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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-? 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, PGC1?, ECH1, Cox8b, Dio2, Cyc1, PGC1?, PPAR?, 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.

SUBMITTER: Chrysovergis K

PROVIDER: S-EPMC4135041 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Chrysovergis K K Wang X X Kosak J J Lee S-H SH Kim J S JS Foley J F JF Travlos G G Singh S S Baek S J SJ Eling T E TE

International journal of obesity (2005) 20140217 12

<h4>Objective</h4>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.<h4>Design/subjects</h4>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 ...[more]

PMID: 24531647

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Project description:Mitochondrial dysfunction and oxidative stress-mediated inflammasome activation play critical roles in the pathogenesis of the non-alcoholic fatty liver disease (NAFLD). Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1), or growth differentiation factor-15 (GDF15), is associated with many biological processes and diseases, including NAFLD. However, the role of NAG-1/GDF15 in regulating oxidative stress and whether this process is associated with absent in melanoma 2 (AIM2) inflammasome activation in NAFLD are unknown. In this study, we revealed that NAG-1/GDF15 is significantly downregulated in liver tissues of patients with steatosis compared to normal livers using the Gene Expression Omnibus (GEO) database, and in free fatty acids (FFA, oleic acid/palmitic acid, 2:1)-induced HepG2 and Huh-7 cellular steatosis models. Overexpression of NAG-1/GDF15 in transgenic (Tg) mice significantly alleviated HFD-induced obesity and hepatic steatosis, improved lipid homeostasis, enhanced fatty acid β-oxidation and lipolysis, inhibited fatty acid synthesis and uptake, and inhibited AIM2 inflammasome activation and the secretion of IL-18 and IL-1β, as compared to their wild-type (WT) littermates without reducing food intake. Furthermore, NAG-1/GDF15 overexpression attenuated FFA-induced triglyceride (TG) accumulation, lipid metabolism deregulation, and AIM2 inflammasome activation in hepatic steatotic cells, while knockdown of NAG-1/GDF15 demonstrated opposite effects. Moreover, NAG-1/GDF15 overexpression inhibited HFD- and FFA-induced oxidative stress and mitochondrial damage which in turn reduced double-strand DNA (dsDNA) release into the cytosol, while NAG-1/GDF15 siRNA showed opposite effects. The reduced ROS production and dsDNA release may be responsible for attenuated AIM2 activation by NAG-1/GDF15 upon fatty acid overload. In conclusion, our results provide evidence that other than regulating lipid homeostasis, NAG-1/GDF15 protects against hepatic steatosis through a novel mechanism via suppressing oxidative stress, mitochondrial damage, dsDNA release, and AIM2 inflammasome activation.

Project description:Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.We used wt and triple ?1,?2,?3-Adrenergic Receptors knockout (?-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.Departing from our initial observation that ?ARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the ?ARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in ?-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in ?ARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and ?-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to ?ARs agonists for the activation of human BAT.

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

Publications

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

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