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Molecular Mechanism of Insulin Resistance in Offspring of Obese Fathers
Author(s) -
Liu Xinhao,
Ozbolt Joshua,
Fuchs Ryan,
Zhang Yizhu,
Consitt Leslie,
Slyvka Yuriy,
Nowak Felicia
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.851.9
Subject(s) - offspring , insulin resistance , endocrinology , medicine , glut4 , insulin , biology , glucose transporter , adipose tissue , obesity , pregnancy , carbohydrate metabolism , genetics
Parental diet and increased BMI are correlated with abnormal metabolic profile of offspring, often as a result of inherited differences in epigenetic marks. Much work has been done to investigate the effect of maternal metabolic abnormalities, such as increased BMI, or protein restriction with pregnancy, on offspring. However fewer studies have been done to investigate the effect of paternal metabolic status on offspring metabolism and disease susceptibility. Hypothesis of our study is insulin resistance developed in offspring is affected by paternal obesity via epigenetic route. Our present goals are 1) to establish the correlation between the paternal obesity induced by high fat diet (HFD) and insulin resistance in offspring; and 2) to investigate the synthesis and trafficking of GLUT4, as this insulin responsive glucose transporter greatly affects the glucose uptake by muscle and adipose cells. To achieve our objectives, male C57B/6 mice were placed on either LFD (Gr1) or HFD (Gr2) for 12 weeks, and then mated with females who had been on LFD. Offspring were maintained on regular chow. Glucose Tolerance Test GTT insulin level was obtained and HOMA was calculated based on blood insulin and glucose level. Gastrocnemius muscles were obtained from male and female offspring at 6 weeks, 6 months and 1 year. Total cell homogenates and subcellular plasma membrane and GSV fraction were analyzed for GLUT‐4 by Western blotting. Results showed there are significantly increased GTT insulin level and HOMA, a measure of inulin sensitivity, in 5–6 weeks in male offspring in Gr2 when compared with Gr1. Expression of total Glut‐4, 46kd band, shows no difference between offspring in Gr1 and Gr2. We have developed a subcellular fractionation protocol to measure the plasma membrane and Glucose Storage Vesicles (GSV) fraction to investigate Glut‐4 trafficking, which can affect GLUT‐4 function independent of a change in total GLUT‐4 protein. Future studies will include PCR quantification of mRNA for key genes involved in GLUT‐4 synthesis or trafficking and analysis of group differences in epigenetic marks. 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.