. Bone morphogenetic protein 4 commits mesenchymal stem cells to the adipose lineage. Other factors, including Wnt signaling, cell density, and cell shape, play a role in lineage commitment. Following commitment to the adipose lineage, growth-arrested preadipocytes can differentiate to adipocytes by treatment with insulin-like growth factor 1, glucocorticoid and an a...
Published on Oct 22, 2004in Journal of Biological Chemistry
Jiajian Liu4
Estimated H-index: 4
,
Stephen R. Farmer43
Estimated H-index: 43
Abstract The differentiation of preadipocytes into adipocytes requires the suppression of canonical Wnt signaling, which appears to involve a peroxisome proliferator-activated receptor γ (PPARγ)-associated targeting of β-catenin to the proteasome. In fact, sustained activation of β-catenin by expression of Wnt1 or Wnt 10b in preadipocytes blocks adipogenesis by inhibiting PPARγ-associated gene expression. In this report, we investigated the mechanisms regulating the balance between β-catenin and...
Published on Oct 15, 2004in Development5.76
Feng Cong5
Estimated H-index: 5
,
Liang Schweizer4
Estimated H-index: 4
,
Harold E. Varmus110
Estimated H-index: 110
Wnt-induced signaling via β-catenin plays crucial roles in animal development and tumorigenesis. Both a seven-transmembrane protein in the Frizzled family and a single transmembrane protein in the LRP family (LDL-receptor-related protein 5/6 or Arrow) are essential for efficiently transducing a signal from Wnt, an extracellular ligand, to an intracellular pathway that stabilizes β-catenin by interfering with its rate of destruction. However, the molecular mechanism by which these two types of me...
Published on Oct 1, 2004in Molecular and Cellular Biology3.73
Bae-Hang Park3
Estimated H-index: 3
,
Li Qiang17
Estimated H-index: 17
,
Stephen R. Farmer43
Estimated H-index: 43
Initiation of adipogenesis in mouse preadipocytes involves the activation of a series of signaling pathways that lead to expression of a cascade of transcription factors regulating production of many hundreds of proteins responsible for the formation of mature adipocytes (22, 31). It is generally accepted that two principal players in this cascade are peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα since adipogenesis does not occur in either PPARγ- or C/EBPα-deficient mesenchymal...
Published on Aug 20, 2004in Journal of Biological Chemistry
Kenneth A. Longo12
Estimated H-index: 12
(UM: University of Michigan),
Wendy S. Wright6
Estimated H-index: 6
(UM: University of Michigan)
+ 5 AuthorsOrmond A. MacDougald59
Estimated H-index: 59
(UM: University of Michigan)
Abstract Wnt is a family of secreted signaling proteins that regulate diverse developmental processes. Activation of canonical Wnt signaling by Wnt10b inhibits differentiation of preadipocytes in vitro. To determine whether Wnt signaling blocks adipogenesis in vivo, we created transgenic mice in which Wnt10b is expressed from the FABP4 promoter. Expression of Wnt10b in adipose impairs development of this tissue throughout the body, with a decline of ∼50% in total body fat and a reduction of ∼60%...
Published on Aug 20, 2004in Journal of Biological Chemistry
Chandan Sharma17
Estimated H-index: 17
(Scott & White Hospital),
Anamika Pradeep1
Estimated H-index: 1
(Scott & White Hospital)
+ 2 AuthorsBasabi Rana1
Estimated H-index: 1
(Scott & White Hospital)
Abstract The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) belongs to the family of nuclear hormone receptors and consists of two isotypes, PPARγ1 and PPARγ2. Our earlier studies have shown that troglitazone (TZD)-mediated activation of PPARγ2 in hepatocytes inhibits growth and attenuates cyclin D1 transcription via modulating CREB levels. Because this process of growth inhibition was also associated with an inhibition of β-catenin expression at a post-translational l...
Published on Jul 1, 2004in The Prostate2.88
Yeong-Shiau Pu34
Estimated H-index: 34
(NTU: National Taiwan University),
Tzyh-Chyuan Hour22
Estimated H-index: 22
(KMU: Kaohsiung Medical University)
+ 3 AuthorsMin-Liang Kuo61
Estimated H-index: 61
(NTU: National Taiwan University)
BACKGROUND Interleukin (IL)-6-mediated anti-apoptotic effects and drug-resistance mechanisms in prostate cancer cells were investigated. METHODS IL-6 levels of PC-3 and LNCaP cells were studied by using ELISA. Protective effects of IL-6 on cytotoxic agent-induced apoptosis were studied by exogenous IL-6 in serum-starved PC-3 cells and by anti-sense IL-6 strategy. Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine IL-6 effects on Bcl-2 family prot...
