Abstract 1376: The Nadph Oxidase Nox4 Controls Mkp1 Expression and Thereby the Development of White Adipose Tissue

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Katrin Schröder ◽  
Judith G Schreiber ◽  
Ralf P Brandes
Keyword(s):  
Adipose Tissue ◽  
Risk Factor ◽  
Cardiovascular Risk ◽  
Nadph Oxidase ◽  
Opposite Effect ◽  
Adipocyte Differentiation ◽  
Underlying Mechanism ◽  
3T3 Fibroblasts ◽  
Proliferation And Differentiation

Obesity is a cardiovascular risk factor. Insulin promotes the formation of adipocytes by promoting fibroblast into adipocyte differentiation. Insulin however also acts as a mitogen for fibroblasts and the balance of insulin-induced proliferation and differentiation is incompletely understood. We hypothesize that the NADPH oxidase Nox4 acts as a central switch between these two processes. In 3T3-fibroblasts Nox4 siRNA reduced the cellular radical formation and attenuated the insulin-stimulated differentiation from fibroblasts into adipocytes. Importantly, insulin-induced proliferation was enhanced by Nox4 siRNA. Accordingly, Nox4 overexpression enhanced differentiation and reduced insulin-stimulated proliferation. We generated Nox4 knockout mice to study the in vivo relevance of this observation: The amount of adipose tissue was reduced in the Nox4−/− animals as compared to their wildtype littermates suggesting indeed an attenuated adipocyte differentiation, whereas fibroblasts obtained from Nox4−/− mice presented with enhanced proliferation. To uncover the underlying mechanism, we focused on the Erk1/2 pathway. Erk1/2 signaling is prevented by dephosphorylation through the dualspecific phosphatase MKP1. Luciferase reportergene assays using the full-length MKP1 promotor revealed that Nox4 siRNA reduced, and overexpression of Nox4 as well as treatment of the cells with H 2 O 2 induced MKP1 promotor activity. Indeed, Nox4 siRNA reduced MKP1 protein expression and thus enhanced basal and insulin-induced activation of Erk1/2 in fibroblasts. Nox4 overexpression had the opposite effect. Importantly, MKP1 expression was also reduced in adipose tissue from Nox4−/− mice. Overexpression of MKP1 in fibroblastes increased insulin-induced differentiation and attenuated proliferation, whereas MKP1 siRNA had the opposite effect. We conclude that Nox4, by regulating MKP1, is essentially involved in adipocyte differentiation and development of obesity.

scholarly journals JAZF1 heterozygous knockout mice show altered adipose development and metabolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jain Jeong ◽  
Soyoung Jang ◽  
Song Park ◽  
Wookbong Kwon ◽  
Si-Yong Kim ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Knockout Mice ◽  
Metabolic Disorders ◽  
Adipocyte Differentiation ◽  
Zinc Finger Protein ◽  
Tissue Mass ◽  
In Vivo Models ◽  
Brown Adipose

Abstract Background Juxtaposed with another zinc finger protein 1 (JAZF1) is associated with metabolic disorders, including type 2 diabetes mellitus (T2DM). Several studies showed that JAZF1 and body fat mass are closely related. We attempted to elucidate the JAZF1 functions on adipose development and related metabolism using in vitro and in vivo models. Results The JAZF1 expression was precisely regulated during adipocyte differentiation of 3T3-L1 preadipocyte and mouse embryonic fibroblasts (MEFs). Homozygous JAZF1 deletion (JAZF1-KO) resulted in impaired adipocyte differentiation in MEF. The JAZF1 role in adipocyte differentiation was demonstrated by the regulation of PPARγ—a key regulator of adipocyte differentiation. Heterozygous JAZF1 deletion (JAZF1-Het) mice fed a normal diet (ND) or a high-fat diet (HFD) had less adipose tissue mass and impaired glucose homeostasis than the control (JAZF1-Cont) mice. However, other metabolic organs, such as brown adipose tissue and liver, were negligible effect on JAZF1 deficiency. Conclusion Our findings emphasized the JAZF1 role in adipocyte differentiation and related metabolism through the heterozygous knockout mice. This study provides new insights into the JAZF1 function in adipose development and metabolism, informing strategies for treating obesity and related metabolic disorders.

scholarly journals Developmental aspects of adipose tissue in GH receptor and prolactin receptor gene disrupted mice: site-specific effects upon proliferation, differentiation and hormone sensitivity

