Center for Basic and Translational Obesity Research
PubMed | Center for Basic and Translational Obesity Research, Boston Childrens Hospital, Clinical Research Center and, The Broad Institute of MIT and Harvard and Cambridge Broad Institute
Type: | Journal: The American journal of clinical nutrition | Year: 2017
Clinical nutrition research often lacks robust markers of compliance, complicating the interpretation of clinical trials and observational studies of free-living subjects.We aimed to examine metabolomics profiles in response to 3 diets that differed widely in macronutrient composition during a controlled feeding protocol.Twenty-one adults with a high body mass index (in kg/mOf 333 metabolites, we identified 152 whose concentrations differed for 1 diet compared with the others, including diacylglycerols and triacylglycerols, branched-chain amino acids, and markers reflecting metabolic status. Analysis of groups of related metabolites, with the use of either principal components or pathways, revealed coordinated metabolic changes affected by dietary composition, including pathways related to amino acid metabolism. We constructed a classifier using the metabolites that differed between diets and were able to correctly identify the test diet from metabolite profiles in 60 of 63 cases (>95% accuracy). Analyses also suggest differential effects by diet on numerous cardiometabolic disease risk factors.Metabolomic profiling may be used to assess compliance during clinical nutrition trials and the validity of dietary assessment in observational studies. In addition, this methodology may help elucidate mechanistic pathways linking diet to chronic disease risk. This trial was registered at clinicaltrials.gov as NCT00315354.
PubMed | Center for Basic and Translational Obesity Research
Type: Journal Article | Journal: Cancer discovery | Year: 2013
PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction-resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction-sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non-small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss.