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    Pro-opiomelanocortin (POMC) neurons form an integral part of the central melanocortin system regulating food intake and energy expenditure. Genetic and pharmacological studies have revealed that defects in POMC synthesis, processing, and receptor signaling lead to obesity. It is well established that POMC is extensively processed by a series of enzymes, including prohormone convertases PC1/3 and PC2, and that genetic insufficiency of both PC1/3 and POMC is strongly associated with obesity risk. However, whether PC1/3-mediated POMC processing is absolutely tied to body weight regulation is not known. To investigate this question, we generated a Pomc-CreER  T2; Pcsk1  lox/lox mouse model in which Pcsk1 is specifically and temporally knocked out in POMC-expressing cells of adult mice by injecting tamoxifen at eight weeks of age. We then measured the impact of Pcsk1 deletion on POMC cleavage to ACTH and α-MSH, and on body weight. In whole pituitary, POMC cleavage was significantly impacted by the loss of Pcsk1, while hypothalamic POMC-derived peptide levels remained similar in all genotypes. However, intact POMC levels were greatly elevated in Pomc-CreER  T2; Pcsk1  lox/lox mice. Males expressed two-fold greater levels of pituitary PC1/3 protein than females, consistent with their increased POMC cleavage. Past studies show that mice with germline removal of PC1/3 do not develop obesity, while mice expressing mutant PC1/3 forms do develop obesity. We conclude that obesity pathways are not disrupted by PC1/3 loss solely in POMC-expressing cells, further disfavoring the idea that alterations in POMC processing underlie obesity in PCSK1 deficiency. © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

    Citation

    Manita Shakya, Surbhi Gahlot, Anne White, C Bruce Verchere, Malcolm J Low, Iris Lindberg. Mice lacking PC1/3 expression in POMC-expressing cells do not develop obesity. Endocrinology. 2021 Mar 10


    PMID: 33693631

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