Epigenetics: How does obesity lead to insulin resistance?
Experiments on mice show that an enzyme called DNA methyltransferase 3a is involved in insulin resistance via an epigenetic mechanism.
- The Rockefeller University, United States
Insulin is a hormone produced by the pancreas that regulates the concentration of glucose in the blood (Saltiel and Kahn, 2001; Taniguchi et al., 2006). Following a meal, insulin secretion increases glucose uptake in muscle and fat, and reduces the production of glucose by the liver, enabling blood glucose levels to be maintained within a precise range. However, in cases of chronic overnutrition, the body can become less responsive to insulin, leading to a state known as insulin resistance. Initially, the pancreas responds by secreting more insulin, but when this can no longer compensate for the impaired insulin response of the liver and other organs, type 2 diabetes develops (Prentki and Nolan, 2006).
Insulin resistance serves as a key link between obesity and type 2 diabetes (Kahn and Flier, 2000), and understanding how obesity causes insulin resistance will improve our knowledge of type 2 diabetes and our ability to treat obesity-related complications. It is likely that the development of obesity-induced insulin resistance involves a complex interplay of genetic and environmental factors (Samuel and Shulman, 2012).
One mechanism by which cells can integrate signals from the environment is through epigenetic changes: these are changes that modify DNA or the proteins that organize the DNA within cells without changing the underlying DNA sequence (Jaenisch and Bird, 2003). DNA methylation, for example, is an epigenetic change that involves adding a methyl group to a cytosine base that is upstream of guanosine. Islands of these CpG sequences are often found in the gene promoters near the start of genes, and the methylation of these bases usually reduces gene expression. Now, in eLife, Sona Kang, Evan Rosen and colleagues in the USA, Denmark and Sweden – including Dongjoo You of the University of California Berkeley as first author – report how a key epigenetic regulator called Dnmt3a contributes to obesity-related insulin resistance (You et al., 2017).
The DNA methyltransferase (Dnmt) family of enzymes catalyze the methylation of DNA (Denis et al., 2011). You et al. noticed that fat cells taken from obese mice contained high levels of two DNA methyltransferases, and experiments on fat cells grown in the laboratory suggested that one of these enzymes – Dnmt3a – had a role in the development of insulin resistance. When the researchers knocked down or inhibited Dnmt3a, the fat cells were able to take up more glucose in response to insulin, even when they had been treated with substances that induce insulin resistance. Similar results were observed in genetically engineered mice that lacked Dnmt3a in their fat cells. When placed on a high fat diet, the knockout mice gained the same amount of weight as wild-type mice, but they demonstrated improved glucose and insulin tolerance, and their fat cells responded more strongly to insulin.
You et al. then performed a screen to check if blocking or overexpressing Dnmt3a changed the level of transcription of various genes. They found that a gene called Fgf21, which encodes a secreted protein that helps fat cells to absorb glucose (Kharitonenkov et al., 2005), was transcribed less when Dnmt3a was overexpressed. Fgf21 is predominantly secreted by the liver, but fat cells are also known to express Fgf21. Based on their findings, You et al. suggest that Dnmt3a can induce insulin resistance in fat cells by methylating the CpG islands in the Fgf21 promoter region. This reduces the expression of Fgf21 genes, which in turn makes fat cells more resistant to insulin. Similar mechanisms might also be at play in human fat cells: people with diabetes had higher methylation levels near the FGF21 gene compared to people without diabetes, and the degree of methylation was also inversely correlated with the levels of FGF21 mRNA.
While insulin resistance may play a fundamental role in the development of type 2 diabetes in obese individuals, currently available anti-diabetic agents that target insulin resistance are limited to a single class of drugs called thiazolidinediones, which are no longer widely used due to potential side effects (Yki-Järvinen, 2004). DNA methylation has been an attractive therapeutic target in other clinical contexts, such as cancer. Therefore, targeting Dnmt3a or Fgf21 could provide new treatment opportunities for obesity-related complications such as insulin resistance.
