Deleting gene eliminates obesity, highly significant for humans
March 8, 2013 — Researchers have discovered that deleting a specific gene in mice prevents them from becoming obese even on a high fat diet, a finding they believe may be replicated in humans.
Perilipin-2 Null Mice are Protected Against Diet-Induced Obesity, Adipose Inflammation and Fatty Liver Disease
The cytoplasmic lipid droplet (CLD) protein perilipin-2 (Plin2) is expressed in multiple non-adipose tissues where it is thought to play a role in regulating their lipid storage properties. However, the extent to which Plin2 functions in nutrient utilization and metabolism, or how it influences the consequences of over feeding, remain unclear. In this study, we demonstrate that the absence of Plin2 prevents high fat-diet (HFD) induced obesity in male and female mice. This response is associated with increased formation of subcutaneous beige adipocyte cells with UCP1 expression, and amelioration of inflammatory foci formation in white adipose tissue and steatosis in the liver. Experiments demonstrate that Plin2 loss results in reduced energy intake and increased physical activity in response to HFD feeding. Our study provides the first evidence that Plin2 contributes to HFD-induced obesity by modulating food intake, and that its absence prevents obesity-associated adipose tissue inflammatory foci and liver steatosis.
“When fed a diet that induces obesity these mice don’t get fat,” said Prof. James McManaman, Ph.D., lead author of the study and vice-chairman of research for Obstetrics and Gynecology at the University of Colorado School of Medicine. “It may be possible to duplicate this in humans using existing technology that targets this specific gene.”
The two-year study, funded by the National Institutes of Health and the U.S. Department of Agriculture, was published last month in the Journal of Lipid Research.
The research team created a strain of mice without the Plin2 gene which produces a protein that regulates fat storage and metabolism. They immediately found that the mice were resistant to obesity.
Usually, mice fed a high fat diet will eat voraciously, yet these showed an unusual restraint. Not only did they eat less, they were more active.
Their fat cells were also 20 percent smaller than typical mice and did not show the kind of inflammation usually associated with obesity, the study said. Obesity-associated fatty liver disease, common in obese humans and rodents, was absent in the mice without the Plin2 gene.
“The mice were healthier,” McManaman said. “They had lower triglyceride levels, they were more insulin-sensitive, they had no incidents of fatty liver disease and there was less inflammation in the fat cells.”
The absence of the gene may cause fat to be metabolized faster, he said.
“Now we want to know why this works physiologically,” McManaman said. “We want to better understand how this affects food consumption.”
According to the study, understanding how Plin2 is involved in the control of energy balance will provide new insights into “the mechanisms by which nutrition overload is detected, and how individuals adapt to, or fail to adapt to, dietary challenges.”
The consequences for people are highly significant since they also possess the Plin2 gene.
“It could mean that we have finally discovered a way to disrupt obesity in humans,” he said. “That would be a major breakthrough.”
The study’s co-authors include David Orlicky, Ph.D., and Paul MacLean, Ph.D., associate professors at the CU School of Medicine and Andrew Greenberg, MD, senior scientist and director of the The Obesity and Metabolism Laboratory at Tufts University.
Press release and photo courtesy of the University of Colorado Denver. You can find the original press release here.