Cited By186
Newest
Published on Jan 1, 2019in Frontiers in Immunology4.72
Octavio Silva-García3
Estimated H-index: 3
,
Juan J. Valdez-Alarcón13
Estimated H-index: 13
,
Víctor M. Baizabal-Aguirre13
Estimated H-index: 13
The Wnt/b-catenin signaling pathway is crucial to regulate cell proliferation and polarity, cell determination, and tissue homeostasis. The activation of Wnt/b-catenin signaling is based on the interaction between Wnt glycoproteins and seven transmembrane receptors—Frizzled (Fzd). This binding promotes recruitment of the scaffolding protein Disheveled (Dvl), which results in the phosphorylation of the co-receptor LRP5/6. The resultant molecular complex Wnt-Fzd-LRP5/6-Dvl forms a structural regio...
Published on May 1, 2019in Food and Chemical Toxicology3.77
Ferran Comas (ISCIII: Instituto de Salud Carlos III), Jèssica Latorre3
Estimated H-index: 3
(ISCIII: Instituto de Salud Carlos III)
+ 9 AuthorsMiquel Costas Salgueiro44
Estimated H-index: 44
Abstract A dual role of hydrogen sulfide (H 2 S) in inflammation is well-reported and recent studies demonstrated adipogenic effects of H 2 S in 3T3-L1 cells. Here, we aimed to investigate the effects of H 2 S on adipocyte differentiation and inflammation. H 2 S concentration in 3T3-L1 culture media was increased during adipocyte differentiation in parallel to adipogenic and Cth gene expression, and its inhibition using DL-Propargyl Glycine (PPG) impaired 3T3-L1 differentiation. GYY4137 and Na 2...
Published on Aug 28, 2019
Haya Al-Sulaiti1
Estimated H-index: 1
,
Alexander Dömling39
Estimated H-index: 39
,
Mohamed A. Elrayess5
Estimated H-index: 5
Published on May 16, 2019in JAMA Oncology22.42
Justin C. Brown1
Estimated H-index: 1
(LSU Health Sciences Center New Orleans),
Bette J. Caan76
Estimated H-index: 76
(KP: Kaiser Permanente)
+ 5 AuthorsJeffrey A. Meyerhardt73
Estimated H-index: 73
(Harvard University)
Importance Patients with colorectal cancer (CRC) are up to 4-fold more likely than individuals without a history of cancer to develop cardiovascular disease. Clinical care guidelines recommend that physicians counsel patients with CRC regarding the association between obesity (defined using body mass index [BMI] calculated as weight in kilograms divided by height in meters squared) and cardiovascular disease risk; however, this recommendation is based on expert opinion. Objective To determine wh...
Published on May 13, 2019in International Journal of Molecular Sciences4.18
Michele Longo12
Estimated H-index: 12
,
Federica Zatterale4
Estimated H-index: 4
+ 5 AuthorsClaudia Miele28
Estimated H-index: 28
Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obes...
Published on Apr 1, 2019in Nature Reviews Endocrinology24.65
Adilson L. Guilherme20
Estimated H-index: 20
(UMMS: University of Massachusetts Medical School),
Felipe Henriques5
Estimated H-index: 5
(UMMS: University of Massachusetts Medical School)
+ 1 AuthorsMichael P. Czech90
Estimated H-index: 90
(UMMS: University of Massachusetts Medical School)
Adipose tissue comprises adipocytes and many other cell types that engage in dynamic crosstalk in a highly innervated and vascularized tissue matrix. Although adipose tissue has been studied for decades, it has been appreciated only in the past 5 years that extensive arborization of nerve fibres has a dominant role in regulating the function of adipose tissue. This Review summarizes the latest literature, which suggests that adipocytes signal to local sensory nerve fibres in response to perturba...
Published on Mar 1, 2019in Obesity Medicine
Vanessa Tardio1
Estimated H-index: 1
(McGill University),
Samantha Kellett (McGill University)+ 1 AuthorsMichael A. Tsoukas9
Estimated H-index: 9
(McGill University)
Abstract Obesity is a major and rapidly growing global health concern and is known to be associated with significant morbidity and mortality. The obese state, irrespective of complication, is associated with chronic systemic inflammation, increasingly recognized as an important risk factor for the development of cardiovascular disease and insulin resistance. Several therapies used to treat obesity and associated comorbidities such as diabetes have been shown to attenuate inflammation and atheros...