Recently, the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, in conjunction with the Affiliated Hospital of Southwest Medical University, clarified the transcriptional regulation mechanism of glucose as a signal molecule on the energy metabolism of adipocytes, and revealed that CREB/ATF basic leucine zipper transcription factor (CREBZF) is a key factor in the glucose sensing signal pathway of adipocytes. The relevant research results are published in the Journal of the National Academy of Sciences (PNAS) in the United States.

Adipose tissue is crucial in maintaining material and energy metabolism homeostasis in the body. White adipocytes can store excess energy, while brown and beige adipocytes can help maintain body temperature through thermogenesis. The heat production process of fat can consume a large amount of energy, so activating the heat production ability of fat cells may be an important way to solve the obesity and related metabolic problems caused by energy surplus. Glucose is an important energy supply substance in the heat production process of adipocytes. However, it is not clear whether glucose can participate as a signaling molecule in regulating the heat production process after being ingested by cells.

In order to investigate the regulatory role of glucose in the heat production process of adipose tissue, researchers placed starving mice in a low temperature environment of 4 ℃ to induce a heat production program in adipose tissue. They found that glucose injection significantly enhanced the body temperature maintenance ability of mice and specifically promoted the expression of heat production related genes in subcutaneous beige adipocytes. In addition, studies have found that in vitro glucose treatment significantly enhances the expression of heat producing genes in primary adipocytes and cell lines of mice, indicating that glucose serves as a signaling molecule involved in transcriptional regulation of heat producing genes, and the protein level of CREBZF is also induced to increase by glucose signaling.

Further research has found that glucose signaling enhances the protein stability of CREBZF by acetylating the lysine 208 site of the CREBZF protein through acetyltransferase CBP/p300; On the contrary, the deacetylase HDAC3 can remove the acetyl group at this site, thereby reducing the protein content of CREBZF in cells. In addition, glucose activated CREBZF and downstream thermoregulatory key factor PGC-1 α Combining and inhibiting its transcriptional activity, thereby exerting an inhibitory effect on the heat production ability of adipocytes.

After administering glucose to CREBZF fat specific knockout mice under low-temperature conditions, the heat production ability and body temperature of the knockout mice further increased, indicating that activation of CREBZF by glucose signals may help stabilize the energy metabolism status of adipose tissue at a higher level, while avoiding excessive energy consumption causing tissue damage. Under physiological conditions, glucose induced CREBZF may prevent excessive activation and unnecessary energy consumption of beige adipocytes. Under pathological conditions, glucose induced activation of CREBZF in adipocytes may be an important cause of impaired thermogenic capacity in the body under conditions of hyperglycemia and obesity.

This study reveals the mechanism by which glucose participates as a signaling molecule in adipocyte thermogenesis. CREBZF in adipocytes can mediate glucose signaling and regulate energy metabolism signaling pathways, playing an important role in glucose sensing. The imbalance of CREBZF in glucose sensing plays a crucial role in the occurrence and development of obesity and related metabolic diseases caused by energy excess.

The research work has received support from the National Key R&D Program, National Natural Science Foundation of China, and Shanghai Municipal Science and Technology Major Projects.

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