1. Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing.
- Author
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Meier DT, Rachid L, Wiedemann SJ, Traub S, Trimigliozzi K, Stawiski M, Sauteur L, Winter DV, Le Foll C, Brégère C, Guzman R, Odermatt A, Böni-Schnetzler M, and Donath MY
- Subjects
- Genome-Wide Association Study, Humans, Hyperphagia genetics, Insulin metabolism, Obesity complications, Obesity genetics, Obesity metabolism, Proprotein Convertase 1 genetics, Diabetes Mellitus, Proinsulin genetics, Proinsulin metabolism
- 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., (© 2022. The Author(s).)
- Published
- 2022
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