2006 ◽  
Vol 191 (1) ◽  
pp. 101-111 ◽  
Author(s):  
David J Flint ◽  
Nadine Binart ◽  
Stephanie Boumard ◽  
John J Kopchick ◽  
Paul Kelly
Keyword(s):  
Adipose Tissue ◽  
Receptor Gene ◽  
Metabolic Effects ◽  
Wild Type ◽  
Extrinsic Factors ◽  
Differentiation Potential ◽  
Site Specific ◽  
Proliferation And Differentiation

Direct metabolic effects of GH on adipose tissue are well established, but effects of prolactin (PRL) have been more controversial. Recent studies have demonstrated PRL receptors on adipocytes and effects of PRL on adipose tissue in vitro. The role of GH in adipocyte proliferation and differentiation is also controversial, since GH stimulates adipocyte differentiation in cell lines, whereas it stimulates proliferation but inhibits differentiation of adipocytes in primary cell culture. Using female gene disrupted (ko) mice, we showed that absence of PRL receptors (PRLRko) impaired development of both internal and s.c. adipose tissue, due to reduced numbers of adipocytes, an effect differing from that of reduced food intake, where cell volume is decreased. In contrast, GHRko mice exhibited major decreases in the number of internal adipocytes, whereas s.c. adipocyte numbers were increased, even though body weight was decreased by 40–50%. The changes in adipose tissue in PRLRko mice appeared to be entirely due to extrinsic factors since preadipocytes proliferated and differentiated in similar fashion to wild-type animals in vitro and their response to insulin and isoproterenol was similar to wild-type animals. This contrasted with GHRko mice, where s.c. adipocytes proliferated, differentiated, and responded to hormones in identical fashion to controls, whereas parametrial adipocytes exhibited markedly depressed proliferation and differentiation potential and failed to respond to insulin or noradrenaline. Our results provide in vivo evidence that both GH and PRL stimulate differentiation of adipocytes but that the effects of GH are site specific and induce intrinsic changes in the precursor population, which are retained in vitro.

scholarly journals Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia

2011 ◽  
Vol 300 (5) ◽  
pp. E877-E885 ◽  
Author(s):  
Qing He ◽  
Zhanguo Gao ◽  
Jun Yin ◽  
Jin Zhang ◽  
Zhong Yun ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Associated Factors ◽  
Transcriptional Activity ◽  
Adipocyte Differentiation ◽  
Gene Promoter ◽  
Underlying Mechanism ◽  
Hypoxia Response Element ◽  
Vegf Gene ◽  
Multiple Signals ◽  
Protein Levels

The transcription factor HIF-1α activity is increased in adipose tissue to contribute to chronic inflammation in obesity. However, its upstream and downstream events remain to be characterized in adipose tissue in obesity. We addressed this issue by investigating adipocyte HIF-1α activity in response to obesity-associated factors, such as adipogenesis, insulin, and hypoxia. In adipose tissue, both HIF-1α mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1α mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1α in both levels. Hypoxia enhanced only HIF-1α protein, not mRNA. PI3K and mTOR activities are required for the HIF-1α expression. Function of HIF-1α protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1α binds to the proximal hypoxia response element in the VEGF gene promoter, and its function is inhibited by a corepressor composed of HDAC3 and SMRT. These observations suggest that of the three obesity-associated factors, all of them are able to augment HIF-1α protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1α mRNA activity. Adipose tissue HIF-1α activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1α is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter.

Direct and indirect effects of leptin on preadipocyte proliferation and differentiation

2006 ◽  
Vol 290 (6) ◽  
pp. R1557-R1564 ◽  
Author(s):  
Blair Wagoner ◽  
Dorothy B. Hausman ◽  
Ruth B. S. Harris
Keyword(s):  
Adipose Tissue ◽  
Conditioned Medium ◽  
Indirect Effects ◽  
Leptin Receptor ◽  
Cell Number ◽  
Direct And Indirect Effects ◽  
Sprague Dawley ◽  
Proliferation And Differentiation

