The Fundamental Differences between Individuals with Early‐onset Obesity and Late‐onset Obesity: An Acetyl‐CoA Approach
Notice bibliographique
Résumé
Introduction Compared to those who only become obese as adults (late‐onset obesity, LOO), those who are persistently overweight since childhood (early‐onset obesity, EOO) have higher risk of diabetes and coronary heart disease. Although differences in disease risk between individuals with early‐ and late‐onset obesity are well recognized, the fundamental differences between them are largely unclear. The current study characterized the levels of acetyl‐CoA, acetyl‐CoA network genes, and H3 histone acetylation in adipose tissue from individuals with EOO and LOO. Method Biopsies of abdominal and femoral subcutaneous adipose tissue (AbSAT & FeSAT) were collected from female participants with EOO (n=16) and LOO (n=17). DXA scans were used to confirm participants were BMI‐ and body composition‐matched. Serum leptin and adiponectin were measured via ELISA. RT‐PCR was used to examine the expression of genes regulating acetyl‐CoA metabolism, and levels of nucleocytosolic acetyl‐CoA and histone H3 acetylation in AbSAT and FeSAT. Results Despite similar fat mass, serum leptin was higher (p<0.01) in LOO (26.24±1.70 ng/ml) than EOO (18.93±1.35 ng/ml). There were no differences in serum adiponectin between the two groups. Adipose tissue acetyl‐CoA levels were greater (p<0.05) in LOO (48.94±4.80 pmol) vs. EOO (34.15±3.584 pmol). For the genes regulating acetyl‐CoA metabolism, adipose tissue mRNA levels of BCKD and ACLY were higher (p<0.05, two‐way ANOVA) in LOO vs. EOO. Compared to EOO, mRNA expression in both AbSAT (p<0.01) and FeSAT (p=0.056, via Tukey’s post‐hoc tests) of ACLY in LOO was higher. Multiple linear regression with 2‐way interactions revealed that ACLY was the only main effector of acetyl‐CoA levels (β=42.67, p<0.05) and acetyl‐CoA network genes, and their interactions explain ~80% of the variation in acetyl‐CoA level (F(21, 18)=3.571, R 2 =0.81 p<0.01). The increased level of acetyl‐CoA in both AbSAT and FeSAT was strongly associated with histone H3 acetylation (AbSAT, r=0.48, p=0.062; FeSAT, r=0.54, p<0.05), LEPTIN expression (AbSAT, r=0.53, p<0.05; FeSAT, r=0.55, p<0.05) and circulating leptin (AbSAT, r=0.57, p<0.01; FeSAT, r=0.63, p<0.01). Discussion In the current study, we found greater acetyl‐CoA levels in adipose tissue of LOO vs EOO that could be explained by the higher abundance of ACLY, which catalyzes the conversion from citrate to acetyl‐CoA. The increased serum leptin in LOO may imply greater leptin resistance, potentially resulting in greater macronutrient intake. With the abundant supply of macronutrients to adipose tissue, ACLY may increase to produce more nucleocytosolic acetyl‐CoA, increasing histone H3 acetylation, turning “on” gene expression. The strong correlation between the acetyl‐CoA, histone H3 acetylation, LEPTIN expression and serum leptin suggests that leptin level in human is possibly epigenetically regulated by histone acetylation. The fundamental difference in the important metabolic intermediate, acetyl‐CoA, between EOO and LOO may help us better understand the development of obesity and the pathogenesis of different obesity‐related diseases in humans. Support or Funding Information Canada Research Chairs Program and Natural Sciences, Engineering Research Council and Horizon Fellowship
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».