New understanding of endoplasmic reticulum

In obese individuals, fat cells are bloated and inflamed because they receive too many nutrients, including lipids.

In these cells, various components cannot work properly anymore and, instead, they activate new proteins to cope with the situation. One of the most challenged organelles in obese fat cells is a maze-like compartment called the endoplasmic reticulum (ER) that makes proteins and lipid droplets and senses the amount of nutrients that enter the cell.

In the September 2007 issue of the Journal of Lipid Research, Margaret F. Gregor and Gokhan S. Hotamisligil review current knowledge about how the ER works in fat cells and is modified in obesity. They show that when a fat cell receives too many nutrients, the ER is overwhelmed and triggers a process called the unfolded protein response (UPR). This process is one of many cellular responses that activate proteins that increase inflammation and can even result in the death of the cell. UPR also causes insulin resistance, a condition in which the production and function of insulin - a hormone produced by the pancreas - is impaired and blood sugar is too high.

The scientists show that by better understanding how the ER works, it may be possible to devise a therapy that enhances the function of the ER and maybe improve the health of obese people. Already, two molecules that protect the ER from obesity-related stress have shown some success in mice. Called PBA and TUDCA, the molecules decreased blood sugar and insulin levels and improved overall response to insulin production.

ER stress may also be reduced by targeting molecules involved in the UPR process. For example, a drug called Salubrinal was recently shown to inhibit one of the UPR-involved molecules and to protect cells from ER stress-induced cell death. Also, there is emerging evidence that anti-diabetic drugs may also work, at least in part, through this mechanism.

A deeper knowledge of how fat cells become dysfunctional will be critical in devising successful therapies in the future, the scientists conclude.

Article: “Adipocyte stress: the endoplasmic reticulum and metabolic disease,” by Margaret F. Gregor and Gokhan S. Hotamisligil