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Gender-dependent progression of systemic metabolic states in early childhood.

ABSTRACT: Little is known about the human intra-individual metabolic profile changes over an extended period of time. Here, we introduce a novel concept suggesting that children even at a very young age can be categorized in terms of metabolic state as they advance in development. The hidden Markov models were used as a method for discovering the underlying progression in the metabolic state. We applied the methodology to study metabolic trajectories in children between birth and 4 years of age, based on a series of samples selected from a large birth cohort study. We found multiple previously unknown age- and gender-related metabolome changes of potential medical significance. Specifically, we found that the major developmental state differences between girls and boys are attributed to sphingolipids. In addition, we demonstrated the feasibility of state-based alignment of personal metabolic trajectories. We show that children have different development rates at the level of metabolome and thus the state-based approach may be advantageous when applying metabolome profiling in search of markers for subtle (patho)physiological changes.

SUBMITTER: Nikkila J

PROVIDER: S-EPMC2483410 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Gender-dependent progression of systemic metabolic states in early childhood.

Nikkilä Janne J Sysi-Aho Marko M Ermolov Andrey A Seppänen-Laakso Tuulikki T Simell Olli O Kaski Samuel S Oresic Matej M

Molecular systems biology 20080603

Little is known about the human intra-individual metabolic profile changes over an extended period of time. Here, we introduce a novel concept suggesting that children even at a very young age can be categorized in terms of metabolic state as they advance in development. The hidden Markov models were used as a method for discovering the underlying progression in the metabolic state. We applied the methodology to study metabolic trajectories in children between birth and 4 years of age, based on ...[more]

PMID: 18523432

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Project description:Hepatocellular carcinoma (HCC) is the most common liver cancer and is highly malignant. Male prevalence and frequent activation of the Ras signaling pathway are distinct characteristics of HCC. However, the underlying mechanisms remain to be elucidated. By exploring Hras12V transgenic mice showing male-biased hepatocarcinogenesis, we performed a high-throughput comparative proteomic analysis based on tandem-mass-tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the tissue samples obtained from HCC (T) and their paired adjacent precancerous (P) of Hras12V transgenic male and female mice (Ras-Tg) and normal liver (W) of wild-type male and female mice (Non-Tg). The further validation and investigation were performed using quantitative real-time PCR and western blot. Totally, 5193 proteins were quantified, originating from 5733 identified proteins. Finally, 1344 differentially expressed proteins (DEPs) (quantified in all examined samples; |ratios| ? 1.5, p < 0.05) were selected for further analysis. Comparison within W, P, and T of males and females indicated that the number of DEPs in males was much higher than that in females. Bioinformatics analyses showed the common and unique cluster-enriched items between sexes, indicating the common and gender-disparate pathways towards HCC. Expression change pattern analysis revealed HCC positive/negative-correlated and ras oncogene positive/negative-correlated DEPs and pathways. In addition, it showed that the ras oncogene gradually and significantly reduced the responses to sex hormones from hepatocytes to hepatoma cells and therefore shrunk the gender disparity between males and females, which may contribute to the cause of the loss of HCC clinical responses to the therapeutic approaches targeting sex hormone pathways. Additionally, gender disparity in the expression levels of key enzymes involved in retinol metabolism and terpenoid backbone/steroid biosynthesis pathways may contribute to male prevalence in hepatocarcinogenesis. Further, the biomarkers, SAA2, Orm2, and Serpina1e, may be sex differences. In conclusion, common and unique DEPs and pathways toward HCC initiated by ras oncogene from sexually dimorphic hepatocytes provide valuable and novel insights into clinical investigation and practice.

Project description:BACKGROUND:Endocrine FGF21 and FGF19 target adipocytes and hepatocytes through betaKlotho (KLB) and FGFR tyrosine kinases effecting glucose, lipid and energy metabolism. Both factors alleviate obesity and metabolic abnormalities which are contributing factors to breast tumor progression. Genomic manipulation of hepatic FGFR4 has uncovered roles of endocrine FGF signaling in both metabolic and cellular homeostasis. Here we determined whether systemic and microenvironmental metabolic alterations caused by the FGFR4 deficiency affect tumorigenesis in breast where FGFR4 is negligible. Breast tumors were induced in the bigenic mice with ablation of FGFR4 and overexpression of TGF? that activates Her2 in the ductal and lobular epithelium surrounded by adipocytes. Mammary tumorigenesis and alterations in systemic and breast microenvironmental metabolic parameters and regulatory pathways were analyzed. RESULTS:Ablation of FGFR4 had no effect on cellular homeostasis and Her2 activity of normal breast tissue. However, the absence of FGFR4 reduced TGF?-driven breast tumor incidence and progression and improved host survival. Notable increases in hepatic and serum FGF21, ileal FGF15/19, adiponectin and adipsin, and decreases in systemic Fetuin A, IGF-1, IGFBP-1, RBP4 and TIMP1 were observed. The ablation affected adipogenesis and secretory function of adipocytes as well as lipogenesis, glycolysis and energy homeostasis associated with the functions of mitochondria, ER and peroxisomes in the breast and tumor foci. Treatment with a chemical inhibitor of NAMPT involved in the pathways inhibited the growth and survival of breast tumor cells and tumor-initiating cell-containing spheres. The FGFR4 ablation also caused elevation of inflammatory factors in the breast. CONCLUSIONS:Although the primary role of FGFR4 in metabolism occurs in hepatocytes, its ablation results in a net inhibitory effect on mammary tumor progression. We suggest that the tumor-delaying effect of FGFR4 deficiency may be in large part due to elevated anti-obesogenic FGF21 that triggers tumor-suppressing signals from both peripheral and breast adipocytes. The predominant changes in metabolic pathways suggested roles of metabolic effects from both peripheral and breast adipocytes on metabolic reprogramming in breast epithelial cells that contribute to the suppression of tumor progression. These results provide new insights into the contribution of systemic and microenvironmental metabolic effects controlled by endocrine FGF signaling to breast carcinogenesis.

Dataset Information

Gender-dependent progression of systemic metabolic states in early childhood.

Publications

Gender-dependent progression of systemic metabolic states in early childhood.

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