Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing

Abstract

Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neurotransmitters and hormones. PC1/3 deficiency and genome-wide association studies relate PC1/3 with early onset obesity. Here, we find that deletion of PC1/3 in obesity-related neuronal cells expressing proopiomelanocortin mildly and transiently change body weight and fail to produce a phenotype when targeted to Agouti-related peptide- or nestin-expressing tissues. In contrast, pancreatic β cell-specific PC1/3 ablation induces hyperphagia with consecutive obesity despite uncontrolled diabetes with glucosuria. Obesity develops not due to impaired pro-islet amyloid polypeptide processing but due to impaired insulin maturation. Proinsulin crosses the blood-brain-barrier but does not induce central satiety. Accordingly, insulin therapy prevents hyperphagia. Further, islet PC1/3 expression levels negatively correlate with body mass index in humans. In this work, we show that impaired PC1/3-mediated proinsulin processing, as observed in human prediabetes, promotes hyperphagic obesity.

Deletion of carboxypeptidase E in beta cells disrupts proinsulin processing and alters beta cell identity in mice

“…Although total islet PC1/3 enzyme activity was not changed in β Cpe KO mice, PC1/3 protein levels were elevated, suggesting that on a per-enzyme basis, PC1/3 activity is likely reduced in β Cpe KO beta cells. To our surprise, even with markedly impaired proinsulin processing and diminished output of mature insulin, β Cpe KO mice failed to develop obesity and hyperglycemia spontaneously or when challenged with a high-fat diet; contrary to a recent report showing Pdx-Cre ERT -mediated Pcsk1 deletion and elevated proinsulin promote the development of obesity in mice (32). It is plausible that elevated proinsulin, possessing 5% activity compared to insulin (33), is sufficient to maintain glucose homeostasis.…”

Cystine/glutamate antiporter system Xc-deficiency impairs insulin secretion

“…We therefore injected whole-body sXc knockout mice with 2mg/kgbw LPS 6 hours before an ipGTT. We confirmed the previously reported increase in insulin secretion and glucose disposal (24) but failed to detect a differential response between WT and KO animals (fig S1a-c). Additionally, plasma IL-1beta levels were similar between genotypes (fig S1d).…”

Metformin restores prohormone processing enzymes and normalizes aberrations in secretion of proinsulin and insulin in palmitate‐exposed human islets

“…Prohormone convertase subtilisin/kexin type 1 (PC1/3) is expressed in different neuroendocrine cells including the pancreatic alpha-and betacells. 12 Together with the chaperone protein carboxypeptidase E (CPE), PC1/3 contributes to the processing of proinsulin to insulin in human pancreatic beta-cells. 13,14 Mutations in PCSK1 coding for PC1/3 12,15 and Cpe coding for CPE 16 have been connected with obesity and glucose intolerance, along with increased proinsulin levels.…”

“…12 Together with the chaperone protein carboxypeptidase E (CPE), PC1/3 contributes to the processing of proinsulin to insulin in human pancreatic beta-cells. 13,14 Mutations in PCSK1 coding for PC1/3 12,15 and Cpe coding for CPE 16 have been connected with obesity and glucose intolerance, along with increased proinsulin levels. However, how proinsulin and insulin secretion from islets are affected under conditions of elevated palmitate levels at normoglycaemia, which is coupled with accentuated glucosestimulated insulin secretion, 11 and how metformin affects the proinsulin and insulin secretion under these conditions have not been determined.…”

“…Prohormone convertase subtilisin/kexin type 1 (PC1/3) is expressed in different neuroendocrine cells including the pancreatic alpha‐ and beta‐cells 12 . Together with the chaperone protein carboxypeptidase E (CPE), PC1/3 contributes to the processing of proinsulin to insulin in human pancreatic beta‐cells 13,14 .…”