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

• Published in: International Journal of Obesity 2014-12, Vol.38 (12), p.1555-1564
• Main Authors: Chrysovergis, K, Wang, X, Kosak, J, Lee, S-H, Kim, J S, Foley, J F, Travlos, G, Singh, S, Baek, S J, Eling, T E
• Format: Article
• Language: English
• Subjects: 692/699/2743/393; 692/700/565; Adipose tissue; Adipose tissue (brown); Adipose Tissue - metabolism; Adipose Tissue - pathology; Animals; Biological and medical sciences; Blotting, Western; Body fat; Cancer; Diet, High-Fat; Eating; Energy; Energy expenditure; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Epidemiology; Food; Food intake; Gene expression; Genes; Glucose tolerance; Growth Differentiation Factor 15 - metabolism; Health Promotion and Disease Prevention; High fat diet; Humans; Immunological tolerance; Insulin; Insulin Resistance; Internal Medicine; Laboratory animals; Lipolysis; Medical research; Medical sciences; Medicine; Medicine & Public Health; Medicine, Experimental; Melanoma; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Morbidity; Mortality; Nonsteroidal anti-inflammatory drugs; Obesity; Obesity - prevention & control; original-article; Oxidative metabolism; Oxidative Stress - drug effects; Prevention; Prevention and actions; Proteins; Public Health; Public health. Hygiene; Public health. Hygiene-occupational medicine; Real-Time Polymerase Chain Reaction; Therapeutic targets; Thermogenesis; Transgenic animals; Transgenic mice; Weight control; Xenografts; Xenotransplantation
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2014.27

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.