ADAMTS5 promotes murine adipogenesis and visceral adipose tissue expansion

Bauters, Dries; Scroyen, Ilse; Deprez-Poulain, Rébecca; Lijnen, H. Roger

doi:10.1160/th16-01-0015

Cited by 17 publications

(17 citation statements)

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“…The role of ADAMTS5 in AT development and diet‐induced fatty liver disease was previously investigated. We confirm in this study that ADAMTS5‐deficient mice developed less subcutaneous and visceral AT and had a smaller liver when fed a HFD as compared to WT mice, as reported previously (Bauters et al, , , ). Furthermore, analysis of the liver revealed less triglyceride accumulation, hepatocyte ballooning, inflammation and fibrosis in livers of Adamts5 − / − ‐J versus Adamts5 +/+ ‐J mice on a HFD.…”

Section: Discussionsupporting

confidence: 92%

ADAMTS5 deficiency in mice does not affect cardiac function

Hemmeryckx

Carai

Lijnen

2019

Cell Biology International

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The aggrecanase ADAMTS5 (A Disintegrin and Metalloproteinase with ThromboSpondin type 1 motifs, member 5) and the cleavage of its substrate versican have been implicated in the development of heart valves. Furthermore, ADAMTS5 deficiency was shown to protect against diet‐induced obesity, a known risk factor for cardiovascular disease. Therefore, in this study, we investigated the potential role of ADAMTS5 in cardiac function using ADAMTS5‐deficient (Adamts5−/−) mice and their wild‐type (Adamts5+/+) counterparts exposed to a standard‐fat or a high‐fat diet (HFD). Eight‐weeks‐old Adamts5−/− and Adamts5+/+ mice were exposed to each diet for 15 weeks. Cardiac function and electrophysiology were analyzed by transthoracic echocardiogram and electrocardiogram at the end of the study. Cleavage of versican, as detected by the appearance of the DPEEAE neo‐epitope on western blotting with protein extracts, was defective in the heart of HFD‐treated Adamts5−/− as compared with Adamts5+/+ mice. ADAMTS5 deficiency led to statistically significant increases in diastolic posterior wall thickness (0.94 ± 0.023 vs. 0.82 ± 0.036 mm; P = 0.0056) and left ventricle volume (47 ± 4.5 vs. 31 ± 2.5 μL; P = 0.0043) in comparison to Adamts5+/+ mice, but only in animals on a HFD. Cardiac function parameters such as ejection fraction, fractional shortening, and stroke volume were unaffected by ADAMTS5 deficiency or diet. Electrocardiogram analysis revealed no ADAMTS5‐specific changes in either diet group. Thus, in the absence of ADAMTS5, cleavage of versican in the cardiac extracellular matrix is impaired, but cardiac function, even upon exposure to a HFD, is not markedly affected.

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Section: Discussionsupporting

confidence: 92%

ADAMTS5 deficiency in mice does not affect cardiac function

Hemmeryckx

Carai

Lijnen

2019

Cell Biology International

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“…The question remained whether the observed effects of ADAMTS5 deficiency on WAT browning were a direct effect. We have previously shown that differentiation of 3T3-F442A preadipocytes into mature adipocytes is impaired with stable Adamts5 gene silencing, and that de novo adipogenesis (fat formation) in Nude mice following injection of 3T3-F442A cells with Adamts5 knockdown was significantly reduced, as compared to control cells [14]. This is compatible with the observed reduction in SC and GON AT mass in Adamts5 −/− mice on HFD.…”

Section: Discussionsupporting

confidence: 83%

“…In general, stimulating thermogenesis in brown and/or beige adipocytes, thereby utilizing large amounts of stored energy (fatty acids and glucose), seems an attractive strategy to increase energy expenditure and thus to treat obesity and diabetes [5], [33], [49], [50]. We confirmed that after a Western-type diet, the weights of gonadal and subcutaneous adipose tissue depots were significantly lower for Adamts5 −/− mice compared to wild-type mice [14]. Hence, the identification of ADAMTS5 as a negative regulator of BAT mass and browning of WAT is potentially very promising for the development of new therapeutic strategies.…”

Section: Discussionsupporting

confidence: 73%

“…It was previously reported that ADAMTS5 is upregulated in WAT of obese mice [11], [13] and plays a role in adipogenesis and WAT development in nutritionally-induced obesity [14]. In the present study, we report a strikingly increased mass of BAT in Adamts5 −/− mice as compared to wild-type mice.…”

Section: Discussionsupporting

confidence: 71%

“…showed a positive correlation between ADAMTS5 expression in AT and inter-individual fat mass differences in genetically identical C57Bl/6J obese mice [13]. Furthermore, we have shown that ADAMTS5 promotes murine adipogenesis and WAT expansion [14]. In the present study, using a diet-induced obesity model in mice, we show that ADAMTS5 deficiency promotes BAT development as well as browning of WAT.…”

Section: Introductionsupporting

confidence: 67%

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Loss of ADAMTS5 enhances brown adipose tissue mass and promotes browning of white adipose tissue via CREB signaling

Bauters¹,

Cobbaut²,

Geys³

et al. 2017

Molecular Metabolism

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ObjectiveA potential strategy to treat obesity – and the associated metabolic consequences – is to increase energy expenditure. This could be achieved by stimulating thermogenesis through activation of brown adipose tissue (BAT) and/or the induction of browning of white adipose tissue (WAT). Over the last years, it has become clear that several metalloproteinases play an important role in adipocyte biology. Here, we investigated the potential role of ADAMTS5.MethodsMice deficient in ADAMTS5 (Adamts5−/−) and wild-type (Adamts5+/+) littermates were kept on a standard of Western-type diet for 15 weeks. Energy expenditure and heat production was followed by indirect calorimetry. To activate thermogenesis, mice were treated with the β3-adrenergic receptor (β3-AR) agonist CL-316,243 or alternatively, exposed to cold for 2 weeks.ResultsCompared to Adamts5+/+ mice, Adamts5−/− mice have significantly more interscapular BAT and marked browning of their subcutaneous (SC) WAT. Thermogenic pathway analysis indicated, in the absence of ADAMTS5, enhanced β3-AR signaling via activation of the cAMP response element-binding protein (CREB). Additional β3-AR stimulation with CL-316,243 promoted browning of WAT in Adamts5+/+ mice but had no additive effect in Adamts5−/− mice. However, cold exposure induced more pronounced browning of WAT in Adamts5−/− mice.ConclusionsThese data indicate that ADAMTS5 plays a functional role in development of BAT and browning of WAT. Hence, selective targeting of ADAMTS5 could provide a novel therapeutic strategy for treatment/prevention of obesity and metabolic diseases.

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