1770-P: Further Evidence Supporting a Potential Role for ADH1B in Obesity

We previously showed that expression of the human cytosolic enzyme, alcohol dehydrogenase 1B (ADH1B), was inversely correlated with measures of obesity and insulin resistance in subcutaneous adipose tissue in Mexican Americans. Here, we sought to determine the relationship between ADH1B RNA, protein expression, adipogenesis and insulin action in human subcutaneous primary adipocytes in culture, derived from lean (BMI < 28 kg.m-2) and obese (BMI ≥ 30 kg.m-2) donors. ADH1B expression increased ∼160-fold during adipogenesis as preadipocytes differentiated into mature adipocytes, reaching maximal levels at 14 days whereas the expression of two homologous genes, ADH1A and ADH1C was relatively unchanged. This indicates that ADH1B may play a role in adipocyte differentiation and proliferation. Adipocytes from lean donors expressed ADH1B at higher levels compared with those from obese donors. Given the multiple passaging of these cells, this indicates likely epigenetic regulation of expression. We performed a meta-analysis of the relationship between ADH1B expression and obesity using data from four populations (Mexican Americans, African Americans, Europeans and Pima Indians). The results showed that BMI was increased by 0.56 standard deviations for each standard deviation of decreased ADH1B expression. This finding illustrates the global relevance of the inverse correlation of ADH1B expression with obesity. Insulin stimulated ADH1B expression dose dependently, with higher levels in the “lean adipocytes.” Phosphorylation of AKT, an important mediator of insulin signaling, was lower in “obese adipocytes” compared with “lean adipocytes” (p<0.01) demonstrating that the “obese adipocytes” were relatively insulin resistant. Knockdown of ADH1B expression resulted in a decrease in insulin-stimulated glucose uptake of 35% (p<0.05). Taken together, these findings show that ADH1B is involved in insulin signaling and action in human subcutaneous adipocytes and that this activity is suppressed in obesity. Disclosure C. Jenkinson: None. L.D. Morales: None. D. Tripathy: None. S.L. Hu: None. J.C. Lopez-Alvarenga: None. R. Duggirala: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. S. Mummidi: None. R. Arya: None. L. Norton: None. J. Blangero: None. A. Diaz-Badillo: None. Funding National Institutes of Health