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The Effects of Mild Intermittent Hypoxia Exposure on the Abdominal Subcutaneous Adipose Tissue Proteome in Overweight and Obese Men: A First-in-Human Randomized, Single-Blind, and Cross-Over Study.

ABSTRACT: Adipose tissue (AT) oxygen tension (pO₂) has been implicated in AT dysfunction and metabolic perturbations in both rodents and humans. Compelling evidence suggests that hypoxia exposure alters metabolism, at least partly through effects on AT. However, it remains to be elucidated whether mild intermittent hypoxia (MIH) exposure impacts the AT proteome. We performed a randomized, single-blind, and cross-over study to investigate the effects of seven consecutive days of MIH (FiO₂ 15%, 3x2h/d) compared to normoxia (FiO₂ 21%) exposure on the AT proteome in overweight/obese men. In vivo AT insulin sensitivity was determined by the gold standard hyperinsulinemic-euglycemic clamp, and abdominal subcutaneous AT biopsies were collected under normoxic fasting conditions following both exposure regimens (day 8). AT proteins were isolated and quantified using liquid chromatography-mass spectrometry. After correction for blood contamination, 1,022 AT protein IDs were identified, of which 123 were differentially expressed following MIH (p < 0.05). We demonstrate for the first time that MIH exposure, which markedly reduces in vivo AT oxygen tension, impacts the human AT proteome. Although we cannot exclude that a single differentially expressed protein might be a false positive finding, several functional pathways were altered by MIH exposure, also after adjustment for multiple testing. Specifically, differentially expressed proteins were involved in redox systems, cell-adhesion, actin cytoskeleton organization, extracellular matrix composition, and energy metabolism. The MIH-induced change in AT TMOD3 expression was strongly related to altered in vivo AT insulin sensitivity, thus linking MIH-induced effects on the AT proteome to metabolic changes in overweight/obese humans.

SUBMITTER: Van Meijel RLJ

PROVIDER: S-EPMC8764283 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population-based cohort of obese adults. DESIGN AND METHODS:Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. RESULTS:In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p < 0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque (p < 0.001 for each). VAT independently associated with C-reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA-IR were significant in univariable analyses but attenuated after multivariable adjustment. CONCLUSION:VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk.

Dataset Information

The Effects of Mild Intermittent Hypoxia Exposure on the Abdominal Subcutaneous Adipose Tissue Proteome in Overweight and Obese Men: A First-in-Human Randomized, Single-Blind, and Cross-Over Study.

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