Cargando…

Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways

Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced obesity, and leads to the loss of the thermogenic phenotype and adipocyte whitening due to increased lipid accumulation. We used th...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Chenhao, Yang, Xuehui, Harrington, Anne, Potts, Christian, Kaija, Abigail, Ryzhova, Larisa, Liaw, Lucy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606454/
https://www.ncbi.nlm.nih.gov/pubmed/37895313
http://dx.doi.org/10.3390/genes14101964
_version_ 1785127320256774144
author Yang, Chenhao
Yang, Xuehui
Harrington, Anne
Potts, Christian
Kaija, Abigail
Ryzhova, Larisa
Liaw, Lucy
author_facet Yang, Chenhao
Yang, Xuehui
Harrington, Anne
Potts, Christian
Kaija, Abigail
Ryzhova, Larisa
Liaw, Lucy
author_sort Yang, Chenhao
collection PubMed
description Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced obesity, and leads to the loss of the thermogenic phenotype and adipocyte whitening due to increased lipid accumulation. We used the Adiponectin-Cre (Adipoq-Cre) strain to activate a ligand-independent Notch1 intracellular domain transgene (N1ICD) to drive constitutive Notch signaling in the adipose tissues (N1ICD;Adipoq-Cre). We previously found that constitutive activation of Notch1 signaling in the PVAT phenocopied the effects of diet-induced obesity. To understand the downstream pathways activated by Notch signaling, we performed a proteomic analysis of the PVAT from control versus N1ICD;Adipoq-Cre mice. This comparison identified prominent changes in the protein signatures related to metabolism, adipocyte homeostasis, mitochondrial function, and ferroptosis. PVAT-derived stromal vascular fraction cells were derived from our mouse strains to study the cellular and molecular phenotypes during adipogenic induction. We found that cells with activated Notch signaling displayed decreased mitochondrial respiration despite similar levels of adipogenesis and mitochondrial number. We observed variable regulation of the proteins related to mitochondrial dynamics and ferroptosis, including PHB3, PINK1, pDRP1, and the phospholipid hydroperoxidase GPX4. Mitochondria regulate some forms of ferroptosis, which is a regulated process of cell death driven by lipid peroxidation. Accordingly, we found that Notch activation promoted lipid peroxidation and ferroptosis in PVAT-derived adipocytes. Because the PVAT phenotype is a regulator of vascular reactivity, we tested the effect of Notch activation in PVAT on vasoreactivity using wire myography. The aortae from the N1ICD;Adipoq-Cre mice had increased vasocontraction and decreased vasorelaxation in a PVAT-dependent and age-dependent manner. Our data provide support for the novel concept that increased Notch signaling in the adipose tissue leads to PVAT whitening, impaired mitochondrial function, increased ferroptosis, and loss of a protective vasodilatory signal. Our study advances our understanding of how Notch signaling in adipocytes affects mitochondrial dynamics, which impacts vascular physiology.
format Online
Article
Text
id pubmed-10606454
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-106064542023-10-28 Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways Yang, Chenhao Yang, Xuehui Harrington, Anne Potts, Christian Kaija, Abigail Ryzhova, Larisa Liaw, Lucy Genes (Basel) Article Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced obesity, and leads to the loss of the thermogenic phenotype and adipocyte whitening due to increased lipid accumulation. We used the Adiponectin-Cre (Adipoq-Cre) strain to activate a ligand-independent Notch1 intracellular domain transgene (N1ICD) to drive constitutive Notch signaling in the adipose tissues (N1ICD;Adipoq-Cre). We previously found that constitutive activation of Notch1 signaling in the PVAT phenocopied the effects of diet-induced obesity. To understand the downstream pathways activated by Notch signaling, we performed a proteomic analysis of the PVAT from control versus N1ICD;Adipoq-Cre mice. This comparison identified prominent changes in the protein signatures related to metabolism, adipocyte homeostasis, mitochondrial function, and ferroptosis. PVAT-derived stromal vascular fraction cells were derived from our mouse strains to study the cellular and molecular phenotypes during adipogenic induction. We found that cells with activated Notch signaling displayed decreased mitochondrial respiration despite similar levels of adipogenesis and mitochondrial number. We observed variable regulation of the proteins related to mitochondrial dynamics and ferroptosis, including PHB3, PINK1, pDRP1, and the phospholipid hydroperoxidase GPX4. Mitochondria regulate some forms of ferroptosis, which is a regulated process of cell death driven by lipid peroxidation. Accordingly, we found that Notch activation promoted lipid peroxidation and ferroptosis in PVAT-derived adipocytes. Because the PVAT phenotype is a regulator of vascular reactivity, we tested the effect of Notch activation in PVAT on vasoreactivity using wire myography. The aortae from the N1ICD;Adipoq-Cre mice had increased vasocontraction and decreased vasorelaxation in a PVAT-dependent and age-dependent manner. Our data provide support for the novel concept that increased Notch signaling in the adipose tissue leads to PVAT whitening, impaired mitochondrial function, increased ferroptosis, and loss of a protective vasodilatory signal. Our study advances our understanding of how Notch signaling in adipocytes affects mitochondrial dynamics, which impacts vascular physiology. MDPI 2023-10-20 /pmc/articles/PMC10606454/ /pubmed/37895313 http://dx.doi.org/10.3390/genes14101964 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Chenhao
Yang, Xuehui
Harrington, Anne
Potts, Christian
Kaija, Abigail
Ryzhova, Larisa
Liaw, Lucy
Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways
title Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways
title_full Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways
title_fullStr Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways
title_full_unstemmed Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways
title_short Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways
title_sort notch signaling regulates mouse perivascular adipose tissue function via mitochondrial pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606454/
https://www.ncbi.nlm.nih.gov/pubmed/37895313
http://dx.doi.org/10.3390/genes14101964
work_keys_str_mv AT yangchenhao notchsignalingregulatesmouseperivascularadiposetissuefunctionviamitochondrialpathways
AT yangxuehui notchsignalingregulatesmouseperivascularadiposetissuefunctionviamitochondrialpathways
AT harringtonanne notchsignalingregulatesmouseperivascularadiposetissuefunctionviamitochondrialpathways
AT pottschristian notchsignalingregulatesmouseperivascularadiposetissuefunctionviamitochondrialpathways
AT kaijaabigail notchsignalingregulatesmouseperivascularadiposetissuefunctionviamitochondrialpathways
AT ryzhovalarisa notchsignalingregulatesmouseperivascularadiposetissuefunctionviamitochondrialpathways
AT liawlucy notchsignalingregulatesmouseperivascularadiposetissuefunctionviamitochondrialpathways