Epigenetic Regulator TET1 May Prevent Beiging of Fat Cells

Obesity is currently a major healthcare concern in the United States, and biomedical researchers are still working to untangle the complexity of the physiological changes that occur as a result of increased fat gain. Human beings have two major types of fat in their bodies which are white and brown adipose tissue (WAT and BAT, respectively). More recently, it was discovered that WAT can undergo a process called “beiging” that results in a darkening of the tissue color and increases its fat burning capacity, similar to what we see in BAT.

Brown and beige adipose tissue are very responsive to cold temperatures. As the tissue gets colder, the more fat is burned to generate heat. This fat-burning effect is driven by a change in gene expression that activates a process called thermogenesis. One of the major genes involved in thermogenesis is uncoupling protein 1 (UCP1), which is highly expressed in mitochondria of brown and beige adipose tissue. Better understanding what activates adipose tissue beiging and thermogenesis is currently a major research interest as it could lead to improved obesity treatment. Although the mechanisms are not yet fully understood, a new study suggests that epigenetics play a major role.

Researchers from UC Berkeley recently found that the expression of Tet methylcytosine dioxygenase 1 (TET1) was inversely correlated with adipocyte beiging and thermogenesis. TET1 is best known as an enzyme with DNA demethylase activity that can remove methyl groups from DNA.

The authors first observed that WAT had high TET1 expression and BAT had low TET1 expression. Cold exposure, which causes adipose tissue to undergo beiging, was downregulated TET1 expression in mice. This led the authors to hypothesize TET1 might be negatively regulating the beiging process by epigenetic mechanisms.

To further explore this idea, the authors used a cell line called 3T3-L1 that can be differentiated into adipocytes (fat cells) and found that as the cells became more like adipocytes, TET1 expression decreased, which is in agreement to their observations in mice.

Next, the authors used RNA silencing as a method to selectively prevent TET1 expression in cultured beige adipocytes. A molecule called forskolin, which activates UCP1, was used to study activation of the thermogenic response. Loss of TET1 increased the thermogenic response of these cells after forskolin treatment as shown by upregulation of genes including Ucp1, Ppargc1a, Cidea, and Elovl3. Importantly, other experiments testing loss of other TET enzymes by RNA silencing (TET2 and TET3) did not have the same effect, which shows TET1 has a unique effect of inhibiting thermogenesis.

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A similar experiment was conducted, this time upregulating TET1 expression rather than silencing it. After forskolin treatment was used to induce thermogenesis, the opposite effect on thermogenic genes was found with most of them being downregulated in TET1 overexpressing beige adipocytes compared to controls.

The authors were curious about the role of TET1 in cold tolerance and found that mice lacking TET1 only in adipose tissue had higher body temperature and respiration compared to controls after exposure to cold. It was confirmed that loss of TET1 increased adipose tissue beiging. Furthermore, these experimental mice were protected from diet-induced obesity after being fed a high-fat diet for 8 weeks.

Finally, the authors wanted to figure out the specific epigenetic mechanism behind how the loss of TET1 increases beiging and thermogenesis in adipose tissue. Once again using the cell culture model, and transfecting cells with different mutants of TET1 with loss of normal function, the authors surprisingly found that the DNA demethylase activity was not required for this effect. Instead, the mechanism was more complex and involved TET1 associating with another epigenetic regulator, histone deacetylase-1 (HDAC-1); this enzyme complex was found to bind to the promoter region of UCP1, preventing its expression.

The results of this study are quite astounding. TET1 was identified to have a role in preventing adipocyte beiging and thermogenesis by associating with HDAC-1 and inhibiting activating of UCP1. Most strikingly, the DNA demethylase function of TET1 was not required for this effect.

This finding really highlights the complex role of epigenetic regulation of energy metabolism and shows that TET1 could be a useful target to consider in the search for treatments for obesity and metabolic diseases.

References

Damal Villivalam S. et al. (2020). TET1 is a beige adipocyte-selective epigenetic suppressor of thermogenesis. Nat Commun. 11(1):4313

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About Brandon Eudy 8 Articles
Brandon received his PhD in Nutritional Sciences from the University of Florida and is currently a postdoctoral scholar at the University of North Carolina at Chapel Hill. He is fascinated with the impact of nutrition on health and physiology and is ever curious about the role of epigenetics in mediating nutrient-gene interactions. Outside of the lab, Brandon provides thought-provoking and informative posts on food, cooking, and nutritional sciences at his blog https://www.realfoodexplored.com.

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