Lipolysis regulation by lysosomal degradation of lipid droplet-associated proteins

Executive Summary of Scientific Report Regulation of adipocyte lipolysis through lysosome-related degradation of lipid droplet-associated proteins – relation to insulin resistance BSF-2007327 Assaf Rudich, M.D., Ph.D., Ben-Gurion University of the Negev Andrew S. Greenberg, M.D., Tufts Adipocyte lipolysis is a fundamental process in energy homeostasis. In conditions like obesity and lipodystrophy, the rate of un-stimulated (basal) lipolysis is increased, contributing to insulin resistance and inflammation. Yet, since insulin is the major anti-lipolytic hormone, insulin resistance is also a cause of enhanced lipolysis, suggesting a vicious cycle. We hypothesized that lysosomal degradation of lipid droplet proteins like perilipn may regulate adipocyte lipolysis, reflecting on fundamental biological processes such as autophagy in the regulation of lipolysis and insulin action. During the funding period, our studies unraveled the following major findings: a. Omental adipose tissue in human obesity, which is (now arguably) thought to have higher lipolytic rate, is characterized by enhanced autophagic flux, a lysosomal-related self-digestion process (Kovsan et al., JCEM 2011). This could be demonstrated by both increased autophagy genes' expression at the mRNA and protein level, and by direct autophagic flux measurements.

b. This is likely a unique phenomenon of adipose tissue, since livers of obese mice exhibit decreased autophagy gene expression, whereas adipose tissue from the same mice expresses higher levels of key autophagy genes (Atg5, LC3 c. There is a strong correlation between the mRNA expression of autopahgy genes, particularly in omental fat, and various clinical parameters of obesity-associated morbidity, including adipocytokines, FFA and direct measures of insulin resistance by hyperinsulinemic clamp studies. .

d. The (patho)physiological significance of elevated autophagy could be proposed by demonstrating in a carefully matched cohort of severely obese but otherwise healthy patients, who only differ in being (or not) insulin resistant, that autophagy gene expression is already increased in the insulin resistant group. These results imply that autophagy is increased along with insulin resistance, but precedes, and therefore may contribute to, cardio-metabolic morbidity that associates with obesity.

Our unpublished cellular data suggest that a "physiological autophagic tone" exists in adipocytes, which regulates lipolytic rate and lipid metabolism (Kovsan et al, Am. J. Physiol. – Endocrinol. Metab. 2010). Dys-regulated autophagy appears to affect both basal, and inflammatory cytokine-stimulated lipolysis, potentially by inducing increased co-localization of autophagosome proteins with lipid droplets.