Leptin has been shown to reduce body fat in vivo. Adipocytes express the leptin receptor; therefore, it is realistic to expect a direct effect of leptin on adipocyte growth and metabolism. In vitro studies examining the effect of leptin on adipocyte metabolism require supraphysiological doses of the protein to see a decrease in lipogenesis or stimulation of lipolysis, implying an indirect action of leptin. It also is possible that leptin reduces adipose mass by inhibiting preadipocyte proliferation (increase in cell number) and/or differentiation (lipid filling). Thus we determined direct and indirect effects of leptin on preadipocyte proliferation and differentiation in vitro. We tested the effect of leptin (0–500 ng/ml), serum from leptin-infused rats (0.25% by volume), and adipose tissue-conditioned medium from leptin-infused rats (0–30% by volume) on preadipocyte proliferation and differentiation in a primary culture of cells from male Sprague-Dawley rat adipose tissue. Leptin (50 ng/ml) stimulated proliferation of preadipocytes ( P < 0.05), but 250 and 500 ng leptin/ml inhibited proliferation of both preadipocyte and stromal vascular cell fractions ( P < 0.01), as measured by [3H]thymidine incorporation. Serum from leptin-infused rats inhibited proliferation of the adipose and stromal vascular fractions ( P = 0.01), but adipose tissue-conditioned medium had no effect on proliferation of either cell fraction. None of the treatments changed preadipocyte differentiation as measured by sn-glycerophosphate dehydrogenase activity. These results suggest that leptin could inhibit preadipocyte proliferation by modifying release of a factor from tissue other than adipose tissue.

scholarly journals Transcription Factor E2F1 Knockout Promotes Mice White Adipose Tissue Browning Through Autophagy Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
Mingchen Xiong ◽  
Weijie Hu ◽  
Yufang Tan ◽  
Honghao Yu ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Underlying Mechanism ◽  
Metabolic Complications ◽  
Autophagy Inhibition ◽  
Transcription Factor E2f1

Obesity is associated with energy metabolic disturbance and is caused by long-term excessive energy storage in white adipose tissue (WAT). The WAT browning potentially reduces excessive energy accumulation, contributing an attractive target to combat obesity. As a pivotal regulator of cell growth, the transcription factor E2F1 activity dysregulation leads to metabolic complications. The regulatory effect and underlying mechanism of E2F1 knockout on WAT browning, have not been fully elucidated. To address this issue, in this study, the in vivo adipose morphology, mitochondria quantities, uncoupling protein 1 (UCP-1), autophagy-related genes in WAT of wild-type (WT) and E2F1–/– mice were detected. Furthermore, we evaluated the UCP-1, and autophagy-related gene expression in WT and E2F1–/– adipocyte in vitro. The results demonstrated that E2F1 knockout could increase mitochondria and UCP-1 expression in WAT through autophagy suppression in mice, thus promoting WAT browning. Besides, adipocytes lacking E2F1 showed upregulated UCP-1 and downregulated autophagy-related genes expression in vitro. These results verified that E2F1 knockout exerted effects on inducing mice WAT browning through autophagy inhibition in vivo and in vitro. These findings regarding the molecular mechanism of E2F1-modulated autophagy in controlling WAT plasticity, provide a novel insight into the functional network with the potential therapeutic application against obesity.

scholarly journals Antiobesity Effects of UnripeRubus coreanusMiquel and Its Constituents: AnIn VitroandIn VivoCharacterization of the Underlying Mechanism

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Dool-Ri Oh ◽  
Yujin Kim ◽  
Eun-jin Choi ◽  
Hunmi-Lee ◽  
Myung-A Jung ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Bioactive Compounds ◽  
Lipid Accumulation ◽  
Weight Control ◽  
Underlying Mechanism ◽  
Serum Glucose ◽  
Mrna Levels ◽  
Dependent Manner

Background. The objective of the present study was to perform a bioguided fractionation of unripeRubus coreanusMiquel (uRC) and evaluate the lipid accumulation system involvement in its antiobesity activity as well as study the uRC mechanism of action.Results. After the fractionation, the BuOH fraction of uRC (uRCB) was the most active fraction, suppressing the differentiation of 3T3-L1 adipocytes in a dose-dependent manner. Moreover, after an oral administration for 8 weeks in HFD-induced obese mice, uRCB (10 and 50 mg/kg/day) produced a significant decrease in body weight, food efficiency ratio, adipose tissue weight and LDL-cholesterol, serum glucose, TC, and TG levels. Similarly, uRCB significantly suppressed the elevated mRNA levels of PPARγin the adipose tissuein vivo. Next, we investigated the antiobesity effects of ellagic acid, erycibelline, 5-hydroxy-2-pyridinemethanol, m-hydroxyphenylglycine, and 4-hydroxycoumarin isolated from uRCB. Without affecting cell viability, five bioactive compounds decreased the lipid accumulation in the 3T3-L1 cells and the mRNA expression levels of key adipogenic genes such as PPARγ, C/EBPα, SREBP-1c, ACC, and FAS.Conclusion. These results suggest that uRC and its five bioactive compounds may be a useful therapeutic agent for body weight control by downregulating adipogenesis and lipogenesis.

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