Genetically Engineered Abolition of p62 in Fat Tissue Causes Obesity in Mice

A recent study linked the scaffold protein p62 (sequestosome 1; SQSTM1), an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell, to the metabolic imbalance that leads to obesity.

Investigators at the Sanford-Burnham Medical Research Institute (La Jolla, CA, USA) had previously worked with a line of obese mice that had been genetically engineered to lack the gene for p62. In the current study, the system was modified so that it was possible to generate lines of mice with p62 lacking only in specific organs or sites in the body.

Results published in the January 2, 2013, issue of the Journal of Clinical Investigation showed that adipocyte specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice were obese. The obese mice lacking p62 in their fat tissues weighed more than control animals, expended less energy, had diabetes, and displayed a hyperinflammatory response.

The results further showed that p62 regulated energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to beta-adrenergic stimuli. Abolition of p62 led to decreased activation of signaling molecules that controlled mitochondrial function.

“Without p62 you are making lots of fat but not burning energy, and the body thinks it needs to store energy,” said contributing author Dr. Jorge Moscat, a professor in the tumor microenvironment program at the Sanford-Burnham Medical Research Institute. “It is a double whammy.”

Related Links:
Sanford-Burnham Medical Research Institute