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

Daniel T. Meier (), Leila Rachid, Sophia J. Wiedemann, Shuyang Traub, Kelly Trimigliozzi, Marc Stawiski, Loïc Sauteur, Denise V. Winter, Christelle Foll, Catherine Brégère, Raphael Guzman, Alex Odermatt, Marianne Böni-Schnetzler and Marc Y. Donath
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Daniel T. Meier: University Hospital Basel
Leila Rachid: University Hospital Basel
Sophia J. Wiedemann: University Hospital Basel
Shuyang Traub: University Hospital Basel
Kelly Trimigliozzi: University Hospital Basel
Marc Stawiski: University Hospital Basel
Loïc Sauteur: University of Basel
Denise V. Winter: University of Basel
Christelle Foll: University of Zurich
Catherine Brégère: University of Basel
Raphael Guzman: University of Basel
Alex Odermatt: University of Basel
Marianne Böni-Schnetzler: University Hospital Basel
Marc Y. Donath: University Hospital Basel

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32509-4

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