Abstract 608: Induction of Lysosomal Biogenesis in Adipose Tissue Macrophages Attenuates Inflammation and Cardiometabolic Disease

Abstract

Adipose tissue inflammation is a fundamental feature of obesity and is strongly implicated in progression to overt cardiometabolic disease. In situ, this response is defined by a notable increase in number of adipose tissue macrophages (ATM’s) surrounding dying adipocytes and a phenotypic switch towards pro-inflammatory “M1” polarization. However, recent data suggest an equally notable upregulation of lysosomal catabolic pathways in these cells, and that inflammatory phenotypes may regulated by these processes. We and others speculate ATM lysosomal biogenesis is an adaptive response that can be harnessed for therapeutic benefit in treating cardiometabolic disease. To this end, we examined the effects of macrophage-specific overexpression of TFEB (mϕ-TFEB), a transcription factor master regulator of lysosomal biogenesis, in a murine model of diet induced obesity. We show broad physiological metabolic benefits including attenuated weight gain, improved body composition, and increased metabolic rate. Further, mϕ-TFEB mice demonstrate increased insulin sensitivity and glucose tolerance (Insulin and Glucose Tolerance Tests). These phenotypes are linked to profound changes in cellular, tissue, and systemic inflammation. mϕ-TFEB overexpression greatly reduces circulating interleukin 1β, and polarizes adipose tissue macrophages isolated from epididymal fat to an anti-inflammatory “M2” state in a manner that is dependent on lysosomal lipolysis. In cultured primary macrophages, TFEB overexpression attenuates LPS-induced proinflammatory M1 activation, and predisposes to IL-4 induced M2 polarization. Thus, harnessing the lysosomal biogenesis response in macrophages abrogates diet induced metabolic pathophysiology, potentially through regulation of inflammatory phenotypes. We postulate that ATM lysosomal biogenesis is a crucial, adaptive cellular response to obesity that can be preemptively induced to slow progression of cardiometabolic disease.