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Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity [ThighMuscle]

ABSTRACT: Some people with obesity are resistant to the adverse metabolic effects of excess adiposity and are considered to have “metabolically healthy obesity” (MHO). However, the mechanisms responsible for MHO are not clear. We performed comprehensive cardiometabolic profiling in 20 adults with MHO (defined by features of normal insulin sensitivity), 20 age-, sex-, and BMI-matched adults with metabolically unhealthy obesity (MUO), and 15 adults who were metabolically healthy and lean (MHL). More than 120 variables were evaluated, including body composition, beta-cell function, 24-hour plasma metabolic profile, rates of de novo lipogenesis and cholesterol synthesis, plasma adipokine concentrations, oxidative stress, plasma lipoprotein profiles, cardiovascular structure/function, skeletal muscle bioactive lipids, and both adipose tissue and skeletal muscle transcriptomics. Using dimensionality reduction approaches, measures of insulinemia and skeletal muscle ceramides were the strongest discriminators of MHO and MUO status. These data clarify the characteristics associated with preserved metabolic health in response to obesity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244120 | GEO | 2024/03/06

REPOSITORIES: GEO

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Project description:Background and aims: Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes (e.g. fasting glucose, serum triglycerides, etc.). The underling mechanisms for those differences are still unclear. This study aimed to analyze the whole blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. Methods: 27 children with OW/OB (10.14 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), epidermal growth factor (EGF) and, vascular endothelial growth factor A (VEGF) were additionally determined. Total-blood RNA was analyzed by 5’-end RNA sequencing. Two different bioinformatics approaches were performed: 1) Differential gene expression analyses using Limma R/Bioconductor software package (analyses adjusted by sex and maturational status) and 2) weighted gene coexpression network analyses (WGCNA). Results: Children with MHO had lower values of pro-inflammatory cytokines TNF-α and IL-6 compared to MUO (p < 0.05). 40 genes were differentially expressed (FDR < 0.05) in children with MHO compared to MUO. WGCNA analysis identified 23 gene coexpression modules (i.e. clusters of genes) with low preservation (Zsummary < 2) in children with MHO compared to MUO. Differential and WGCNA gene expression patterns identified 32 genes linked to metabolism, mitochondrial and immune functions. Conclusions: Whole blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. The identified gene expression patterns related to metabolism, mitochondrial and immune functions can promote a better understanding of cardiovascular disease prognosis in individuals with MHO.

Project description:Background/aims: Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type‐2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO) opening the possibility that FGF21 is a cross‐talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion. Methods/study design: In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole‐body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro. Results: Serum FGF21 concentrations were more than two‐fold higher in MUHO as compared to 37 MHO subjects (457 ±378 vs. 211 ±123 pg/mL; p<0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p<0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, ‐15% and ‐40%, respectively; p<0.01 both), reduced adiponectin expression (‐20%; p<0.05), markedly reduced adiponectin release (‐60%; p<0.01), and substantially increased leptin (+60%; p<0.01) and interleukin‐6 (+50%; p<0.001) release. Interpretation/conclusions: The hepatokine FGF21 exerts weak lipogenic and anti‐adipogenic actions and marked adiponectin‐suppressive and leptin and interleukin‐6 release‐promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes. We analysed in vitro differentiated preadipocytes from 20 human donors treated with FGF21 or control cultures.

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Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity [ThighMuscle]

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