Finding Factors Important to Stoking Brown Fat
An international research team including NIDDK-supported scientists has newly identified a molecular factor key to the activation of energy-burning brown fat, furthering possibilities for targeting brown fat in treatment of obesity.
Unlike white adipose tissue (fat), which stores energy derived from the food we eat and expands in volume when calorie consumption exceeds bodily energy expenditure (calorie-burning), brown fat “burns” energy, releasing it as heat. Because active brown fat has been found in adult humans, its characteristics and development are being studied intensively to determine if it might be or harbor a treatment target for obesity and metabolic diseases. Through experiments in laboratory-grown mouse cell lines, male mice, and human tissue samples, researchers sought in this study to identify key molecular factors, called transcription regulators, controlling activation and maintenance of patterns of gene expression—turning genes “off” or “on”—specific to brown fat. Using a technique that enabled them to assess thousands of active chromosomal regions in cells simultaneously, they detected in mouse brown fat a DNA sequence motif associated with binding by a family of transcription regulators called nuclear factor I. Further experiments revealed that one member of this family, nuclear factor I A (NFIA), was highly enriched in mouse brown fat compared to other tissues, such as white fat and muscle. Brown fat cells share a common progenitor with skeletal muscle cells. Thus, to confirm a role for NFIA in defining brown fat, the scientists introduced NFIA into laboratory-grown mouse muscle precursor cells. These cells developed characteristics of fat cells and their gene expression was modified, with brown fat genes “turned on” and muscle genes “turned off.” Conversely, when NFIA was inhibited in laboratory-grown mouse brown fat cells, expression of brown fat-specific genes decreased significantly, indicating that NFIA is needed for both activation and maintenance of genes determining brown fat identity. Examining the underlying mechanism involved, the researchers found evidence in cell-based experiments that NFIA facilitates binding of PPARγ—the master transcriptional regulator governing fat cell development—to regions of the genome associated with brown fat-specific genes. This co-localization resulted in significantly increased expression of the genes examined.
Moving from cells to whole organisms, experiments in mouse models appeared to confirm that NFIA is important to brown fat development and suppresses muscle cell development. The researchers then analyzed samples of human brown fat from volunteers. They found that samples from patients with a tumor causing activation of brown fat surrounding the kidneys showed higher expression of the genes encoding NFIA, as well as other brown fat-specific genes, than similar samples obtained from patients with other tumors. Analyses of brown fat cells and white fat cells cultured from tissue samples from shoulder and belly areas, respectively, of other volunteers, also showed higher NFIA expression in the brown fat cells. Taken together, the study results suggest that NFIA is a key factor in brown fat activation and development in mice and may act similarly in humans. Future studies may reveal ways to manipulate NFIA and its ability to “reprogram” cells to become brown fat as part of therapeutic strategies for obesity.