Molecular Mechanism of Insulin Resistance in Offspring of Obese Fathers

• Published in: The FASEB journal 2017-04, Vol.31 (S1)
• Main Authors: Liu, Xinhao, Consitt, Leslie, Nowak, Felicia, Slyvka, Yuriy
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.31.1_supplement.lb727

Abstract only Parental diet and increased BMI are correlated with abnormal metabolic profile of offspring. Male offspring of high fat diet‐fed obese father have increased mesenteric adipose tissue (MAT) at 12 months and show increased systemic insulin resistance (IR) when compared to that of lean father. Hypothesis of our study is IR develops in offspring due to abnormal adipokine production under epigenetic regulation in adipose tissue, decreasing glucose uptake in muscle contributing to systemic IR. Our present goals are 1) to investigate the synthesis and trafficking of GLUT4 in muscle, the largest organ using glucose; and 2) to investigate the differential gene expression pattern focusing on adipokines and intracellular signaling molecules and differentially methylated sites in MAT in IR offspring. To achieve our objectives, male C57B/6 mice were placed on either LFD (10%) (Gr1) or HFD (45%) (Gr2) for 12 weeks, and then mated with females who had been on LFD. Offspring were maintained on regular chow. Glucose Insulin resistance Index was calculated based on blood insulin and glucose level at 30 mins of Glucose Tolerance Test. Gastrocnemius muscles and MAT were obtained from male offspring at 12 months. Total cell homogenates, subcellular plasma membrane, and GSV fractions were analyzed for GLUT‐4 by Western blot. Results showed increased Insulin resistance Index (IRI), a measure of insulin sensitivity, in 12 months in male offspring in Gr2 when compared with Gr1. Expression of total Glut‐4, 46kd band, shows no difference between Gr1 and Gr2. We developed a subcellular fractionation protocol to measure GLUT‐4 in the plasma membrane and Glucose Storage Vesicles (GSV) to investigate Glut‐4 trafficking which can affect GLUT‐4 function independent of a change in total GLUT‐4. Additional studies will include microarray analysis and methylation specific PCR of MAT. Identification of the underlying epigenetic mechanism of the change in insulin sensitivity will allow us to develop the diagnostic, therapeutic, and preventative strategies against obesity and diabetes in the offspring of obese parents.