Summary: Islets of Langerhans from mice overnourished during infancy displayed DNA methylation patterns normally seen in much older animals.
Source: Baylor College of Medicine
Researchers at Baylor College of Medicine report a mechanism that helps explain how overnutrition in early life can cause long-term metabolic problems such as diabetes. Published in the journal Environmental Epigenetics, the study examined epigenetic changes in the pancreatic Islets of Langerhans, the clusters of cells that produce insulin and other hormones.
In this study, mice that experienced excess nutrition during the first 21 days after birth—an equivalent of infancy—acquired increased DNA methylation marks in their pancreatic islets. Control mice also accumulated similar methylation changes, but only later in life. These findings suggest that early overnutrition accelerates epigenetic aging in islets, potentially contributing to lifelong impairment in glucose regulation.
“It has been known for decades that mice overnourished during the suckling period remain overweight and are at higher risk for metabolic disease throughout life,” said corresponding author Dr. Robert A. Waterland, professor of pediatrics — nutrition at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital and professor of molecular and human genetics at Baylor. “Our work addresses how early dietary excess could produce persistent changes in the epigenome of insulin-producing cells.”
Previous human and animal studies have linked altered DNA methylation in pancreatic islets with type 2 diabetes and islet dysfunction. However, the origin of those methylation changes was not well understood. To investigate whether early postnatal overnutrition can permanently change islet epigenetics, the researchers compared genome-scale DNA methylation profiles from islets of overnourished and control male mice at two ages: 21 days (weaning) and 180 days (middle age).
Overnutrition was modeled by altering litter size during the suckling period. Normal litters of about ten pups served as the control group, while litters reduced to four pups created an overnourished group whose pups had greater access to maternal milk and became heavier by weaning. This natural manipulation reliably produces early-life nutritional excess without introducing additional experimental stressors.
Genome-wide methylation profiling revealed a clear pattern: islets from control mice gradually gained DNA methylation with age, while islets from overnourished mice showed many of those methylation increases already at weaning. Strikingly, a substantial portion of the methylation changes found in middle-aged control islets overlapped with those present in the much younger, 21-day-old overnourished islets.
“By the time of weaning, islets from overnourished mice already resembled the epigenetic state of much older animals,” Dr. Waterland explained. “We interpret these results as evidence that early postnatal overnutrition drives accelerated epigenetic aging in pancreatic islets. Since glucose regulation naturally deteriorates with age, premature epigenetic aging may be a key factor linking infant overnutrition to increased diabetes risk later in life.”
The team validated DNA methylation differences using quantitative bisulfite pyrosequencing and assessed gene expression changes by RT-PCR. They found that genomic regions with higher methylation in exocrine compared with endocrine pancreas were the ones that tended to gain methylation in islets during aging. These epigenetic shifts were inversely correlated with mRNA expression of genes important for beta cell function, including Rab3b, Cacnb3, Atp2a3 and Ins2. Together, these data support a model in which an age-associated epigenetic drift moves islet cells toward an exocrine-like methylation state, and that early overnutrition accelerates that drift.
Diabetes remains a major global health challenge. In the U.S. alone, millions are affected and face elevated risks of complications such as cardiovascular disease, kidney failure, vision loss and limb amputation. The present findings emphasize the importance of optimal nutrition during critical developmental windows and suggest that preventing overnutrition in infancy could reduce risk for metabolic disease later in life.
“With pediatric overnutrition and obesity increasing worldwide, understanding the long-term consequences of excessive early feeding is urgent,” said Dr. Waterland. “Our results indicate that targeting nutrition during infancy may be an effective strategy to prevent adult metabolic disease by avoiding premature epigenetic aging in key tissues like pancreatic islets.”
Source:
Baylor College of Medicine
Media Contacts:
Homa Shalchi – Baylor College of Medicine
Image Source:
The image is in the public domain.
Original Research: Open access
“Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets.” Ge Li, Tihomira D Petkova, Eleonora Laritsky, Noah Kessler, Maria S Baker, Shaoyu Zhu, Robert A Waterland. Environmental Epigenetics. doi: 10.1093/eep/dvz015
Abstract
Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets
Pancreatic islets from type 2 diabetes patients display altered DNA methylation that contributes to islet dysfunction and disease onset, yet the origins of those epigenetic changes are not fully known. This study tested whether islet DNA methylation changes with aging and whether early postnatal overnutrition causes persistent methylation alterations. The authors performed genome-scale methylation profiling on islets from male mice that were either overnourished (suckled in small litters) or reared in control litters, examined at postnatal day 21 and day 180. Methylation differences were validated by quantitative bisulfite pyrosequencing and linked to gene expression by RT-PCR. Regions hypermethylated in exocrine relative to endocrine pancreas tended to gain methylation in islets with aging, and those methylation increases correlated inversely with expression of genes relevant to beta cell function. Small-litter islets exhibited methylation changes at weaning and in adulthood, and many loci affected by early overnutrition overlapped with age-associated methylation changes in controls. These results indicate that aging-associated increases in DNA methylation reflect an epigenetic drift toward an exocrine pancreas pattern, and that early postnatal overnutrition accelerates this drift.