NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice
Abstract We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated...
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Nature Portfolio
2021
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oai:doaj.org-article:9f677621309b4cbab1cff5fd380160192021-12-02T15:07:47ZNOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice10.1038/s41598-021-95720-12045-2322https://doaj.org/article/9f677621309b4cbab1cff5fd380160192021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95720-1https://doaj.org/toc/2045-2322Abstract We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C–C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A’s effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.Fangfei GuoMarcus SeldinMiklós PéterfySarada CharugundlaZhiqiang ZhouStephen D. LeeAlice MoutonPrashant RajbhandariWenchao ZhangMatteo PellegriniPeter TontonozAldons J. LusisDiana M. ShihNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021) |
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Medicine R Science Q |
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Medicine R Science Q Fangfei Guo Marcus Seldin Miklós Péterfy Sarada Charugundla Zhiqiang Zhou Stephen D. Lee Alice Mouton Prashant Rajbhandari Wenchao Zhang Matteo Pellegrini Peter Tontonoz Aldons J. Lusis Diana M. Shih NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice |
| description |
Abstract We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C–C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A’s effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling. |
| format |
article |
| author |
Fangfei Guo Marcus Seldin Miklós Péterfy Sarada Charugundla Zhiqiang Zhou Stephen D. Lee Alice Mouton Prashant Rajbhandari Wenchao Zhang Matteo Pellegrini Peter Tontonoz Aldons J. Lusis Diana M. Shih |
| author_facet |
Fangfei Guo Marcus Seldin Miklós Péterfy Sarada Charugundla Zhiqiang Zhou Stephen D. Lee Alice Mouton Prashant Rajbhandari Wenchao Zhang Matteo Pellegrini Peter Tontonoz Aldons J. Lusis Diana M. Shih |
| author_sort |
Fangfei Guo |
| title |
NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice |
| title_short |
NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice |
| title_full |
NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice |
| title_fullStr |
NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice |
| title_full_unstemmed |
NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice |
| title_sort |
notum promotes thermogenic capacity and protects against diet-induced obesity in male mice |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/9f677621309b4cbab1cff5fd38016019 |
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