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  • Original Article
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Animal Models

NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism

Abstract

Objective:

Obesity is a major health problem associated with high morbidity and mortality. NSAID-activated gene (NAG-1) is a TGF-β superfamily member reported to alter adipose tissue levels in mice. We investigated whether hNAG-1 acts as a regulator of adiposity and energy metabolism.

Design/Subjects:

hNAG-1 mice, ubiquitously expressing hNAG-1, were placed on a control or high-fat diet for 12 weeks. hNAG-1-expressing B16/F10 melanoma cells were used in a xenograft model to deliver hNAG-1 to obese C57BL/6 mice.

Results:

As compared with wild-type littermates, transgenic hNAG-1 mice have less white fat and brown fat despite equivalent food intake, improved glucose tolerance, lower insulin levels and are resistant to dietary- and genetic-induced obesity. hNAG-1 mice are more metabolically active with higher energy expenditure. Obese C57BL/6 mice treated with hNAG-1-expressing xenografts show decreases in adipose tissue and serum insulin levels. hNAG-1 mice and obese mice treated with hNAG-1-expressing xenografts show increased thermogenic gene expression (UCP1, PGC1α, ECH1, Cox8b, Dio2, Cyc1, PGC1β, PPARα, Elvol3) in brown adipose tissue (BAT) and increased expression of lipolytic genes (Adrb3, ATGL, HSL) in both white adipose tissue (WAT) and BAT, consistent with higher energy metabolism.

Conclusion:

hNAG-1 modulates metabolic activity by increasing the expression of key thermogenic and lipolytic genes in BAT and WAT. hNAG-1 appears to be a novel therapeutic target in preventing and treating obesity and insulin resistance.

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Acknowledgements

We thank David Goulding, Page Myers and the Necropsy core for their technical help. We thank Drs Paul Wade and Xiaoling Li for critical reading of this manuscript. There are no conflicts of interests. This research was supported by NIH, NIEHS Intramural Research Program (Eling) Z01- ES010016–14 and in part, the Center of Excellence in Livestock Diseases and Human Health, University of Tennessee (Baek).

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Correspondence to T E Eling.

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Chrysovergis, K., Wang, X., Kosak, J. et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. Int J Obes 38, 1555–1564 (2014). https://doi.org/10.1038/ijo.2014.27

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