Circulating Growth Arrest-Specific 6 Protein Is Associated With Adiposity, Systemic Inflammation, and Insulin Resistance Among Overweight and Obese Adolescents

Hsiao, Fone-Ching; Lin, Yuh Feng; Hsieh, Po Shiuan; Chu, Nain-Feng; Shieh, Yi‐Shing; Hsieh, Chang Hsun; Lee, Chien Hsing; Hung, Yi Jen

doi:10.1210/jc.2012-3179

Cited by 47 publications

(35 citation statements)

References 43 publications

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“…4c). Other disease-related genes that were upregulated by CR were the diabetes-related ankyrin repeat protein ( ANKRD23 ), whose expression in SM is increased under diabetic conditions [51] and the growth arrest-specific 6 ( GAS6 ) gene, which is strongly associated with adiposity, inflammation, and insulin resistance status among overweight people [52] (Fig. 4c).…”

Section: Resultsmentioning

confidence: 99%

Long-lasting effect of obesity on skeletal muscle transcriptome

et al. 2017

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BackgroundReduced physical activity and increased intake of calorically-dense diets are the main risk factors for obesity, glucose intolerance, and type 2 diabetes. Chronic overnutrition and hyperglycemia can alter gene expression, contributing to long-term obesity complications. While caloric restriction can reduce obesity and glucose intolerance, it is currently unknown whether it can effectively reprogram transcriptome to a pre-obesity level. The present study addressed this question by the preliminary examination of the transcriptional dynamics in skeletal muscle after exposure to overnutrition and following caloric restriction.ResultsSix male rhesus macaques of 12–13 years of age consumed a high-fat western-style diet for 6 months and then were calorically restricted for 4 months without exercise. Skeletal muscle biopsies were subjected to longitudinal gene expression analysis using next-generation whole-genome RNA sequencing. In spite of significant weight loss and normalized insulin sensitivity, the majority of WSD-induced (n = 457) and WSD-suppressed (n = 47) genes remained significantly dysregulated after caloric restriction (FDR ≤0.05). The MetacoreTM pathway analysis reveals that western-style diet induced the sustained activation of the transforming growth factor-β gene network, associated with extracellular matrix remodeling, and the downregulation of genes involved in muscle structure development and nutritional processes.ConclusionsWestern-style diet, in the absence of exercise, induced skeletal muscle transcriptional programing, which persisted even after insulin resistance and glucose intolerance were completely reversed with caloric restriction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3799-y) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Long-lasting effect of obesity on skeletal muscle transcriptome

et al. 2017

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“…We found that this cleavage, which generates a ‘soluble Axl’ (sAxl), also occurred when Axl was activated by cross-linking antibodies. Elevated sAxl in blood has recently been reported to mark multiple human disease and trauma states, including aortic aneurysm 37 , lupus flares 38 , pneumonia infection 39 , preeclampsia 40 , coronary bypass 41 , and insulin resistance 42 . We suggest that Axl cleavage, and the generation of a sAxl-GAS-6 complex, is triggered by the inflammation-induced exposure of PtdSer in these settings, and may be a broadly useful diagnostic biomarker for inflammation in human disease.…”

Section: Discussionmentioning

confidence: 99%

Diversification of TAM receptor tyrosine kinase function

et al. 2014

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Apoptotic cell clearance is critical for both tissue homeostasis and the resolution of inflammation. We found that the TAM receptor tyrosine kinases Axl and Mer played distinct roles as phagocytic receptors in these two settings, where they exhibited divergent expression, regulation, and activity. Mer acted as a tolerogenic receptor in resting macrophages and in settings of immune suppression. Conversely, Axl was an inflammatory response receptor whose expression was induced by pro-inflammatory stimuli. Axl and Mer displayed distinct ligand specificities, ligand-receptor complex formation in tissues, and receptor shedding upon activation. These differences notwithstanding, phagocytosis by either protein was strictly dependent on receptor activation that was triggered by bridging TAM receptor–ligand complexes to the ‘eat-me’ signal phosphatidylserine on apoptotic cell surfaces.

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“…This dietary synergy was still evident in parameters such as female femur length and bone marrow adiposity measured in 30 week old mice using this high fat model (32). Vitamin K is fat soluble, hence, increasing levels of adiposity with increasing age may reduce serum levels of vitamin K, and therefore reduce levels of VKDPs produced by organs other than the liver (eg, bone specific osteocalcin) as the liver could be prioritised for the utilization of vitamin K for clotting fac- levels of Gas6 were associated with obesity (which displayed increased blood pressure (BP)) and insulin resistance in adolescents (34), and Gas6 levels were increased in the secretome from atherosclerotic plaques (35). These data suggest the increased levels of Gas6 in the aorta from female HF/HF offspring may, ultimately, result in greater susceptibility in these animals to vascular disease.…”

Section: Discussionmentioning

confidence: 99%

Maternal High-Fat Diet and Offspring Expression Levels of Vitamin K–Dependent Proteins

2014

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Studies suggest that bone growth and development and susceptibility to vascular disease in later life are influenced by maternal nutrition during intrauterine and early postnatal life. There is evidence for a role of vitamin K-dependent proteins (VKDPs) including osteocalcin, matrix Gla protein, periostin, and growth-arrest specific- protein 6, in both bone and vascular development. We have examined whether there are alterations in these VKDPs in bone and vascular tissue from offspring of mothers subjected to a nutritional challenge: a high-fat diet during pregnancy and postnatally, using 6-week-old mouse offspring. Bone site-specific and sex-specific differences across femoral and vertebral bone in male and female offspring were observed. Overall a high-fat maternal diet and offspring diet exacerbated the bone changes observed. Sex-specific differences and tissue-specific differences were observed in VKDP levels in aorta tissue from high-fat diet-fed female offspring from high-fat diet-fed mothers displaying increased levels of Gas6 and Ggcx compared with those of female controls. In contrast, differences were seen in VKDP levels in femoral bone of female offspring with lower expression levels of Mgp in offspring of mothers fed a high-fat diet compared with those of controls. We observed a significant correlation in Mgp expression levels within the femur to measures of bone structure of the femur and vertebra, particularly in the male offspring cohort. In summary, the current study has highlighted the importance of maternal nutrition on offspring bone development and the correlation of VKDPs to bone structure.

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Circulating Growth Arrest-Specific 6 Protein Is Associated With Adiposity, Systemic Inflammation, and Insulin Resistance Among Overweight and Obese Adolescents

Cited by 47 publications

References 43 publications

Long-lasting effect of obesity on skeletal muscle transcriptome

Long-lasting effect of obesity on skeletal muscle transcriptome

Diversification of TAM receptor tyrosine kinase function

Maternal High-Fat Diet and Offspring Expression Levels of Vitamin K–Dependent Proteins

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