image: This is a schematic description of fundamental epigenetic mechanisms. view more
Credit: ©DIfE
As the study shows, a high-fat diet during pregnancy and lactation leads to epigenetic* changes in the offspring. These changes affect metabolic pathways regulated by the gut hormone GIP**, whereby the adult offspring are more susceptible to obesity and insulin resistance, the precursor to type 2 diabetes. Similar mechanisms cannot be ruled out in humans, according to Pfeiffer.
The lead authors Michael Kruse and Farnaz Keyhani-Nejad recently published the results in collaboration with researchers of Helmholtz Zentrum München in the journal Diabetes (Kruse et al., 2016; 65:1-11; DOI: 10.2337/db15-0478).
As scientists throughout the world observe, children of obese mothers have a higher risk of obesity and metabolic disorders. Recent findings suggest that diet-related epigenetic effects may also play a causal role in this. Since humans and mice are genetically very similar, many scientists use mouse models to study such relationships under controlled conditions. Such studies on humans are not possible.
This study focused on the epigenetic effects on the GIP-regulated metabolic pathways that are triggered by the maternal diet during pregnancy and lactation. GIP is a hormone that the gut releases after food intake and which stimulates the secretion of insulin from the pancreas. It influences the metabolism of fat cells and fat oxidation in skeletal muscles and as anabolic hormone promotes the build-up of body mass. These effects are mediated by the GIP via the GIP receptor. If this receptor is lacking as in the Gipr-/- mouse, the hormone can no longer exert its natural effect, and the animals are normally protected from obesity and insulin resistance. Since the Gipr-/- mouse model is well suited for the study of GIP-regulated metabolic pathways, the researchers used this mouse strain for their study. The wild-type strain of the mouse model served as control.
First, the researchers divided the mouse mothers into three groups, who were fed different chow during pregnancy and lactation:
- Group 1: Gipr-/- mice who received a high-fat diet
- Group 2: Gipr-/- mice who received regular chow
- Group 3: Wild-type mice with intact GIP receptor, who received regular chow
After weaning, all offspring of the three groups were fed normal chow for 22 weeks followed by a high-fat diet for an additional 20 weeks.
As the scientists observed, the adult offspring of groups 1 and 3 gained a significant amount of fat mass during the 20-week high-fat diet although they ate less than the offspring of group 2. They also had heightened levels of cholesterol, glucose, and insulin in the blood. In addition, they exhibited increased adipose tissue inflammation and enlarged fat cells and oxidized less fat in their muscles. Furthermore, the researchers found that the activity of different genes was altered in group 1 and 3 in comparison to group 2. These genes play a role in fat oxidation in muscles and in inflammatory processes in adipose tissue or are involved in the regulation of energy consumption by the brain.
"The altered gene activity could partially be traced back to DNA methylation***, that is, epigenetic changes," said Pfeiffer. "Our results indicate that the GIP also plays a role in energy consumption, which is controlled by the brain, probably indirectly by reducing the insulin sensitivity of the hypothalamus," the endocrinologist added. This is an entirely new finding. It remains to be seen to what extent these results can be applied to humans. More research on this topic is needed. However, it is clear that diet not only has a direct influence on the individual, but also may affect the offspring.
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Background Information:
* Epigenetics is a relatively young field of research. It investigates altered gene functions that are not due to a change in the DNA sequence, but may nevertheless be inherited. Recent studies have increasingly suggested that diet as an environmental factor can lastingly affect gene activity, e.g. through chemical alteration (methylation) of the DNA nucleotides.
** GIP: Gastric inhibitory polypeptide
*** Explanations for the figure:
DNA methylations occur when methyl groups bind to the DNA. These can either activate or inactivate genes.
Nucleosome: Eight histone proteins form the core of a nucleosome, around which 147 base pairs of a DNA strand are wound.
Histone tail: The tails of the histone protrude from the nucleosome and can be modified by epigenetic factors. Thus, the binding of the DNA to the corresponding nucleosome is changed, so that the DNA, for example, is accessible to transcription enzymes and a specific gene is activated.
Epigenetic factors alter histone tails e.g. by transferring methyl or acetyl groups to lysine side chains. This can hinder or facilitate the activation of a gene. The direct methylation of the DNA permanently changes gene expression when it occurs in the control regions of genes (so-called CpG islets), which are made accessible through the modification of the histones.
The German Center for Diabetes Research (DZD) is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Zentrum München - German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. More information on the DZD can be found at http://www.dzd-ev.de.
The German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE) is a member of the Leibniz Association. It investigates the causes of diet-related diseases in order to develop new strategies for prevention and therapy and to provide dietary recommendations. Its research focus includes the causes and consequences of the metabolic syndrome, which is a combination of obesity, high blood pressure, insulin resistance and lipid metabolism disorder, the role of diet in healthy aging, and the biological basis of food choices and eating habits. More information at http://www.dife.de. The DIfE is a partner of the German Center for Diabetes Research (DZD), which was founded in 2009 and has since been funded by the BMBF.
The Leibniz Association is a network of 88 institutions that conduct applied basic research and provide scientific infrastructure. Leibniz institutes currently employ ca. 18,100 people - among them 9,200 scientists - with a total annual budget of nearly 1.64 billion euros. The Leibniz Association is characterized by the diversity of the topics and disciplines focused on at its institutions. The research museums of the Leibniz Association preserve and explore the natural and cultural heritage and are showcases of research, places of learning and fascination for science. More information at http://www.leibniz-gemeinschaft.de
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Journal
Diabetes