Glucose-sensing mechanism that controls thermogenesis

Adipocytes, also known as fat cells, come in three main types: white, brown, and beige. White fat cells are structurally quite simple, comprising a single fat molecule and a few organelles. The function of white adipocytes is to store energy, insulate from extreme temperatures, and cushion organs.

Most fat cells in humans are white. In contrast, brown fat cells comprise several fat molecules and many cellular organelles, making them structurally much more complex. They get their brown color from iron in the organelles. In infancy, brown fat cells predominate, which is related to their main function—generating heat through non-shivering thermogenesis. This process helps protect infants from hypothermia. Beige fat cells have features of both white and brown fat cells. 

When the body is exposed to cold, glucose uptake is elevated in brown and beige fat cells, with glucose supplying the energy for thermogenesis. Despite the known involvement of glucose, however, the role of glucose signaling in regulating thermogenesis has not been well understood. 

Recently, a research team identified the transcription factor CREB/ATF bZIP (CREBZF) as an important mediator of glucose effects in adipose tissue. This study was published in PNAS.  

Specifically, this study demonstrated that glucose signals are essential for the regulation of thermogenic activity in beige adipocytes. In addition, the CREBZF protein is potently induced by glucose and mediates the effects of glucose on energy homeostasis in adipose tissue.  

To investigate the roles of glucose in regulating thermogenic activity in adipocytes, mice were injected with glucose under cold conditions. The researchers found that after glucose injection, mice showed enhanced browning of white adipose tissue, i.e., the emergence of beige fat cells in white adipose tissue in response to a demand for thermogenesis. The mice also showed resistance to cold stress. The researchers also found that levels of CREBZF were stimulated by glucose in the beige fat cells.  

Surprisingly, the researchers found that adipose-specific CREBZF deficiency further increased glucose-induced thermogenesis and browning.  

The researchers determined that glucose increases the stability of CREBZF through transacetylase CBP/p300-mediated acetylation of the K208 site on the CREBZF protein. In contrast, deacetylase HDAC3 functions to remove the acetyl group at the K208 site. Glucose-induced CREBZF further interacts with PGC-1α and inhibits the thermogenic activity.   

They also determined that in physiological conditions, glucose-induced CREBZF may protect beige adipocytes from hyperactivation and unnecessary energy dissipation. In addition, glucose-dependent activation of CREBZF may be the mechanism for reduced thermogenic capacity and energy expenditure in pathological conditions such as hyperglycemic insulin resistance and obesity.   

The findings of this study advance the understanding of glucose signals in regulating energy metabolism in adipose tissue. The reversible acetylation of CREBZF controlled by glucose provides a fine-tuned regulatory mechanism that couples nutrient signals to energy homeostasis and the browning of adipose tissue.