Abstract
Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m−2) or obese (BMI ≥ 30 kg m−2) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.
Highlights
The twin epidemics of obesity and type 2 diabetes (T2D), present major economic, social and medical challenges[1,2,3]
We found alcohol dehydrogenase 1B (ADH1B) protein expression regulates the adipokine fatty acid binding protein 4 (FABP4, known as adipocyte FABP or aP2) during adipocyte differentiation and ADH1B expression was suppressed by OB/Insulin resistance (IR)
Given our previous results in Mexican Americans, we performed an aggregation of standardized beta values from correlations between ADH1B expression and BMI or fasting plasma glucose, respectively, in four populations
Summary
The twin epidemics of obesity and type 2 diabetes (T2D), present major economic, social and medical challenges[1,2,3]. We previously reported[22] that gene expression of the cytosolic enzyme, alcohol dehydrogenase 1B (ADH1B) was strongly and significantly inversely correlated with 15 obesity-related traits tested. We made this discovery in our ongoing population genetic studies of T2D, obesity and insulin resistance in a Mexican American population from San Antonio, Texas. Those studies consisted of genome-wide gene expression analyses in abdominal subcutaneous adipose tissue following a standard 75 g glucose Oral Glucose Tolerance Test in 75 subjects. There is an ATACseq double peak immediately upstream of the transcriptional start site in adipose tissue (UCSC browser, accessed 3/23/2019), indicating potential open “active” chromatin available for the binding of transcription factors
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