Characterizing the Role of Angiopoietin-like 4 in Energy Homeostasis

The lipoprotein lipase inhibitory function of Angiopoietin-like 4 (ANGPTL4) has been extensively characterized. The purpose of this research is to identify the domain of ANGPTL4 responsible for its lipolytic function and to characterize its physiological and metabolic effects. Also given its lipolytic function, I will try to identify a possible therapeutic role for ANGPTL4. The introduction outlines the members of the ANGPTL family of proteins. It reviews the physiological functions of ANGPTL4 in metabolism, inflammation, wound healing and angiogenesis. Finally, it examines adipocyte lipolysis and its role in energy expenditure. The first chapter addresses the in vivo effects of overexpression of the ANGPTL4 fibrinogen-like domain on adipose tissue lipolysis and energy expenditure. I hypothesize that the N-terminal coiled-coil domain (CCD) of ANGPTL4 was not required for its lipolytic function. Here I show that the FLD of ANGPTL4 alone stimulates adipocyte lipolysis via the cAMP-PKA pathway. Adenoviral overexpression of ANGPTL4 FLD in mice protects mice against high fat diet induced obesity and ectopic steatosis; increases energy expenditure by inducing beiging of white adipose tissue; and improves glucose homeostasis. The second chapter addresses the role of ANGPTL4 in glucose homeostasis and seeks to identify the domain responsible for the ANGPTL4-dependent improvement in glucose tolerance in mice. Here I demonstrate that overexpression of ANGTPL4 in mice on high fat diet housed at thermoneutrality and in mice on chow diet improves glucose tolerance by decreasing gluconeogenesis.The third chapter addresses the role of ANGPTL4 in the regulation of thermogenesis upon cold exposure. Mice lacking ANGPTL4 have lower body temperature and lower energy expenditure when housed at 4C, room temperature and thermoneutrality. In addition, mice deficient in ANGPTL4 have lower body temperature than wild-type counterparts. Overall, this study has identified ANGPTL4 as a critical regulator of energy expenditure and as a potential therapeutic target