Lysosomal Cathepsin D contributes to cell death during adipocyte hypertrophy

Obesity has reached epidemic proportions in most of the western world. With obesity comes a variety of adverse health effects such as insulin resistance, dyslipidemia, hypertension, glucose intolerance, and hepatic steatosis. It has become clear that a state of low grade chronic inflammation, typically associated with obesity, and characterized by macrophage infiltration of adipose tissue (AT) and increased production of pro-inflammatory cytokines, plays a crucial role in the development of insulin resistance. The pathogenic mechanisms resulting in AT macrophage recruitment are under intense investigation and remain incompletely understood. We recently demonstrated that lysosomal permeabilization, and subsequent Cathepsin B (CTSB) activation, occurs at the early stages of high fat diet induced weight gain and is preceded by macrophage infiltration into hypertrophied AT resulting in adipocyte cell death through mitochondrial dysfunction. In this report, we demonstrated that another key Cathepsin, Cathepsin D (CTSD), is also activated at the early stages of weight gain. In addition, activated CTSD induced proapoptotic protein activation. In conclusion, our data identify lysosomal CTSD as a potential key mediator of adipocyte cell death during weight gain and obesity.