The Genetics of Obesity Meets Basic Cell Biology Through Prohormone Convertase 1/3

Examination of individuals with “extreme phenotypes” has revealed some rare monogenic disorders that were previously unknown. Monogenic obesity is one example of a severe phenotype that associates with mutations from specific genes that play roles in the regulation of metabolism and energy expenditure (1). One of these genes is PCSK1, which encodes a prohormone-processing enzyme, prohormone convertase (PC)1/3, in tissues that produce metabolic hormones. The story of the link between PC1/3 and obesity illustrates the need for basic cell biological investigations to reveal mechanisms of how gene variants can lead to the development of a metabolic disorder. In their article in this issue of Endocrinology, Prabhu et al (2) have taken the cell biology approach in an elegant study to determine the link between a variant of PCSK1, known as N222D, and obesity. PCs are enzymes that process, or convert, prohormones and proproteins into bioactive peptides. Currently, 9 members of the PC family of endoproteolytic enzymes have been identified in mammals (reviewed in Reference 3). Three of them, PC1/3, PC2, and PC5, are found primarily in the secretory granules of endocrine and neuroendocrine tissues in which prohormone processing occurs, and they function optimally in the high-Ca , low-pH environment within secretory granules. Both PC1/3 and PC2 have been localized within the secretory granules of the anterior and neurointermediate lobes of the pituitary, pancreatic islets, the endocrine cells of the heart, and neuropeptide-rich regions of the intestine and brain. Both PC1/3 and PC2 act in a concerted manner to cleave prohormones, the peptide hormone products of which regulate several metabolic processes. For example, PC1/3 and PC2 cleave proopiomelanocortin in the anterior pituitary to yield ACTH and -MSH, respectively (4), which are both key peptides in the regulation of energy expenditure. Proglucagon is processed to glucagon in the -cells of pancreatic islets by PC2, and to glucagon-like peptide-1 and glucagon-like peptide-2 in intestinal L cells by PC1/3 (5, 6), and these hormones are responsible for nutrient homeostasis. Finally, proinsulin is cleaved in a sequential manner to yield insulin in the pancreatic -cell. The B chain-C peptide junction is cleaved by PC1/3, followed by cleavage at the C peptide-A chain junction by PC2 (7, 8). These examples illustrate the importance of PC1/3 and PC2 in metabolic regulation and predict disturbances in nutrient homeostasis and energy expenditure upon disruption of their functions. Such disturbances would result in development of diseases such as diabetes, obesity, or metabolic syndrome. Interestingly, impairment of PC1/3 activity, in particular, is strongly linked to the development of early-onset obesity. The PCSK1 gene resides in a 5.6-MB interval within chromosome 5q that links with obesity-associated traits (9, 10). A number of recent genome-wide association studies have identified variants in PCSK1 that are associated with monogenic early-onset obesity (11–13). The elucidation of the role of PC1/3 in the development of obesity has been driven by the initial finding of PC1/3 deficiency in a subject who showed extreme childhood obesity, abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism, and elevated plasma levels of unprocessed proinsulin and proopiomelanocortin (14). This report identified 2 mutations in the PCSK1 gene that caused a deficiency in PC1/3 activity: a heterozygous G483Rmutationthatpreventsremovalof theC-terminal tail of PC1/3 and causes its retention in the endoplasmic reticulum(ER);andaframeshiftmutationthatcreatesapremature stop codon within the catalytic domain (Figure 1). The re-