The Fundamental Differences between Individuals with Early-onset Obesity and Late-onset Obesity: An Acetyl-CoA Approach

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, R2=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.