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.
Highlights
We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose
At euthanasia (14-week diet feeding), we observed that the associated virus (AAV)-Notum treated mice had significantly decreased body weight (Fig. 1g) but similar weights of epididymal white adipose tissue (WAT), retroperitoneal WAT, and interscapular brown adipose tissues (BAT) compared to the AAV-green fluorescence protein (GFP) treated mice (Fig. 1h)
This study demonstrates that hepatic overexpression of NOTUM leads to decreased diet-induced obesity, improved glucose homeostasis, and increased lipolysis capacity in mice
Summary
We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. Purified NOTUM induced a thermogenic program in white and brown pre-adipocyte cell lines and primary pre-adipocytes in vitro, and overexpression of NOTUM using adenoviral delivery increased Ucp[1] expression in both white and brown adipose tissues and enabled the mice to maintain a core body temperature during cold e xposure[9]. Consistent with these data, aged male liver-specific Notum knockout mice on a chow diet exhibited increased obesity and impaired glucose homeostasis compared to the wild-type m ice[18], suggesting an anti-obesity function of liver-derived NOTUM
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