PLoS One. 2015 Apr 1;10(4):e0119941. doi: 10.1371/journal.pone.0119941.

Transcriptomic Identification of ADH1B as a Novel Candidate Gene for Obesity and Insulin Resistance in Human Adipose Tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES)

 

Short Title: Obesity Gene in Mexican Americans

 

Joanne E. Curran1, Satish Kumar1, Douglas T. Cromack2,6, Shirley L. Hu3, Dawn K. Coletta4, Thomas D. Dyer1, Rector Arya1, Melanie Carless5, Devjit Tripathy6,7, John Blangero1, Ravindranath Duggirala1, Harald H. Göring1, Ralph A. DeFronzo6,7 Christopher P. Jenkinson1

 

1South Texas Diabetes and Obesity Insitute, University of Texas Health Science Center at San Antonio, TX, 2Division of Orthopedics, Department of Medicine, 7Division of Diabetes, Department of Medicine3Division of Nephrology, 4School of Life Sciences, Arizona State University, Tempe, AZ, 5Texas Biomedical Research Institute, San Antonio, TX,6South Texas Veterans Health Care System, San Antonio, TX,

 

Key words: Type 2 diabetes, Insulin Resistance, Obesity, Gene Expression, Mexican Americans, VAGES, ADH1B, Transcriptomics

 

Address for correspondence:

Christopher P. Jenkinson, Ph.D.

Professor of Medicine

Department of Medicine, Division of Diabetes

The University of Texas Rio Grande Valley

7703 Floyd Curl Drive

San Antonio, Texas 78229-3900

Phone: 210-567-6691, FAX: 210-567-6554; Email: jenkinsonc@uthscsa.edu


ABSTRACT

Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 309 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. Transcriptomic analysis was performed following quantile normalization across all tissues. After accounting for covariate effects of age and sex, the number of gene probes with significant expression above baseline was approximately 31,000. We performed multivariate regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). Quantile-quantile plots within each trait were used to select 52 genes with significant (FDR ≤ 10-4) distortion of observed vs. expected significance of correlation. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10-60) as a prime candidate for involvement in multiple relevant metabolic pathways. We compared the Illumina BeadChip derived ADH1B expression data to quantitative real time PCR data and observed significant inverse correlations with waist circumference (2.8 x 10-9), BMI (5.4 x 10-6), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.

 

SYNOPSIS

  1. Transcriptomic analysis of adipose tissue, using multivariate regression and gene sets analysis led to identification of alcohol dehydrogenase 1B (ADH1B) as a candidate gene for T2D-related traits
  2. ADH1B is highly and specifically expressed in adipose tissue
  3. ADH1B RNA expression is strongly inversely correlated with obesity and insulin resistance
  4. ADH1B protein expression was inversely correlated with BMI
  5. Circulating endogenous ethanol was inversely correlated with BMI
  6. There is currently no clear physiological role for adipose ADH1B, nor for circulating endogenous ethanol

 

Conclusions

Based on these preliminary findings we hypothesize that ADH1B contributes to obesity/insulin resistance by promoting efficient metabolism of energy from ethanol, moderating its storage as fat. In normal healthy insulin sensitive individuals with low BMI, the very high levels of adipose ADH1B function predominantly to remove excess endogenous ethanol from the circulation and convert it to acetyl CoA for energy production in the Krebs cycle. The endogenous ethanol is produced by continual low level secretion by the microflora of the gut microbiome. In individuals with high BMI, adipose tissue insulin resistance leads to decreased ADH1B expression and reduction in the conversion of endogenous ethanol to acetyl CoA and energy production.

 

cj fig1

Proposed Role for ADH1B in Obesity and Insulin Resistance. Endogenous ethanol, from the microbiome, is converted by adipose ADH1B to energy production via acetaldehyde, acetate and acetyl CoA which enters the citrate cycle. Thus, elevated levels of ADH1B could plausibly promote efficient metabolism of energy from alcohol, moderating its storage as fat.

 

 

 

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann