SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity.
OBJECTIVE
Sirtuin 1 (SIRT1) is implicated in the regulation of mitochondrial function, energy metabolism, and insulin sensitivity in rodents. No studies are available in humans to demonstrate that SIRT1 expression in insulin-sensitive tissues is associated with energy expenditure and insulin sensitivity.


METHODS
Energy expenditure (EE), insulin sensitivity, and SIRT1 mRNA adipose tissue expression (n = 81) were measured by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and quantitative RT-PCR in 247 nondiabetic offspring of type 2 diabetic patients.


RESULTS
High EE during the clamp (r = 0.375, P = 2.8 x 10(-9)) and high DeltaEE (EE during the clamp - EE in the fasting state) (r = 0.602, P = 2.5 x 10(-24)) were associated with high insulin sensitivity. Adipose tissue SIRT1 mRNA expression was significantly associated with EE (r = 0.289, P = 0.010) and with insulin sensitivity (r = 0.334, P = 0.002) during hyperinsulinemic-euglycemic clamp. Furthermore, SIRT1 mRNA expression correlated significantly with the expression of several genes regulating mitochondrial function and energy metabolism (e.g., peroxisome proliferator-activated receptor gamma coactivator-1beta, estrogen-related receptor alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A), and with several genes of the respiratory chain (e.g., including NADH dehydrogenase [ubiquinone] 1alpha subcomplex 2, cytochrome c, cytochrome c oxidase subunit IV, and ATP synthase).


CONCLUSIONS
Impaired stimulation of EE by insulin and low SIRT1 expression in insulin-sensitive tissues is likely to reflect impaired regulation of mitochondrial function associated with insulin resistance in humans.
Rutanen
Jarno
J
Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.
Yaluri
Nagendra
N
Modi
Shalem
S
Pihlajamäki
Jussi
J
Vänttinen
Markku
M
Itkonen
Paula
P
Kainulainen
Sakari
S
Yamamoto
Hiroyasu
H
Lagouge
Marie
M
Sinclair
David A
DA
Elliott
Peter
P
Westphal
Christoph
C
Auwerx
Johan
J
Laakso
Markku
M
D000328:Adult; D000818:Animals; D015992:Body Mass Index; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018482:Muscle, Skeletal / Q000502:physiology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values; D056564:Sirtuin 1 / Q000235:genetics*
D012333:RNA, Messenger; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1