Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2

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 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.

Bone Morphogenetic Protein Signaling Agonist SB4 (BMPSB4) Inhibits Corticotroph Pituitary Neuroendocrine Tumors by Activation of Autophagy via a BMP4/SMADs-Dependent Pathway

“…The transcriptional level of POMC is regulated by the transcription factor CREB, which is phosphorylated at serine-133 and translocates to the nucleus to bind to target gene promoters. 20,21 We detected lower levels of p-CREB (serine-133) following BMPSB4 treatment, and the RNA sequencing results also suggested changes in the cAMP signaling pathway. These results suggest that POMC inhibition by BMPSB4 may be achieved by inhibiting the cAMP−PKA− CREB signaling pathway.…”

“…Previous studies have emphasized the significance of CREB phosphorylation in ACTH production. 20,21 Western blotting indicated that BMPSB4 reduced p-CREB levels in a concentration-dependent manner (Figure 3H). POMC encodes a preproprotein that produces ACTH after tissue-specific posttranslational processing.…”

Effect of Short Photoperiod on Behavior and Brain Plasticity in Mice Differing in Predisposition to Catalepsy: The Role of BDNF and Serotonin System

“…Our results are in agreement with data demonstrating the implication of the CREB/CRE transcriptional pathway in circadian clock timing in the suprachiasmatic nucleus, the locus of the master mammalian clock [ 51 ]. Furthermore, it was shown that the inhibition of hypothalamic CREB using a short-hairpin RNA lentiviral vector resulted in increased body-mass gain and reduced energy expenditure [ 52 ]. These findings are in agreement with the results of the present work, indicating a body weight rise in CBA mice exposed to a short photoperiod.…”

Mifepriston fore safe pregnancy termination in 2nd trimester

“…Beta endorfin endorphin is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin [8,9,10].…”