The Fundamental Differences between Individuals with Early‐onset Obesity and Late‐onset Obesity: An Acetyl‐CoA Approach
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".