Researchers at LSU's Pennington Biomedical Research Center have developed and validated a new genetic animal model that gives scientists a more precise way to study brown and beige fat, specialized tissues that use energy to produce heat and play an important role in metabolism.
The UCP1-IRES-Cre animal model closely follows UCP1 expression, a protein that plays a central role in the heat-producing function of brown and beige fat, while reducing unintended genetic activity. The new tool could help researchers better understand how thermogenic fat contributes to energy expenditure, body weight regulation and metabolic health.
A more precise tool for studying brown fat
Brown adipose tissue, commonly known as brown fat, helps the body produce heat by using stored energy. Beige fat cells can also develop thermogenic properties and contribute to this process. Because of their role in energy metabolism, brown and beige fat have become important areas of research in obesity and metabolic health.
Scientists frequently use genetic tools called Cre animal models to study the function of specific cell types. Widely used UCP1-Cre models have allowed researchers to target brown and beige fat, but previous research has shown that some of these models can also produce unintended genetic activity in the brain and other tissues.
That can make it difficult to determine whether an experimental effect is caused by changes in thermogenic fat or by genetic activity elsewhere in the body.
To address this challenge, the Pennington Biomedical team characterized a knock-in model in which Cre expression is regulated by the same genetic mechanisms that control the body's natural UCP1 gene. The researchers found that the new model closely corresponded with UCP1 expression in brown fat in both males and females and showed substantially less unintended Cre-activity in the brain than previously reported UCP1-Cre models.
"This model gives researchers a more precise way to study the contribution of thermogenic adipose tissue while reducing the potential for unintended effects in the brain and other tissues," said Dr. Heike Muenzberg-Gruening, Director of the Central Leptin Signaling Laboratory . "When we are studying how a particular tissue contributes to metabolism, we need to be confident that the genetic tools we use are actually targeting that tissue."
The researchers found that reporter activity sometimes extended beyond areas where UCP1 protein was present. This was particularly evident in some white fat depots. The finding is consistent with the way the model permanently labels cells that have previously expressed UCP1. In other words, the reporter can provide a record of past UCP1 production even after current UCP1 protein levels have declined.
This characteristic could give researchers a way to investigate the history and development of thermogenic fat cells, including changes that occur as white fat takes on characteristics of beige fat.
The UCP1-IRES-Cre animal line was originally generated in the laboratory of the late Dr. Randall Mynatt at Pennington Biomedical. Although the animal line was generated previously, its tissue specificity and research utility had not been systematically characterized or described in the scientific literature.
The UCP1-IRES-Cre animal line will be available to researchers through The Jackson Laboratory (JAX), a major international repository and distributor of research animal models. JAX has accepted the line for distribution to the research community and making the resource available to researchers studying metabolism, adipose tissue biology and energy balance.
"Having this animal model accepted by The Jackson Laboratory and made available to researchers around the world is an important next step," said Muenzberg-Gruening. "JAX accepts animal models that are expected to be useful resources for the community and provides an independent indication of the potential value of this resource for researchers studying metabolism, adipose tissue biology, and energy balance."
The researchers say the UCP1-IRES-Cre model provides an improved genetic tool for studying thermogenic adipocytes and may help reduce potential confounding effects in research examining energy expenditure, thermoregulation and metabolic health. Its availability through JAX will allow researchers beyond Pennington Biomedical to incorporate the model into studies of metabolism, adipose tissue biology and energy balance.
The study, " A UCP1-IRES-Cre Knock-In Mouse Enables Specific Brown Adipocyte Targeting Without CNS Off-Target Expression ," published in Scientific Reports, was conducted by researchers in Pennington Biomedical's Neurobiology of Nutrition and Metabolism, Central Leptin Signaling, Matrix Biology and Gene Regulation and Metabolism Laboratories. Researchers included Joshua Meyer, Jaclyn Williams, Jennifer Bailey, Ji Suk Change, Carrie Elks and Muenzberg-Gruening.
About LSU's Pennington Biomedical Research Center
The Pennington Biomedical Research Center is at the forefront of medical discovery as it relates to understanding the triggers of obesity, diabetes, cardiovascular disease, cancer and dementia. Pennington Biomedical has the vision to lead the world in promoting nutrition and metabolic health and eliminating metabolic disease through scientific discoveries that create solutions from cells to society. The Center conducts basic, clinical and population research, and is a campus in the LSU System.
