Abstract
BackgroundSirtuin1 (SIRT1) regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models. In humans, SIRT1 genetic variants associate with fasting energy expenditure. To investigate the relevance of SIRT1 for human metabolism and caloric restriction, we analyzed SIRT1 genetic variants in respect to the outcome of a controlled lifestyle intervention in Caucasians at risk for type 2 diabetes.MethodsA total of 1013 non-diabetic Caucasians from the Tuebingen Family Study (TUEF) were genotyped for four tagging SIRT1 SNPs (rs730821, rs12413112, rs7069102, rs2273773) for cross-sectional association analyses with prediabetic traits. SNPs that associated with basal energy expenditure in the TUEF cohort were additionally analyzed in 196 individuals who underwent a controlled lifestyle intervention (Tuebingen Lifestyle Intervention Program; TULIP). Multivariate regressions analyses with adjustment for relevant covariates were performed to detect associations of SIRT1 variants with the changes in anthropometrics, weight, body fat or metabolic characteristics (blood glucose, insulin sensitivity, insulin secretion and liver fat, measured by magnetic resonance techniques) after the 9-month follow-up test in the TULIP study.ResultsMinor allele (X/A) carriers of rs12413112 (G/A) had a significantly lower basal energy expenditure (p = 0.04) and an increased respiratory quotient (p = 0.02). This group (rs12413112: X/A) was resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p = 0.04), had less increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p = 0.05) and an attenuated decline in liver fat (GG: -38.4%, X/A: -7.5%; p = 0.01).ConclusionSIRT1 plays a role for the individual lifestyle intervention response, possibly owing to decreased basal energy expenditure and a lower lipid-oxidation rate in rs12413112 X/A allele carriers. SIRT1 genetic variants may, therefore, represent a relevant determinant for the response rate of individuals undergoing caloric restriction and increased physical activity.
Highlights
Sirtuin1 (SIRT1) regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models
SIRT1 genetic variants in the Tuebingen Family Study (TUEF)/TULIP cohort Four SNPS of the SIRT1 gene (~35 kb, 9 exons) on chromosome 10q21.3 were selected from the HapMap according the selection criteria for genotyping: rs730821 (A/G, minor allele frequency (MAF) = 0.186 in the TUEF cohort, promoter), rs12413112 (G/A, MAF = 0.114, intron4), rs7069102 (G/C, MAF = 0.301, intron4) and rs2273773 (T/C, MAF = 0.058, intron5)
Cross-sectional TUEF study We first verified whether SIRT1 genetic variants associate with basal energy expenditure in the TUEF cohort, as shown before in a Finnish population [6]
Summary
Sirtuin (SIRT1) regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models. SIRT1 genetic variants associate with fasting energy expenditure. To investigate the relevance of SIRT1 for human metabolism and caloric restriction, we analyzed SIRT1 genetic variants in respect to the outcome of a controlled lifestyle intervention in Caucasians at risk for type 2 diabetes. G. forkhead transcription factor FOXO1, nuclear factor NF-κB (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) or PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1 alpha). Due to its ubiquitous expression, SIRT1 activity is relevant for many insulin-sensitive organs. SIRT1 down-regulates fat storage by increased lipolysis via the inactivation of PPARγ (peroxisome proliferator-activated receptor gamma) [3]. In skeletal muscle of obese mice, SIRT1 mediates the insulin sensitizing effect of resveratrol. Modest overexpression of SIRT1 protects mice against high-fat diet induced glucose intolerance and hepatic steatosis [8], so that SIRT1 may represent a promising future pharmacological target to prevent the metabolic sequelae of chronic exposure to a high-fat diet
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