1633-P: CRISPLD2 Is Secreted by Adipocytes and Can Reduce Adipocyte Size

Obesity is a primary risk factor for type 2 diabetes, with excess adiposity leading to worsening insulin resistance and an increase in adipose tissue inflammation. Conversely, during weight loss there is improved insulin sensitivity with decreased adiposity, including a decrease in adipocyte size, clearance of lipid, and changes to the inflammatory signaling milieu. Adipocyte-secreted factors during weight loss could be a novel target to aid in improved outcomes in diabetes and obesity. We previously identified a novel adipocyte-secreted protein, CRISPLD2, that is uniquely up-regulated in expression and secretion during weight loss. CRISPLD2 secretion is up-regulated by lipolytic signals, down-regulated by insulin, and correlates strongly with insulin sensitivity in humans. We have now found that secreted CRISPLD2 is able to specifically alter gene expression, including an increase ccl2 transcription in 3T3-L1 adipocytes by almost 2-fold (p<0.005). However, the signaling pathways, receptor, and function of CRISPLD2 within adipocytes and adipose tissue have yet to be determined. To determine if excess exogenous CRISPLD2 can alter adipose function, we developed a transgenic mouse with doxycycline-inducible adipose-specific overexpression of CRISPLD2. Induced CRISPLD2 overexpression over 4 weeks leads to a significant decrease in adipocyte size in visceral adipose tissue in lean animals, despite no change in overall adipose depot size. Finally, utilizing IP-MS, we found that CRISPLD2 binds several adipocyte cell surface proteins, intriguingly including nucleolin, which has been previously shown to function as a receptor in inflammatory pathways. Taken together, these data suggest that CRISPLD2 may function as a novel adipokine, playing a role in lipid turnover and adipocyte size in weight loss.