Adipocyte Secretion in Metabolic Syndrome

Abstract

Metabolic syndrome is characterized by chronic, low grade inflammation of the adipose organ and increased basal white adipocyte lipolysis. These processes may promote insulin resistance and cell senescence. Dr. Ann Hertzel and Dr. David Bernlohr showed that, in response to lipolysis, adipocytes secrete hundreds of proteins unconventionally (UPS). Among the most abundant of these secreted proteins is fatty acid binding protein 4 (FABP4), a leaderless lipid carrier and known agonist of several mechanisms of insulin resistance, hepatic steatosis, and atherosclerosis. The mechanism of secretion is not well understood, and proteins may be secreted freely or in vesicles. Another notable aspect of lipolytic UPS is its dependence on autophagy, which leads to the hypothesis that it may rely on sphingosine-1-phosphate (S1P) pathway.

Additionally, the chronic inflammatory state of the adipose organ may lead to cellular senescence. The molecule 4-hydroxynonenal (4-HNE), a product of lipid peroxidation, may promote cellular senescence via the carbonylation of DNA and proteins. In 2015, Hauck and Bernlohr showed vastly increased intracellular levels of 4-HNE in adipocytes treated with inflammatory cytokines. The passive membrane diffusion of 4-HNE is plausible because it is small and amphipathic yet largely nonpolar. If 4-HNE is secreted from adipocytes, it may act in a paracrine manner and cause local cells to senesce. Adipocyte senescence may result in a decrease in triglyceride storage ability. When this occurs subcutaneously, visceral fat depots become preferred for triglyceride storage – a hallmark progression of obesity and its comorbities. 4-HNE secretion from adipocytes has not been shown in biochemistry literature but is hypothesized to be under lipolytic or inflammatory control due to its high abundance in obese adipocyte cytoplasm. Characterizing the mediating factors of UPS and 4-HNE secretion may show that adipocyte secretions can exacerbate metabolic syndrome and promote cell senescence. Furthermore, showing that adipocytes secrete 4-HNE may introduce an area of study for researchers of aging processes, especially as they relate to obesity and metabolic syndrome.