White Adipose Tissue Response of Obese Mice to Ambient Oxygen Restriction at Thermoneutrality: Response Markers Identified, but no WAT Inflammation

Abstract

Obesity is associated with white adipose tissue (WAT) hypoxia and inflammation. We aimed to test whether mild environmental oxygen restriction (OxR, 13% O2), imposing tissue hypoxia, triggers WAT inflammation in obese mice. Thirteen weeks diet-induced obese male adult C57BL/6JOlaHsd mice housed at thermoneutrality were exposed for five days to OxR versus normoxia. WAT and blood were isolated and used for analysis of metabolites and adipokines, WAT histology and macrophage staining, and WAT transcriptomics. OxR increased circulating levels of haemoglobin and haematocrit as well as hypoxia responsive transcripts in WAT and decreased blood glucose, indicating systemic and tissue hypoxia. WAT aconitase activity was inhibited. Macrophage infiltration as marker for WAT inflammation tended to be decreased, which was supported by down regulation of inflammatory genes S100a8, Ccl8, Clec9a, Saa3, Mgst2, and Saa1. Other down regulated processes include cytoskeleton remodelling and metabolism, while response to hypoxia appeared most prominently up regulated. The adipokines coiled-coil domain containing 3 (CCDC3) and adiponectin, as well as the putative WAT hormone cholecystokinin (CCK), were reduced by OxR on transcript (Cck, Ccdc3) and/or serum protein level (adiponectin, CCDC3). Conclusively, our data demonstrate that also in obese mice OxR does not trigger WAT inflammation. However, OxR does evoke a metabolic response in WAT, with CCDC3 and adiponectin as potential markers for systemic or WAT hypoxia.

Extracellular and intracellular functions of coiled-coil domain containing 3

“…CCDC3 has been shown to be implicated in inflammation and immunity. Both CCDC3 transcript and protein are reduced in the white adipose tissue of oxygen-restricted obese mice, suggesting that CCDC3 could be a marker for hypoxia in the white adipose tissue ( Hoevenaars et al., 2019 ). Endothelial cells (ECs) need to be activated by pro-inflammatory molecules, such as TNF-α, to exert their functions.…”

Cloning grass carp (Ctenopharyngodon idella) ccdc3 and its expression affected by nutrition state, insulin, and glucagon

“…Furthermore, CCDC3 knockdown can reduce the levels of epithelial mesenchymal transition (EMT)–related factors and considerably alleviate the proliferative, migratory, and invasive capacities of C33 and HeLa cells (Zhang et al, 2019). In addition, CCDC3 is a molecular marker in multiple biological processes, such as cancer cell proliferation (Ke et al, 2022; Mao et al, 2023), radiotherapy (Dan et al, 2023), stress development (Dieckmann et al, 2020; Hoevenaars et al, 2019; Saelao et al, 2019), and kidney interstitial disease function (Barwinska et al, 2021).…”