Background: CD47 is a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune function. Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function and energy homeostasis. Genetic deletion of CD47 has been shown to protect mice from diet-induced obesity and its-associated metabolic complications. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and metabolic disease was determined.
Methods: Two obese mouse models (diet induced obese mice and leptin deficient ob/ob mice) were utilized. For diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet for 6 weeks to induce obesity and glucose intolerance. Then these mice were treated with CD47ASO or control ASO for 8 weeks with continuous HF diet feeding. For genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. Body weight was monitored weekly. By the end of study, glucose tolerance test, indirect calorimetry, body composition and cold exposure experiments were performed.
Results: We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue, reduced hepatic lipogenic gene expression and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. CD47ASO treated mice displayed increased energy expenditure. Interestingly, these mice displayed increased voluntary wheel running distance in metabolic cage, which was associated with increased lean mass and expression of uncoupling proteins (UCP2 and UCP3) in skeletal muscle. Food intake or cold tolerance was comparable between control ASO and CD47 ASO treated mice.
Conclusions: These findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.