You et al.’s study raises several key questions that could be addressed in future studies. First, the mechanism underlying the upregulation of Dnmt3a in obesity is not clear. Second, the repression of Fgf21 appears to explain only some of the downstream actions of Dnmt3a. Further research may be able to identify additional genes and pathways that are regulated by Dnmt3a, which could help with the development of alternative treatments for insulin resistance.
References
-
Obesity and insulin resistanceJournal of Clinical Investigation 106:473–481.https://doi.org/10.1172/JCI10842
-
FGF-21 as a novel metabolic regulatorJournal of Clinical Investigation 115:1627–1635.https://doi.org/10.1172/JCI23606
-
Islet beta cell failure in type 2 diabetesJournal of Clinical Investigation 116:1802–1812.https://doi.org/10.1172/JCI29103
-
Critical nodes in signalling pathways: insights into insulin actionNature Reviews Molecular Cell Biology 7:85–96.https://doi.org/10.1038/nrm1837
-
ThiazolidinedionesNew England Journal of Medicine 351:1106–1118.https://doi.org/10.1056/NEJMra041001
Article and author information
Author details
Publication history
- Version of Record published: December 14, 2017 (version 1)
Copyright
© 2017, Choi et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,670
- Page views
-
- 421
- Downloads
-
- 15
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Epigenetics: How does obesity lead to insulin resistance?
eLife 6:e33298.
https://doi.org/10.7554/eLife.33298
Further reading
-
- Cell Biology
Sorting nexins (SNX) are a family of proteins containing the Phox homology domain, which shows a preferential endo-membrane association and regulates cargo sorting processes. Here, we established that SNX32, an SNX-BAR (Bin/Amphiphysin/Rvs) sub-family member associates with SNX4 via its BAR domain and the residues A226, Q259, E256, R366 of SNX32, and Y258, S448 of SNX4 that lie at the interface of these two SNX proteins mediate this association. SNX32, via its PX domain, interacts with the transferrin receptor (TfR) and Cation-Independent Mannose-6-Phosphate Receptor (CIMPR), and the conserved F131 in its PX domain is important in stabilizing these interactions. Silencing of SNX32 leads to a defect in intracellular trafficking of TfR and CIMPR. Further, using SILAC-based differential proteomics of the wild-type and the mutant SNX32, impaired in cargo binding, we identified Basigin (BSG), an immunoglobulin superfamily member, as a potential interactor of SNX32 in SHSY5Y cells. We then demonstrated that SNX32 binds to BSG through its PX domain and facilitates its trafficking to the cell surface. In neuroglial cell lines, silencing of SNX32 leads to defects in neuronal differentiation. Moreover, abrogation in lactate transport in the SNX32-depleted cells led us to propose that SNX32 may contribute to maintaining the neuroglial coordination via its role in BSG trafficking and the associated monocarboxylate transporter activity. Taken together, our study showed that SNX32 mediates the trafficking of specific cargo molecules along distinct pathways.
-
- Cell Biology
- Stem Cells and Regenerative Medicine
Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange with the external environment. Little is known about the transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation and subsequent regeneration of pulmonary capillaries, as well as their response to stress. Here, we show that the transcription factor Atf3 is essential for the regenerative response of the mouse pulmonary endothelium after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in endothelial development, differentiation, and migration. During lung alveolar regeneration, this EC population expands and increases the expression of genes involved in angiogenesis, blood vessel development, and cellular response to stress. Importantly, endothelial cell-specific loss of Atf3 results in defective alveolar regeneration, in part through increased apoptosis and decreased proliferation in the endothelium. This leads to the general loss of alveolar endothelium and persistent morphological changes to the alveolar niche, including an emphysema-like phenotype with enlarged alveolar airspaces lined with regions that lack vascular investment. Taken together, these data implicate Atf3 as an essential component of the vascular response to acute lung injury that is required for successful lung alveolar regeneration.
