Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals.
The global prevalence of prediabetes and type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal impaired fasting blood glucose and glucose intolerance on the metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal prediabetes increases the susceptibility to diabetes in offspring through gametic epigenetic alterations. In our findings, paternal prediabetes led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of prediabetic fathers exhibited altered gene expression patterns in the pancreatic islets, with down-regulation of several genes involved in glucose metabolism and insulin signaling pathways. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal prediabetes, including reproducible changes in methylation over several insulin signaling genes. Paternal prediabetes altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapping with that of pancreatic islets in offspring. Our study uniquely revealed that prediabetes can be inherited transgenerationally through the mammalian germ line by an epigenetic mechanism.
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Yanchang
Y
Wei
Cai-Rong
CR
Yang
Yan-Ping
YP
Wei
Zhen-Ao
ZA
Zhao
Yi
Y
Hou
Heide
H
Schatten
Qing-Yuan
QY
Sun
D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D003433:Crosses, Genetic; D019175:DNA Methylation / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics*; D044127:Epigenesis, Genetic; D005220:Fathers; D005260:Female; D020022:Genetic Predisposition to Disease; D018149:Glucose Intolerance / Q000235:genetics; D040582:Inheritance Patterns / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008297:Male; D008322:Mammals / Q000235:genetics*; D011236:Prediabetic State / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013094:Spermatozoa / Q000378:metabolism; D013311:Streptozocin
D007328:Insulin; D013311:Streptozocin