SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention--the TULIP Study.
BACKGROUND
Sirtuin1 (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.


METHODS
A 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.


RESULTS
Minor 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).


CONCLUSIONS
SIRT1 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.
Weyrich
Peter
P
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Germany. peter.weyrich@med.uni-tuebingen.de
Machicao
Fausto
F
Reinhardt
Julia
J
Machann
Jürgen
J
Schick
Fritz
F
Tschritter
Otto
O
Stefan
Norbert
N
Fritsche
Andreas
A
Häring
Hans-Ulrich
HU
D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D015992:Body Mass Index; D031204:Caloric Restriction; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D008019:Life Style; D008099:Liver / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D040242:Risk Reduction Behavior; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics*; D044465:White People / Q000235:genetics*
C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins