Endocrine Abstracts (2007) 13 P186

Mitochondrial genes related to energy homoeostasis are dysregulated in obesity and type 2 diabetes in human adipose tissue

Kirsty C McGee1, Faddy J Hardo1, Adam R Baker1, Gyanendra Tripathi1, Steven J Creely1, Nancy F da Silva1, Sudhesh Kumar1, John C Clapham2 & Philip G McTernan1

1University of Warwick, Unit for Diabetes & Metabolism, CSRI, Coventry, United Kingdom; 2Department of Molecular Pharmacology, AstraZeneca R&D, Molndal, Sweden.

Mitochondrial dysfunction has been implicated in the pathogenesis of obesity and Type 2 Diabetes Mellitus (T2DM). Recent research has investigated the role of mitochondria in skeletal muscle and suggesting mitochondrial dysregulation may be linked to T2DM. To date few studies have focused on the role of human adipose tissue (AT) in energy homoeostasis. Therefore we investigated a number of mitochondrial genes including PPARγ co-activator1 (PGC1α, mitochondrial biogenesis, ND1 and ND4 (NADH Dehydrogenase subunits I and IV, mitochondrial number) and SIRT3 (implicated in PGC1α inhibition). We examined the effect of obesity and T2DM status by collecting abdominal subcutaneous (Abd Sc) and omental (Om) AT (n=35, age: 29–48 yrs; BMI: 20.1–33.9 kg/m2); Abd Sc diabetic AT (n=7, age: 29.4–44.2 yrs, BMI:52.4–67.5 kg/m2). Our findings determined that in Abd Sc AT adiposity and T2DM significantly reduced FAS (P=0.013) COX4 (P=0.0003), and UCP2 (P<0.001) mRNA, whilst PGC1α (P=0.003) mRNA was increased. In Om fat, FAS, PGC1α, COX4 and UCP2 mRNA (P<0.0001) were all reduced. Depot specific differences were also observed. SIRT3 protein expression was reduced in T2DM Abd Sc AT (P<0.001), however no significant effect was observed with adiposity in either depot. In addition, adiposity was found to have no significant effect on either NDI nor NDIV mRNA expression in AT.

In summary these studies highlight that in Abd Sc and Om AT genes related to energy metabolism of the mitochondria appears to be reduced with a similar pattern observed in Abd Sc AT from T2DM subjects, whilst PGC1α is increased in obesity. SIRT3 is also reduced in T2DM AT, whilst NDI and IV show no expression difference between different AT. Thus suggesting a role for mitochondrial dysfunction in human adipose tissue in obesity and diabetes, although mitochondria number is not reduced. The causes of which are unclear, however candidate factors may include oxidant stress as well as lipotoxicity.

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