Obesity, or excess adipose tissue, is the most prevalent public health problem in developed countries and is the major factor predisposing to type 2 diabetes, coronary artery disease, and the metabolic syndrome. Adipose tissue mass is the net outcome of adipocyte formation, death and cell size, and imbalances in any of these processes contribute to obesity. This project tackles the little-studied death component in this equation by investigating mechanisms of fat cell death in vivo and in culture. It has been previously shown that differentiated adipocytes die upon loss of the nuclear receptor PPAR?. We designed a novel genetic setup, in which adipocytes that lose PPAR? express nuclear Yellow Fluorescent Protein (nYFP), facilitating tracking of the rapidly disappearing PPAR?-deprived adipocytes within the cellular complexity of a constantly remodeled adipose tissue. Our analyses indicate that these cells exhibit dramatic lipid droplet breakdown, but no evidence of DNA fragmentation or membrane breaching, indicating non-apoptotic, non-necrotic death. We reproduced these phenomena in adipogenic cultures, where deletion of PPAR? caused lipid droplet loss and synchronous cellular disintegration within 72 h, indicating that the process is innately programmed and does not depend on systemic signals or interaction with immune cells. Moreover, this in vitro system facilitates cellular and molecular studies of the death mechanism. Indeed, using this system, we show here that loss of PPAR? elicits induction of the NLRP3 inflammasome, invoking a compelling similarity of the death process to adipocyte death in obese mice and human patients. Based on these observations, we hypothesize that the PPAR?-deprived and obese adipocyte death pathways are convergent and propose three specific aims for elucidating their detailed mechanisms and physiological significance.
Specific Aim 1 will deconstruct the death pathway elicited by PPAR? ablation in vitro and in vivo.
Specific Aim 2 will compare the death pathway of obese adipocytes to that of PPAR?-deprived adipocytes.
Specific Aim 3 will come full circle to determine the contribution of endogenous PPAR? regulation to adipocyte death in obesity. These studies will provide crucial insights into the physiological basis of adipocyte death and illuminate mechanisms that govern adipose tissue dynamics, impinging on obesity, diabetes and metabolic disease.
Obesity is a major cause of Type 2 diabetes (T2D) and the metabolic syndrome, and the control of adiposity is top priority in managing these morbidities. Adipocyte death impacts adipose tissue mass and composition and thorough understanding of its regulation will provide key insights for the prevention, management and treatment of obesity and its sequelae. This project will illuminate the mechanistic basis of adipocyte death, impinging on adipose tissue turnover in normal and morbid physiological settings, and providing a novel attack point in the battle against obesity and the metabolic syndrome.
