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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Cells - 11(2022), 13 vom: 22. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zanesco, Ariane Maria [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.07.2022 Date Revised 02.10.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/cells11131996 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM343255723 |
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| 100 | 1 | |a Zanesco, Ariane Maria |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2 |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 12.07.2022 | ||
| 500 | |a Date Revised 02.10.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CREB | |
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| 650 | 7 | |a Proprotein Convertase 2 |2 NLM | |
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| 700 | 1 | |a Mendes, Natalia F |e verfasserin |4 aut | |
| 700 | 1 | |a Engel, Daiane F |e verfasserin |4 aut | |
| 700 | 1 | |a Gaspar, Rodrigo S |e verfasserin |4 aut | |
| 700 | 1 | |a Sidarta-Oliveira, Davi |e verfasserin |4 aut | |
| 700 | 1 | |a Donato, José |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Velloso, Licio A |e verfasserin |4 aut | |
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