Topic Overview:

Obesity and metabolic syndrome are global health threats. Insulin resistance and metabolic complications of obesity are strongly associated with intracellular accumulation of triacylglycerol (TG); however, the mechanisms underlying TG accumulation and its relationship to lipid-induced toxic metabolic effects (lipotoxicity) remain unclear.

Protection against lipotoxicity requires a carefully regulated balance between triglyceride synthesis and hydrolysis. Adipose triglyceride lipase (ATGL) was recently identified as the rate-limiting enzyme mediating TG hydrolysis and is, therefore, a critical determinant of storage/production of toxic, as well as essential, lipid metabolites. Nevertheless, ATGL’s role in these processes, particularly in nonadipose tissues in which ATGL is also expressed, remains poorly understood.

Kershaw has demonstrated that: (1) ATGL is expressed, highly regulated, and functionally relevant in adipose and nonadipose tissues and (2) modulation of ATGL-mediated TG hydrolysis influences lipid and glucose homeostasis in vitro and in vivo in a tissue/cell type-specific manner.

Emerging evidence indicates that ATGL-mediated TG hydrolysis may preferentially direct lipids toward oxidation via peroxisome proliferator-activated receptor alpha (PPARα)-dependent mechanisms, suggesting that therapeutic activation of ATGL may improve tissue-specific and systemic lipid homeostasis. In this seminar, Kershaw will review how the identification of ATGL has led to a drastic revision of the traditional model of lipolysis, how ATGL-mediated TG hydrolysis influences lipid and glucose homeostasis in a tissue-specific manner, and how these findings might influence human disease.