Genetic deficiency for proprotein convertase subtilisin/kexin type 2 in mice is associated with decreased adiposity and protection from dietary fat-induced body weight gain

Background: Proprotein convertase subtilisin/xexin type 2 (PCSK2) is an endoproteinase responsible for proteolytic activation of a number of precursors to active neuropeptides and peptide hormones, known to influence glucose homeostasis, food intake and ultimately body mass. In this study, we examined the consequences of PCSK2 deficiency on these phenotypic traits. Study Design: Weight gain with age under diets of different fat contents was monitored. White adipose tissue (WAT) and muscle masses were evaluated. Plasma levels of triglycerides, leptin, ghrelin, insulin and proglucagon-derived peptides were measured as well as leptin and acetyl coenzyme-alpha carboxylase (ACC alpha) mRNA levels in adipose tissue. Results: Compared with their Pcsk2(+/+) littermates, Pcsk2(-/-) mice weighed significantly less as weanlings and as adults. As adults, they carried noticeably less fat mass, with similar lean muscle mass: their plasma leptin level and adipose tissue leptin mRNA level were accordingly lower. PCSK2 deficiency did not affect food intake or the level of the orexigenic hormone ghrelin. However, PCSK2 deficiency resulted in decreased plasma triglycerides and reduced ACCa mRNA levels in WAT. Interestingly, unlike their Pcsk2(+/+) littermates, Pcsk2(-/-) were resistant to enhanced body weight gain when fed a high-fat diet. Consistent with a role of PCSK2 in body mass gain, diet-induced or genetically obese mice were found to contain significantly higher levels of PCSK2 mRNA in their brain and stomach than their lean counterparts. Conclusion: Collectively, these results suggest that PCSK2 contributes to increase in body mass through the various regulatory peptides generated through its action. It represents a potential target in the prevention and treatment of obesity. International Journal of Obesity (2010) 34, 1599-1607; doi:10.1038/ijo.2010.90; published online 25 May 2010