Endothelial-adipocyte Cx43 Mediated Gap Junctions Can Regulate Adiposity.

Publisher: Oxford University Press Country of Publication: England NLM ID: 101770668 Publication Model: Print Cited Medium: Internet ISSN: 2633-8823 (Electronic) Linking ISSN: 26338823 NLM ISO Abbreviation: Function (Oxf) Subsets: MEDLINE

Original Publication: [Oxford, UK] : Oxford University Press, [2020]-

Adipocytes*/metabolism ; Adiposity* ; Connexin 43*/metabolism ; Connexin 43*/genetics ; Endothelial Cells*/metabolism ; Gap Junctions*/metabolism; Animals ; Humans ; Male ; Mice ; Adipose Tissue/metabolism ; Cell Communication ; Coculture Techniques ; Diet, High-Fat/adverse effects ; Lipid Metabolism ; Mice, Inbred C57BL ; Obesity/metabolism ; Obesity/pathology ; Obesity/genetics ; Phosphorylation

Obesity is a multifactorial metabolic disorder associated with endothelial dysfunction and increased risk of cardiovascular disease. Adipose capillary adipose endothelial cells (CaECs) plays a crucial role in lipid transport and storage. Here, we investigated the mechanisms underlying CaEC-adipocyte interaction and its impact on metabolic function. Single-cell RNA sequencing (scRNAseq) revealed an enrichment of fatty acid handling machinery in CaECs from high fat diet (HFD) mice, suggesting their specialized role in lipid metabolism. Transmission electron microscopy (TEM) confirmed direct heterocellular contact between CaECs and adipocytes. To model this, we created an in vitro co-culture transwell system to model the heterocellular contact observed with TEM. Contact between ECs and adipocytes in vitro led to upregulation of fatty acid binding protein 4 in response to lipid stimulation, hinting intercellular signaling may be important between ECs and adipocytes. We mined our and others scRNAseq datasets to examine which connexins may be present in adipose capillaries and adipocytes and consistently identified connexin 43 (Cx43) in mouse and humans. Genetic deletion of endothelial Cx43 resulted in increased epididymal fat pad (eWAT) adiposity and dyslipidemia in HFD mice. Consistent with this observation, phosphorylation of Cx43 at serine 368, which closes gap junctions, was increased in HFD mice and lipid-treated ECs. Mice resistant to this post-translational modification, Cx43S368A, were placed on an HFD and were found to have reduced eWAT adiposity and improved lipid profiles. These findings suggest Cx43-mediated heterocellular communication as a possible regulatory mechanism of adipose tissue function.
(© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)

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T32 HL007284 United States HL NHLBI NIH HHS; University of Virginia; HL120840 United States NH NIH HHS; AHA915176 Lipedema Foundation

Keywords: adipose; adiposity; capillaries; heterocellular contact; metabolism; obesity

0 (Connexin 43)
0 (GJA1 protein, human)
0 (GJA1 protein, mouse)

Date Created: 20240710 Date Completed: 20240910 Latest Revision: 20241030

20241031

PMC11384900

10.1093/function/zqae029

38984993