SFEBES2008 Poster Presentations Diabetes, metabolism and cardiovascular (51 abstracts)
Weight gain, on the background of human PPARγ haploinsufficiency, exposes a metabolic phenotype
Catherine Mitchell 1 , Nadia Al-Ali 1 , David Savage 2 , Helen Simpson 1 , Jian’an Luan 3 , Robert Semple 2 , Maura Agostini 1 , Nicholas Wareham 3 , Mark Gurnell 1 , Stephen O’Rahilly 2 & V Krishna Chatterjee 1
Departments of 1Medicine, 2Clinical Biochemistry, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK; 3MRC Epidemiology Unit, Cambridge, UK.
Peroxisome proliferator activated receptor gamma (PPARγ), a ligand-inducible transcription factor, is essential for adipocyte differentiation and lipogenesis. We previously described a kindred in which some individuals were heterozygous for a frameshift/premature stop mutation, (A553ΔAAAiT)fs.185(stop186) in PPARγ, with the truncated protein being non-functional and lacking dominant negative activity1. PPARγ null heterozygotes had normal fasting insulin and glucose, but doubly heterozygous subjects, with an additional defect in the gene encoding muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A), exhibited severe insulin resistance1.
Here, we report sequential observations over seven years, from an adult, heterozygous, PPARγ null male, during which period overnutrition and reduced physical activity have resulted in weight gain. When first studied in 2000, his weight and metabolic profile were normal (BMI 25.8 kg/m2; fasting insulin 46 pmol/l (<60); TG 1.5 mmol/l (<1.7), HDL-C 1.02 mmol/l (>1.03). Modest, progressive weight gain and reevaluation in 2005 (BMI 29.6 kg/m2, fasting insulin 146 pmol/l; TG 5.7 mmol/l; HDL-C 0.56 mmol/l) and in 2007 (BMI 31.7 kg/m2; fasting insulin 286 pmol/l; TG 5.2 mmol/l; HDL-C 0.69 mmol/l) indicate development of marked insulin resistance and dyslipidaemia. A hyperinsulinaemic-euglycaemic clamp study (2005) confirmed peripheral insulin resistance at high dose insulin (1.5 mU/kg per minute; peripheral glucose disposal: PPARγ null subject 5.7 mg/kg per minute, BMI matched male controls (n=9) 7.5±0.8 mg/kg per minute; glucose metabolic clearance rate: PPARγ null subject 6.1 ml/kg per minute, controls 9.6±0.9 ml/kg per minute). The deterioration in his metabolic profile is significantly greater than values from 82 normal subjects (MRC Ely population cohort) with a comparable change in BMI.
Our data indicate that modest weight gain on the background of human PPARγ haploinsufficiency exposes a metabolic phenotype, which contrasts with preservation of insulin sensitivity in heterozygous PPARγ null mice even following high fat feeding. We suggest a model in which receptor haploinsufficiency, in combination with a second ‘hit’ (either genetic or overnutrition), leads to severe insulin resistance.
1. Nat Genet 2002 31 379–384.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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