Researchers from the Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified an epigenetic marker and two genes that caused heart failure in the children and grandchildren of fruit flies with high-fat-diet-induced heart dysfunction. Reversing the epigenetic modification or over-expressing the two genes protected subsequent generations from the negative heart effects of their parents’ diet.
The findings of the study (“Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila”), which appears in Nature Communications, helps explain how obesity-related heart failure is inherited and uncovered potential targets for treatment, according to the scientists.
“Obesity is strongly correlated with lipotoxic cardiomyopathy, heart failure, and thus mortality. The incidence of obesity has reached alarming proportions worldwide, and increasing evidence suggests that the parents’ nutritional status may predispose their offspring to lipotoxic cardiomyopathy. However, to date, mechanisms underlying intergenerational heart disease risks have yet to be elucidated. Here we report that cardiac dysfunction induced by high-fat diet (HFD) persists for two subsequent generations in Drosophila and is associated with reduced expression of two key metabolic regulators, adipose triglyceride lipase (ATGL/bmm) and transcriptional cofactor PGC-1,” wrote the investigators.
“We provide evidence that targeted expression of ATGL/bmm in the offspring of HFD-fed parents protects them, and the subsequent generation, from cardio-lipotoxicity. Furthermore, we find that intergenerational inheritance of lipotoxic cardiomyopathy correlates with elevated systemic H3K27 trimethylation. Lowering H3K27 trimethylation genetically or pharmacologically in the offspring of HFD-fed parents prevents cardiac pathology. This suggests that metabolic homeostasis is epigenetically regulated across generations.”
“Scientists have hoped for many years to identify the genetic basis of obesity, but answers remained puzzling and elusive,” said Rolf Bodmer, PhD, senior author of the paper and director and professor in the development, aging, and regeneration program at SBP. “Our findings reveal an inheritance mechanism behind heart failure fueled by a high-fat diet. We also uncovered an epigenetic factor and genetic targets that could be explored to protect individuals from the effects of their parents’ or grandparents’ poor diet.”
There is evidence in humans that diet during pregnancy can have lasting effects on children. Babies born following a Dutch famine during World War II had higher rates of obesity and coronary heart diseases. Mothers who are overweight or obese are more likely to have children who have diabetes or other health difficulties. However, studying the underlying genetic and molecular mechanisms that are responsible for these observations have been difficult, hindering scientists’ ability to break the chain of inheritance.
Eighty percent of genes that cause disease in humans are also found in the fly. Additionally, their tube-shaped heart consists of only 80 cardiomyocytes (in humans, this tube folds into the four chambers of our heart). Their similarity to humans, simplicity and short life cycle—a new generation is born every fifteen days—make fruit flies an excellent model for studying the genes that contribute to human heart health, noted the researchers.
In the study, the scientists fed fruit flies a diet rich in coconut oil for five days. These flies became overweight and developed traits that mimic human lipotoxic heart disease—the accumulation of fat in heart cells—and lead to heart failure, including irregular heartbeat (arrhythmia) and weakened heart contractions. Their children and grandchildren also had heart dysfunction, even when fed a normal diet.
By comparing generations of flies born from parents who ate normal diets, the scientists identified an inherited epigenetic marker called trimethylated lysine 27 in histone 3 (H3K27me3). Reducing the level of this epigenetic mark throughout the fruit fly protected the two subsequent generations from heart dysfunction.
The researchers also identified two genes involved in metabolism that were turned down in the next two generations of flies, called bmm and PGC-1. Revving up the flies’ metabolism by overexpressing these genes also protected the hearts of the children and grandchildren of flies that ate a fatty diet. This protection lasted even if the subsequent generation consumed coconut oil.
This study provides the proof-of-concept results needed to embark on further explorations, said the scientists.
“Next, we want to determine how and when these genetic and epigenetic changes are inherited, and to what extent they arise from the mother or father,” said Bodmer. “We want to study fruit fly development at all stages—from egg to embryo to adulthood—to determine what the inherited primary changes are and at which point these changes are implemented to cause metabolic imbalance and lipotoxic heart disease. The answers we gain may help us learn how to intervene and stop these changes from passing to the next generation.”
