Role of acylation stimulating protein in the regulation of lipoprotein lipase activity and fatty acid trapping

Obesity and its comorbidities are an ever-expanding cost of affluent societies. Energy homeostasis is mediated by a network of hormonal signals that originates from many tissues, including white adipose tissue (WAT). Acylation stimulating protein (ASP) is a lipogenic hormone secreted by WAT that stimulates triglyceride (TG) storage (i.e. non-esterified fatty acid (NEFA) trapping) by increasing glucose uptake and NEFA esterification. ASP deficient mice are characterized by reduced body weight and WAT mass and delayed postprandial TG and NEFA clearance. The key enzyme in the regulation of TG clearance is lipoprotein lipase (LPL). The overall objective of this thesis was to examine the mechanisms by which ASP deficiency leads to delayed postprandial TG clearance and altered body composition in KO mice and to regulate, in coordination with other hormones, energy balance and metabolic profile in morbidly obese subjects following weight loss.; Novel findings in this thesis suggest that (1) in 3T3-L1 adipocytes, ASP increases hydrolysis, uptake and esterification of TG-rich lipoproteins (in situ LPL activity) by increasing NEFA trapping within the adipocytes thus decreasing NEFA inhibition of LPL activity, (2) In ex vivo study in mice, ASP deficiency was found not to result in any intrinsic tissue differences in glucose or NEFA oxidation or storage in WAT, skeletal muscle or liver, however, NEFA trapping was enhanced in brown adipose tissue (BAT) of KO mice. Moreover, ASP enhances in situ LPL activity, TG clearance and lipogenesis in WAT while in muscle ASP induces the opposite effects to those in WAT and increases lipolysis and (3) In in vivo study on morbidly obese subjects following gastric-bypass induced weight loss, the changes in ASP and adiponectin were predictive of weight loss, improved insulin sensitivity and apolipoprotein B concentration. In addition, the orexigenic gastric hormone, ghrelin, remains below normal levels in all subjects following surgery, which may favors maintenance of weight loss.; In conclusion, these findings underscore the central role of WAT and ASP pathway in the regulation of TG clearance and energy homeostasis and suggest that, in vivo, an effective ASP pathway favors NEFA trapping in the physiological depot, which would promote optimal insulin activity.