Mice lacking PC1/3 expression in POMC-expressing cells do not develop obesity
| Autor: | Malcolm J. Low, Anne White, Surbhi Gahlot, Manita Shakya, Iris Lindberg, C. Bruce Verchere |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Proteolysis Mutant 030209 endocrinology & metabolism Peptide hormone Biology Germline 03 medical and health sciences 0302 clinical medicine Endocrinology Central melanocortin system Internal medicine medicine Research Articles chemistry.chemical_classification medicine.diagnostic_test digestive oral and skin physiology medicine.disease Obesity 030104 developmental biology Enzyme medicine.anatomical_structure nervous system chemistry hormones hormone substitutes and hormone antagonists Tamoxifen medicine.drug |
| Zdroj: | Endocrinology |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/endocr/bqab055 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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