Many of us eagerly reach for the thermostat to crank up the heat a little as summer turns to fall, and now, a team of red-hot researchers studying heat generation in adipose tissue have discovered that the ten-eleven translocation 1 (TET1) DNA demethylase forms part of an epigenetic thermostat that could provide a means to treat serious metabolic disorders.
The formation of beige/brown adipose from white adipose induced by environmental cues such as cold temperatures leads to heat production (thermogenesis) via fat burning; therefore, a mechanistic understanding of this process may identify druggable targets to burn off excess adipose tissue. As the rather radiant researchers led by Sona Kang at the University of California, Berkeley already knew that epigenomic alterations accompany changes in adipocyte state, they next sought to investigate whether the DNA methylation machinery plays a role in beige adipocyte thermogenesis.
So, throw a few more logs on the fire and read this hotly-anticipated study to see how Damal Villivalam and colleagues deciphered this rather heated question by concentrating on TET1.
- Tet1 expression increases during white adipogenesis and decreases during beige/brown adipogenesis
- Cold temperatures and other stimulators of thermogenesis inhibit Tet1 expression
- Tet1 loss-of-function in beige adipocytes via short hairpin RNA amplifies the induced expression of thermogenesis-associated genes and mitochondrial respiration, while lentiviral overexpression of Tet1 has the opposite effect
- Adipose-selective Tet1 knockout mice demonstrate that TET1 normally suppresses beige/brown adipose formation and thermogenesis
- Tet1 knockout mice display improved cold tolerance, elevated energy expenditure, and increased formation of beige/brown fat, which leads to reduced overall adiposity
- Knockout mice have protection from diet-induced obesity, glucose intolerance, and insulin resistance
- RNA-sequencing of knockout mouse adipose tissue incubated at various temperatures shows that TET1 represses thermogenesis-associated gene expression profiles
Hot stuff indeed! Overall, the authors hope that their description of a TET1–HDAC1 epigenetic thermostat in beige adipocytes will foster the development of therapeutic strategies to boost energy expenditure and reduce adipose levels in patients with metabolic disorders.
For more on this warmly-welcomed study, hot-step your way over to Nature Communications, August 2020.