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Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2

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Author(s):
Zanesco, Ariane Maria ; Mendes, Natalia F. ; Engel, Daiane F. ; Gaspar, Rodrigo S. ; Sidarta-Oliveira, Davi ; Donato, Jose ; Velloso, Licio A.
Total Authors: 7
Document type: Journal article
Source: CELLS; v. 11, n. 13, p. 20-pg., 2022-07-01.
Abstract

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 alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-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 alpha-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. (AU)

FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
Grantee:Licio Augusto Velloso
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 19/00330-7 - Effect of palmitate treatment in pc1/3 expression in a hypothalamic cell lineage
Grantee:Ariane Maria Zanesco
Support Opportunities: Scholarships in Brazil - Master