A humanized osteopontin mouse model and its application in immunometabolic obesity studies

Grün, Nicole G.; Zeyda, Karina; Moreno-Viedma, Verónica; Strohmeier, Karin; Staffler, Günther; Zeyda, Maximilian; Stulnig, Thomas M.

doi:10.1016/j.trsl.2016.07.009

Cited by 3 publications

(7 citation statements)

References 33 publications

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“…FOXO1 plays critical roles in the transcriptional regulation of genes involved in lipid metabolism, adipocyte differentiation, and gluconeogenesis [52], and the Foxo1 gene is regulated by the AHR [39]. SPP1 (osteopontin) is a sensitive marker for obesity in mice and humans [53–55]. Loss of the Spp1 gene causes obesity resistance in mice fed a high-fat diet [56] and is a gene regulated by the AHR [43].…”

Section: Discussionmentioning

confidence: 99%

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice

et al. 2017

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Inhibition of the aryl hydrocarbon receptor (AHR) prevents Western diet-induced obesity and fatty liver in C57Bl/6J (B6) male mice. The AHR is a ligand-activated nuclear receptor that regulates genes involved in xenobiotic metabolism and T cell differentiation. Here, we tested the hypothesis that AHR antagonism would also prevent obesity and fatty liver in female mice and that B6 mice (higher-affinity AHR) and congenic B6.D2 mice (lower-affinity AHR) would differentially respond to AHR inhibition. Female and male adult B6 and B6.D2 mice were fed control and Western diets with and without α-naphthoflavone, an AHR inhibitor. A nonlinear mixed model analysis was developed to project asymptote body mass. We found that obesity, adiposity, and liver steatosis were reduced to near control levels in all female and male B6 and B6.D2 experimental groups fed Western diet with α-naphthoflavone. However, differences were noted in that female B6.D2 versus B6 mice on Western diet became more obese; and in general, female mice to that of male mice had a greater fat mass to body mass ratio, were less responsive to α-naphthoflavone, and had reduced liver steatosis and hepatomegaly. We report that male mice fed Western diet containing α-naphthoflavone or CH-223191, another AHR inhibitor, caused reduced mRNA levels of several liver genes involved in metabolism, including Cyp1b1 and Scd1, offering evidence for a possible mechanism by which the AHR regulates obesity. In conclusion, although there are some sex- and Ahr allelic-dependent differences, AHR inhibition prevents obesity and liver steatosis in both males and females regardless of the ligand-binding capacity of the AHR. We also present evidence consistent with the notion that an AHR-CYP1B1-SCD1 axis is involved in obesity providing potentially convenient and effective targets for treatment.

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Section: Discussionmentioning

confidence: 99%

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice

et al. 2017

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“…Adoptive transfer of these senescence‐associated T cells (SA‐T cells) into the lean mice feeding a normal diet induces AT inflammation and IR . In addition, the humanized mouse model of OPN/SPP1 (hSPP1) has facilitated research regarding the roles of this molecule in obesity and IR . Compared to wild‐type (WT) animals, low‐fat diet‐fed hSPP1 mice are not different in body weight, fasting serum insulin and behavioural characteristics but have already enlarged adipocytes and elevated levels of hSSP1 expression in their gonadal AT and liver .…”

Section: Adaptive Immune Responsesmentioning

confidence: 96%

“…In addition, the humanized mouse model of OPN/SPP1 (hSPP1) has facilitated research regarding the roles of this molecule in obesity and IR . Compared to wild‐type (WT) animals, low‐fat diet‐fed hSPP1 mice are not different in body weight, fasting serum insulin and behavioural characteristics but have already enlarged adipocytes and elevated levels of hSSP1 expression in their gonadal AT and liver . After HFD feeding, homozygous hSPP1 mice did not express mouse SSP1 (mSPP1) in their ATs (gonadal and subcutaneous) and in the liver while WT mice had significantly elevated levels of mSPP1 mRNA in their ATs and liver in comparison with respective lean controls .…”

Section: Adaptive Immune Responsesmentioning

confidence: 99%

“…After HFD feeding, homozygous hSPP1 mice did not express mouse SSP1 (mSPP1) in their ATs (gonadal and subcutaneous) and in the liver while WT mice had significantly elevated levels of mSPP1 mRNA in their ATs and liver in comparison with respective lean controls . However, the expression of human SPP1 mRNA remained unchanged in gonadal AT but was significantly increased in subcutaneous AT and decreased in the liver of hSSP1 mice compared to lean controls . Furthermore, serum levels of human SPP1 also remained unchanged in these mice .…”

Section: Adaptive Immune Responsesmentioning

confidence: 99%

“…However, the expression of human SPP1 mRNA remained unchanged in gonadal AT but was significantly increased in subcutaneous AT and decreased in the liver of hSSP1 mice compared to lean controls . Furthermore, serum levels of human SPP1 also remained unchanged in these mice . In addition, Khan et al have revealed that adoptive transfer of Th1 cells into HFD‐fed TCR‐β −/− mice, which are protected from inflammation, causes immune cells infiltration in the AT and subsequent IR .…”

Section: Adaptive Immune Responsesmentioning

confidence: 99%

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An update on immune dysregulation in obesity‐related insulin resistance

2019

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Obesity is associated with chronic low‐grade inflammation of the adipose tissue (AT) that might develop into systemic inflammation, insulin resistance (IR) and an increased risk of type 2 diabetes mellitus (T2DM) in severe obese rodents and humans. In the lean state, small normal adipocytes and AT macrophages interact with each other to maintain metabolic homeostasis but during obesity, enlarged adipocytes secrete inflammatory mediators and express immune receptors to recruit immune cells and aggravate the inflammation. The better understanding of the obesity‐related inflammatory milieu and the sequential events leading to IR could be helpful in designing new preventive and therapeutic strategies. The present review will discuss the cellular and molecular abnormalities participating in the pathogenesis of obesity in obese individuals as well as high‐fat diet (HFD)‐fed mice, a mouse model of obesity.

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Grun et al. Novel murine model for studying human obesity and its complications

2016

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A humanized osteopontin mouse model and its application in immunometabolic obesity studies

Cited by 3 publications

References 33 publications

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice

An update on immune dysregulation in obesity‐related insulin resistance

Grun et al. Novel murine model for studying human obesity and its complications

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