Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2
Background: The hypothalamic proopiomelanocortin (Pomc) neurons act as first-order sensors of systemic energy stores, providing signals that regulate caloric intake and energy expenditure. In experimental obesity, dietary saturated fatty acids affect Pomc endopeptidases (PCs), resulting in the abnor...
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2022-06-01
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| author | Ariane Maria Zanesco Natalia F. Mendes Daiane F. Engel Rodrigo S. Gaspar Davi Sidarta-Oliveira José Donato Licio A. Velloso |
| author_facet | Ariane Maria Zanesco Natalia F. Mendes Daiane F. Engel Rodrigo S. Gaspar Davi Sidarta-Oliveira José Donato Licio A. Velloso |
| author_sort | Ariane Maria Zanesco |
| collection | DOAJ |
| description | Background: The hypothalamic proopiomelanocortin (Pomc) neurons act as first-order sensors of systemic energy stores, providing signals that regulate caloric intake and energy expenditure. In experimental obesity, dietary saturated fatty acids affect Pomc endopeptidases (PCs), resulting in the abnormal production of the neurotransmitters α-melanocyte-stimulating hormone (α-MSH) and β-endorphin, thus impacting energy balance. The cAMP response element-binding protein (CREB) is one of the transcription factors that control the expression of Pomc endopeptidases; however, it was previously unknown if dietary fats could affect CREB and consequently the expression of Pomc endopeptidases. Methods: Here, we used single-cell RNA sequencing analysis, PCR, immunoblot, ELISA and immunofluorescence histological assays to determine the impact of a high-fat diet (HFD) on the expression and function of hypothalamic CREB and its impact on the melanocortinergic system. Results: The results indicate that CREB is expressed in arcuate nucleus Pomc neurons and is activated as early as nine hours after the introduction of a high-fat diet. The inhibition of hypothalamic CREB using a short-hairpin RNA lentiviral vector resulted in increased diet-induced body-mass gain and reduced energy expenditure. This was accompanied by reduced expression of the Pomc endopeptidases, protein convertase 2, which are encoded by Pcsk2, and by the loss of the high-fat-diet-induced effect to inhibit the production of α-MSH. Conclusions: This study provides the first evidence for the involvement of CREB in the abnormal regulation of the hypothalamic Pomc endopeptidase system in experimental obesity. |
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| language | English |
| last_indexed | 2024-03-09T22:02:07Z |
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| spelling | doaj.art-f3cd4626eece49dc9ef157ba17e4cc452023-11-23T19:47:50ZengMDPI AGCells2073-44092022-06-011113199610.3390/cells11131996Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2Ariane Maria Zanesco0Natalia F. Mendes1Daiane F. Engel2Rodrigo S. Gaspar3Davi Sidarta-Oliveira4José Donato5Licio A. Velloso6School of Medicical Sciences, University of Campinas, Campinas 13083-887, BrazilSchool of Medicical Sciences, University of Campinas, Campinas 13083-887, BrazilSchool of Medicical Sciences, University of Campinas, Campinas 13083-887, BrazilSchool of Medicical Sciences, University of Campinas, Campinas 13083-887, BrazilSchool of Medicical Sciences, University of Campinas, Campinas 13083-887, BrazilDepartment of Physiology and Biophysics, University of São Paulo, São Paulo 05508-900, BrazilSchool of Medicical Sciences, University of Campinas, Campinas 13083-887, BrazilBackground: The hypothalamic proopiomelanocortin (Pomc) neurons act as first-order sensors of systemic energy stores, providing signals that regulate caloric intake and energy expenditure. In experimental obesity, dietary saturated fatty acids affect Pomc endopeptidases (PCs), resulting in the abnormal production of the neurotransmitters α-melanocyte-stimulating hormone (α-MSH) and β-endorphin, thus impacting energy balance. The cAMP response element-binding protein (CREB) is one of the transcription factors that control the expression of Pomc endopeptidases; however, it was previously unknown if dietary fats could affect CREB and consequently the expression of Pomc endopeptidases. Methods: Here, we used single-cell RNA sequencing analysis, PCR, immunoblot, ELISA and immunofluorescence histological assays to determine the impact of a high-fat diet (HFD) on the expression and function of hypothalamic CREB and its impact on the melanocortinergic system. Results: The results indicate that CREB is expressed in arcuate nucleus Pomc neurons and is activated as early as nine hours after the introduction of a high-fat diet. The inhibition of hypothalamic CREB using a short-hairpin RNA lentiviral vector resulted in increased diet-induced body-mass gain and reduced energy expenditure. This was accompanied by reduced expression of the Pomc endopeptidases, protein convertase 2, which are encoded by Pcsk2, and by the loss of the high-fat-diet-induced effect to inhibit the production of α-MSH. Conclusions: This study provides the first evidence for the involvement of CREB in the abnormal regulation of the hypothalamic Pomc endopeptidase system in experimental obesity.https://www.mdpi.com/2073-4409/11/13/1996proopiomelanocortinobesitydietsaturated fatty acidCREB |
| spellingShingle | Ariane Maria Zanesco Natalia F. Mendes Daiane F. Engel Rodrigo S. Gaspar Davi Sidarta-Oliveira José Donato Licio A. Velloso Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2 Cells proopiomelanocortin obesity diet saturated fatty acid CREB |
| title | Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2 |
| title_full | Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2 |
| title_fullStr | Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2 |
| title_full_unstemmed | Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2 |
| title_short | Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2 |
| title_sort | hypothalamic creb regulates the expression of pomc processing enzyme pcsk2 |
| topic | proopiomelanocortin obesity diet saturated fatty acid CREB |
| url | https://www.mdpi.com/2073-4409/11/13/1996 |
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