Study Sparks Excitement in the Scientific Community

Blocking abnormally spread stress signals between liver cells in obesity preserves organ function and prevents disease The Sabri Ülker Metabolic Research Center, housed within Harvard University and conducting research on genetics and complex diseases, continues to produce groundbreaking studies in the scientific community. According to a recent study published in Cell Metabolism, blocking abnormally spread stress signals between liver cells in obesity preserves organ function and prevents disease. A study by the Sabri Ülker Metabolic Research Center team on "endoplasmic reticulum stress effects and functional loss in obesity" demonstrates both how crucial intercellular communication is for metabolic control and how correcting disruptions in this communication network can lead to the development of simple yet effective new therapeutic approaches. Obesity, which has become a global epidemic in recent years, is defined as a disease that creates ground for a cluster of metabolic problems resulting from abnormal and excessive fat accumulation in the body. Body weight depends on the correct balance between energy intake and energy expenditure. When this balance is disrupted toward increased energy intake, fat cell capacity is exceeded in our bodies, resulting in excessive fat accumulation in tissues. Fat accumulation, due to the stress and inflammation it creates in cells, can cause immuno-metabolic disorders such as diabetes, cardiovascular disease, and even cancer, negatively affecting quality and length of life. Previously, Prof. Dr. Gökhan Hotamışlıgil, Director of the Sabri Ülker Metabolic Research Center, and his team demonstrated that the dysfunction of organelles—cellular compartments—under metabolic stress is an important mechanism underlying these diseases, focusing particularly on endoplasmic reticulum studies.

How stress spreads in cells and the underlying molecular mechanisms are becoming clear

The endoplasmic reticulum is an organelle that performs vital cellular functions such as lipid and protein synthesis and secretion. The metabolic function of this organelle in the cell and body, revealed through studies at the Sabri Ülker Metabolic Research Center, represents a new approach. Stress and functional disorders in the endoplasmic reticulum play an important role in metabolic and degenerative neurodegenerative diseases, with many groups using this target to explore therapeutic applications and treatment options. According to a recent study published in Cell Metabolism on endoplasmic reticulum stress effects and functional loss in obesity, endoplasmic reticulum stress (ERS) plays a pathophysiological role in obesity-related insulin resistance and hepatic steatosis. This study clarifies how stress occurring within cells spreads from one cell to another, disrupting the functions of the entire organ, and elucidates the underlying molecular mechanisms. In many tissues and organs in our body, intercellular communication can play both positive (good neighbor) and negative (innocent bystander) roles in maintaining metabolic balance (homeostasis). This study by Prof. Hotamışlıgil, Amir Tirosh, and colleagues demonstrates that in liver tissue, an excessively harmful communication network strains the entire system and disrupts organ function. While investigating the mechanisms underlying this, they highlight the importance of gap junctions between neighboring cells and point out dysfunction in a protein from the "connexin" family that serves as a channel in these junction areas during obesity. According to the study, ER stress and obesity cause a severe increase in both the expression and activity of Cx43, a channel protein from the connexin family, in hepatocytes, the primary parenchymal cells of the liver. Through this channel, stress originating in one cell spreads to neighboring cells at inappropriate speed and intensity, resulting in functional disruption.

Researchers developed a specialized genetic model

Following the discovery of this molecular network, researchers developed a specialized genetic model in mice that closes the Cx43 channel specifically in the liver to reveal the importance of this mechanism throughout the body. These studies show that when the Cx43 channel is closed, both stress spreading between cells is halted and obesity-related insulin resistance and hepatic steatosis are prevented, with glucose metabolism remaining normal throughout the body. As a result, the abnormal increase in the Cx43 channel, which normally mediates connections between healthy cells, triggers metabolic disease through metabolic stress spreading, increases the tendency toward hepatic steatosis, and negatively affects whole-body glucose metabolism. In summarizing this study simply, Prof. Hotamışlıgil states, "While normally healthy communication between cells is of great importance for stress management, an inappropriate increase in this communication and disruption of its content can make stress unmanageable."  

For the full article:

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30604-5

Harvard press release:

https://www.hsph.harvard.edu/news/press-releases/stressed-liver-cells-spread-stress/