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

Abstract

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-a carboxylase (ACCa) mRNA levels in adipose tissue. Results: Compared with their Pcsk2þ / þ littermates, Pcsk2 À/À 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 þ / þ littermates, Pcsk2 À/À 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.

Effect of a common variant of the PCSK2 gene on reduced insulin secretion

“…In addition, they exhibit fasting hypoglycaemia, reduced blood glucose and reduced circulating glucagon during intraperitoneal glucose tolerance testing. Processing of proglucagon and proinsulin is severely impaired in these mice [26,27]. Furthermore, supporting the notion of PC2 effects on proglucagon processing, we observed that the PCSK2 variant was associated with lower glucagon levels in hyperglycaemic individuals.…”

The Multifaceted Proprotein Convertases: Their Unique, Redundant, Complementary, and Opposite Functions

“…Heterozygotes display accelerated weight gain, glucose intolerance, and susceptibility to diet-induced obesity (7,37). PC2-null mice exhibit microsomia at birth, catch-up growth after birth, lipodysgenesis, glucose tolerance, and dietinduced obesity resistance as adults (8,38). It therefore appears that the two enzymes are the ying and yang of body mass and energy homeostasis, with PC1/3 playing a restraining role and PC2 playing a promoting one.…”

PCSK2-null mice exhibit delayed intestinal motility, reduced refeeding response and altered plasma levels of several regulatory peptides

“…Interestingly, absence of PCSK2 is associated with pancreatic alpha cell hyperplasia and dramatic accumulation of proglucagon in these cells (Zhu et al, 2002). This pancreatic prohormone is alternatively processed to GLP-1 by PCSK1 (Webb et al, 2004), leading to markedly increase of the plasma levels of this peptide and other proglucagon-processing intermediates (Anini et al, 2010). The fasting plasma levels of GLP-like immunoreactivity in WT mice were greater for GLP-2 (0.7-0.8 ng/ml) than for GLP-1 (10-15 pg/ml).…”

“…Cellular expression of CCK, GLP-1, NPY and SS has been shown to be altered in PCSK2-KO mice (Anini et al, 2010;Furuta et al, 1997;Miller et al, 2003;Rehfeld et al, 2002).…”

“…It exhibited microsomia at birth, mild hypoglycaemia, improved glucose tolerance (Furuta et al, 1997) as well as resistance to dietinduced weight gain (Anini et al, 2010). This phenotype could partly be due to alterations in the peptidergic system regulating feeding and gastrointestinal (GI) physiology.…”