Published on: January 9, 2017

Report Source: DeutschesZentrumfuerDiabetesforschung DZD

 Abstract: Mice having strong tendency to obesity already exhibits epigenetic changes at six weeks of age, inducing the liver to amplify its production of the enzyme DPP4 and release the same into the circulation. For the long term, this favors the development of a fatty liver. Much alike changes in DNA methylation are also detectable in humans with fatty liver which suggest a similar causal chain.

Complete report:

Mice having strong tendency to obesity already exhibits epigenetic changes at six weeks of age, inducing the liver to amplify its production of the enzyme DPP4 and release the same into the circulation. For the long term, this favors the development of a fatty liver. Much alike changes in DNA methylation are also detectable in humans with fatty liver which suggest a similar causal chain.

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The team of diabetes researchers from Finland, Sweden and France, has now published its results in the journal Diabetes.

DPP4 stands for dipeptidyl peptidase 4, an enzyme that inhibits the action of important intestinal hormones(Glucagon-like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP)) of the glucose metabolism by cleaving due to which they lose their effect. Numerous studies have shown that high blood glucose levels stimulate the body’s production of the enzyme. This indicates, people with non-alcoholic fatty liver disease have high DPP4 levels in the liver and in the blood. Until now, however, it was unclear whether increased DPP4 is a consequence or a trigger of fatty liver disease.

To find answers to the above questions, the scientists studied the gene regulation of the DPP4 gene in mice that are prone to obesity. Similar to identical twins, all animals of this breeding line are genetically identical. Nevertheless, some of the mice gain much more weight under the same high-fat diet and at the adult age of about 20 weeks develop a fatty liver. This suggests that the differences in weight development are due to epigenetic effects.

In their study, the researchers showed that already at the age of six weeks in the mice with a rapid weight gain, the DPP4 gene was less methylated at four specific loci, i.e. epigenetically altered, compared to the other mice. As a result, the enzyme synthesis in the liver as well as the enzyme concentrations in the blood increased significantly, depending on the blood glucose level, even before the animals developed a fatty liver.

According to the first author of publication, Christian Baumeier, “Perhaps the methylation of the gene can be compared with a dimming switch, which regulates the transcription of the gene and thus the amount of the enzyme formed. If the sites in the gene are methylated, the DPP4 synthesis in the liver cells is ‘dimmed’, that means reduced and reversed.” Furthermore, the scientists observed that later only those adult animals had a fatty liver that exhibited higher DPP4 level in the liver due to reduced methylation. “Our results clearly show that the increased concentrations of DPP4 in the liver and blood that were measured in the obese animals were not the consequence of a fatty liver. Rather the opposite was true, the altered epigenetic regulation of the gene was responsible for the development of the fatty liver,” added Sophie Saussenthaler, who shared the first authorship with Baumeier.

The greater analyses of the study has shown that the DPP4 gene in human liver is regulated by epigenetic changes just as in mice. In tissue samples from patients with severe fatty liver disease, the gene was less methylated. The degree of fat content in the liver correlated with the degree of DPP4 gene methylation and the amount of enzymes produced by the liver.

“Taken together, our results indicate that the epigenetic changes of the DPP4 gene associated with obesity have a negative effect on the liver metabolism already in young people, long before a fatty liver develops,” Annette Schürmann, leader of the study and head of the Department of Experimental Diabetology at DIfE said. “Therefore, in further studies, we should investigate how and at what point DPP4 inhibitors can be used in diabetes therapy to prevent the development of non-alcoholic fatty liver disease,” she added.

Journal Reference:

  1. Christian Baumeier, Sophie Saussenthaler, Anne Kammel, Markus Jähnert, Luisa Schlüter, Deike Hesse, MickaëlCanouil, Stephane Lobbens, Robert Caiazzo, Violeta Raverdy, François Pattou, Emma Nilsson, JussiPihlajamäki, Charlotte Ling, Philippe Froguel, Annette Schürmann, Robert W. Schwenk.Hepatic DPP4 DNA Methylation Associates With Fatty LiverDiabetes, 2017; 66 (1): 25 DOI: 2337/db15-1716

Note: The above story is based on materials provided by DeutschesZentrumfuerDiabetesforschung DZD