Impact of B cell specific neutral lipid accumulation on B cell activation and function

Abstract

Abstract Obesity and its resultant inflammation have been shown to lead to a multitude of disease states, including Type II diabetes and cancer. Immune cells play a role in perpetuating obesity related diseases. B cells have been shown to infiltrate the visceral adipose tissue of obese individuals, where they activate other immune cells and produce autoantibodies. This study examined the impact of B cell neutral lipid accumulation on B cell function and activation, using B cell specific comparative gene identification-58 (CGI-58) knockout mice (bCKO). CGI-58 is the co-activator of adipose triglyceride lipase, a key enzyme initiating lipid droplet lipolysis. CGI-58 knockout and flox control mice were fed a low-fat diet for 16 or 32 weeks. B cells from bCKO mice exhibited a higher level of neutral lipid accumulation than other cell types and flox control B cells. Unimmunized bCKO mice showed increased percentages of spontaneous germinal center B cells compared to flox controls. Isolated bCKO B cells survived in culture significantly better than flox control B cells, which was concurrent with decreased levels of cellular and mitochondrial ROS and mitochondrial membrane potential in bCKO B cells compared to flox B cells. Furthermore, bCKO mice had increased numbers of crown-like structures in their visceral adipose tissues and elevated protein levels in their urine, predictors of metabolic disorder. Together, our results suggest that neutral lipid accumulation in B cells alone leads to non-specific survival and activation of B cells by downregulating ROS production and modulating mitochondrial functions. Supported by a grant from NIH (RO1 GM064625)