Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic disease and increase after gastric bypass surgery in humans

Abstract

Context: Mouse studies suggest that adropin, a peptide hormone, is required for metabolic homeostasis and prevention of obesity-associated insulin resistance. Whether obesity and insulin resistance are associated with low plasma adropin levels in humans is not known.

Objectives: Our objective was to investigate the hypothesis that obesity and indicators of insulin resistance are associated with low adropin levels and determine whether weight loss regulates adropin levels.

Design and participants: Plasma was obtained from 85 female [age 21-67 yr, body mass index (BMI) 19.4-71.5 kg/m2] and 45 male (age 18-70 yr, BMI 19.1-62.6 kg/m2) volunteers for other clinical studies. The impact of Roux-en-Y gastric bypass was investigated in 19 obese females (BMI 37-65 kg/m2) using samples collected at baseline and 1-12 months after surgery.

Results: Adropin levels correlate negatively with BMI (r=-0.335, P<0.001) and age (r=-0.263, P=0.003). Age-adjusted adropin levels are higher in males [4.1 ng/ml; 95% confidence interval (CI)=3.6-4.6 ng/ml] than females (3.0 ng/ml; 95% CI=2.6-3.4 ng/ml) (P=0.001). In all subjects, lower age-adjusted adropin levels were observed in overweight (3.3 ng/ml; 95% CI=2.8-3.8 ng/ml, P=0.033) and obese (2.7 ng/ml; 95% CI=2.1-3.3 ng/ml, P=0.001) compared with healthy-weight subjects (4.1 ng/ml; 95% CI=3.6-4.5 ng/ml). This effect was gender specific (weight category×gender, P<0.001) and was observed in males only. Aging and diagnosis with two or more metabolic syndrome risk factors was associated with low adropin levels, irrespective of sex. Adropin concentrations increased after Roux-en-Y gastric bypass, peaking 3 months after surgery (P<0.01).

Conclusions: Although males exhibit higher adropin levels that are reduced by obesity, aging and markers of insulin resistance are associated with low plasma adropin irrespective of sex.

Fig. 1.

Meal intake and overnight fasting have no significant effect on plasma adropin levels in female volunteers. Plasma adropin levels were measured throughout the day and after an overnight fast. Meal times are indicated by letters (B, breakfast; L, lunch; S, snack; D, dinner).

Fig. 2.

Analysis of the impact of obesity and aging on plasma adropin levels in males and females. A, Plasma adropin levels as a function of BMI; B, plasma adropin levels as a function of age; C, age-adjusted plasma adropin levels in subjects categorized as being of healthy weight (BMI = 18.5–24.9 kg/m²), overweight (BMI = 25–29.9 kg/m²), or obese (BMI > 30 kg/m²). Multivariate analysis indicated that the effect of obesity is sex specific. There was a significant effect of gender (P < 0.05), with higher levels in males (plasma adropin levels = 3.7 ± 0.2 ng/ml) relative to females (3.0 ± 0.2 ng/ml). Significance (*, P < 0.05; **, P < 0.01) was determined using Bonferroni post hoc analysis. D, BMI-adjusted plasma adropin levels by age group. The difference between those under 30, 40–50, and 50 yr and older was significant in all subjects (*, P < 0.05 vs. <30 yr by post hoc analysis using Bonferroni's analysis). There was a trend (P = 0.058) for an effect of gender on plasma adropin levels.

Fig. 3.

Low plasma adropin levels in individuals with metabolic risk factors. A, Plasma adropin levels (age-adjusted) in subjects grouped by MSRF score (0, 1, 2, or more than 3). Significantly different from MSRF = 0 or as indicated: *, P < 0.05; **, P < 0.01 (post hoc analysis using Bonferroni's correction for multiple comparisons). B, Negative correlation between fasting plasma adropin and fasting TG in males (shaded circles) and females (open circles). The data used shown in this analysis are natural log transformed.

Fig. 4.

Gastric bypass surgery is associated with increased plasma adropin levels in obese females (n = 19). A, Impact of gastric bypass on obesity. All subjects lost weight in the 12 months after surgery. B, Impact of RYGB on plasma adropin levels. The effect of surgery on adropin levels was significant (P < 0.01), with plasma adropin levels significantly higher 3 months after surgery relative to levels at baseline and 1 month (*, P < 0.05 vs. baseline; **, P < 0.01 vs. baseline and 1 month).