In a new article published in Nature Cell Biology (September 2017), Danish Diabetes Academy PhD student Therese Juhlin Larsen, and her colleagues Naja Zenius Jespersen and Camilla Scheele from Rigshospitalet in Copenhagen, contributed with data from human material to a Japanese study identifying an important transcriptional regulator of brown fat in mice.
BROWN FAT AS A THERAPEUTIC TARGET?
Within the past decade it was discovered that adult humans have active brown adipose tissue. Brown fat cells get activated when the body is exposed to cold stimulation and burn glucose and lipids to generate heat. Brown adipose tissue can thereby increase the overall energy expenditure. In mouse models increased mass and activity of brown adipose tissue result in enhanced energy expenditure, improved glucose and triglyceride clearance, and protection against high fat-diet induced weight gain. By identifying factors of importance for brown fat development and activation new potential therapies for obesity and metabolic diseases may be developed.
MAPPING OF IMPORTANT FACTORS FOR BROWN FAT DEVELOPMENT
In the current study formaldehyde-assisted isolation of regulatory elements (FAIRE) followed by high-throughput sequencing, was used to identify open chromatin regions where transcriptional regulators can bind and influence the genetic program. In a murine model nuclear factor I-A (NFIA) was found to bind brown-fat specific enhancers thus activating the brown fat gene program. Furthermore, NFIA facilitates the binding of the master transcriptional regulator of adipogenesis namely peroxisome proliferator-activated receptor gamma (PPARgamma) and NFIA thereby functions as a transcriptional regulator of brown fat. Interestingly, ectopic expression of NFIA in murine myoblasts and white preadipocytes induced the brown fat gene program, while brown fat from whole-body knockout of NFIA showed an increase in muscle-specific genes, thus indicating that NFIA plays a crucial role in lineage determination of precursor cells.
NFIA gene expression and protein levels are higher in brown fat tissue compared to white fat tissue in mice. This observation led to the question if NFIA also plays a role in human brown fat development. Fat tissue samples and cultured primary fat cells from three different human studies confirmed that NFIA is upregulated in brown fat compared to white fat. It is therefore very likely that NFIA also regulates the brown fat-specific gene program in humans. Identifying factors that regulate NFIA may lead to novel therapies focusing on activation of brown fat as a therapeutic target against obesity and its complications.
Source: Nature Cell Biology