Brown adipose tissue (BAT) dissipates energy through UCP1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Preliminary studies identified a novel role of CD47 in regulating BAT function and its contribution to energy homeostasis and the development of obesity. CD47, a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune function, was upregulated in adipose tissue from obese animals. Moreover, CD47 deficiency protected mice from diet- induced obesity (DIO) through activation of BAT function (e.g. enhanced mitochondria uncoupling and heat production) and increased energy expenditure. These data suggest that CD47 is a negative regulator of BAT activity. Therefore, inhibition of CD47 signaling might be a novel anti-obesity strategy, which is further supported by a recent human genome-wide study showing the association of single-nucleotide polymorphisms in CD47 gene with body weight and BMI. In this proposal the mechanisms by which CD47 downregulates brown fat cell function will be determined in Aim 1. The contribution of brown adipocyte specific CD47 deficiency on obesity development will be determined in Aim 2. Whether inhibition of CD47 signaling by CD47- antisense oligo (ASO) treatment activates BAT and prevents/ameliorates obesity development in animal models will be determined in Aim 3. These studies will not only provide novel information on the mechanisms by which CD47 down-regulates brown fat function and its contribution to energy homeostasis and the development of obesity, but also test the anti-obesity potential of a CD47-ASO in obese mouse models. Therefore these studies have clinical significance.