U.S. Department of Health and Human Services

Fat Cell Gene May Protect Against Type 2 Diabetes

New research describes how adipose (fat) tissue can protect the body from type 2 diabetes by influencing systemic insulin sensitivity. Insulin, a hormone produced in the pancreas, stimulates the uptake of glucose in multiple tissues, providing fuel for cells. Adipocytes (fat cells) are sensitive to fluctuations in nutrient availability; they are able to sense and respond to changes in glucose levels. For example, in response to insulin and high levels of glucose, glucose uptake is stimulated in adipose tissue by the transporter protein GLUT4. In obesity, however, GLUT4’s activity is reduced in adipose tissue, blocking glucose from entering the fat cells and leading to adverse whole body metabolic effects, including insulin resistance. How this altered adipose tissue glucose metabolism causes whole body insulin resistance has remained a key question. 

Knowing that GLUT4 is central to regulation of adipose tissue metabolism, the researchers analyzed changes in the levels of gene activity in mice that were genetically engineered to have high levels of GLUT4 in adipose tissue or to lack GLUT4 specifically in that tissue. This approach enabled the scientists to identify factors involved in the adipocyte glucose response. They observed that a set of genes involved in producing fats was upregulated in mice with high levels of adipose GLUT4 and downregulated in mice lacking adipose GLUT4. High levels of these fat producing genes in fat cells were previously shown to be associated with the metabolic benefits of enhanced glucose tolerance and insulin sensitivity. Mice with high levels of adipose GLUT4 displayed both of these characteristics, despite being obese. The scientists discovered that, in the mice, the enhanced glucose tolerance and insulin sensitivity required a factor called ChREBP. 

To extend their findings to humans, the researchers looked at levels of expression—gene activity—of the ChREBP and GLUT4 genes and insulin sensitivity in over a hundred individuals without diabetes (with normal glucose levels) and with widely ranging body mass index values. They found that adipose levels of ChREBP expression correlated strongly with GLUT4 expression levels and insulin sensitivity, consistent with a role for ChREBP in GLUT4 mediated glucose metabolism. Because not all obese people are insulin resistant, the investigators looked at ChREBP levels and insulin stimulated glucose uptake in obese individuals with widely ranging insulin sensitivity.

They observed that ChREBP was strongly correlated with insulin sensitivity, suggesting that ChREBP could be a protective factor against obesity associated insulin resistance. Additional experiments to understand the mechanism of this protection identified a novel form of ChREBP, called ChREBP β, and higher levels of this form specifically predicted insulin sensitivity in humans. 

These results indicate the importance of ChREBP in regulating adipocyte and whole body glucose control and insulin sensitivity, showing that some features of fat cells can play a critical role in protecting the body against type 2 diabetes. Selective activation of ChREBP β in adipocytes could be a new therapeutic strategy for preventing and treating type 2 diabetes and obesity related metabolic diseases. 

Herman MA, Peroni OD, Villoria J, et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484: 333 338, 2012.