The in vivo effects of the Pro12Ala PPARgamma2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank.
OBJECTIVE
To investigate the phenotypic effects of common polymorphisms on adipose tissue metabolism and cardiovascular risk factors, we set out to establish a biobank with the unique feature of allowing a prospective recruit-by-genotype approach. The first use of this biobank investigates the effects of the peroxisome proliferator-activated receptor (PPAR) Pro12Ala polymorphism on integrative tissue-specific physiology. We hypothesised that Ala12 allele carriers demonstrate greater adipose tissue metabolic flexibility and insulin sensitivity.


METHODS
From a comprehensive population register, subjects were recruited into a biobank, which was genotyped for the Pro12Ala polymorphism. Twelve healthy male Ala12 carriers and 12 matched Pro12 homozygotes underwent detailed physiological phenotyping using stable isotope techniques, and measurements of blood flow and arteriovenous differences in adipose tissue and muscle in response to a mixed meal containing [1,1,1-(13)C]tripalmitin.


RESULTS
Of 6,148 invited subjects, 1,072 were suitable for inclusion in the biobank. Among Pro12 homozygotes, insulin sensitivity correlated with HDL-cholesterol concentrations, and inversely correlated with blood pressure, apolipoprotein B, triglyceride and total cholesterol concentrations. Ala12 carriers showed no such correlations. In the meal study, Ala12 carriers had lower plasma NEFA concentrations, higher adipose tissue and muscle blood flow, and greater insulin-mediated postprandial hormone-sensitive lipase suppression along with greater insulin sensitivity than Pro12 homozygotes.


CONCLUSIONS
This study shows that a recruit-by-genotype approach is feasible and describes the biobank's first application, providing tissue-specific physiological findings consistent with the epidemiological observation that the PPAR Ala12 allele protects against the development of type 2 diabetes.
Tan
G D
GD
Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford OX3 7LJ, UK. garry.tan@oxlip.ox.ac.uk
Neville
M J
MJ
Liverani
E
E
Humphreys
S M
SM
Currie
J M
JM
Dennis
L
L
Fielding
B A
BA
Karpe
F
F
D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000409:Alanine; D019943:Amino Acid Substitution; D001483:Base Sequence; D001783:Blood Flow Velocity; D015992:Body Mass Index; D049628:Body Size; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply; D047495:PPAR gamma / Q000235:genetics*; D011110:Polymorphism, Genetic; D011392:Proline; D012042:Registries
D017931:DNA Primers; D005230:Fatty Acids, Nonesterified; D047495:PPAR gamma; D011392:Proline; D000409:Alanine