Puberty Status Modifies the Effects of Genetic Variants, Lifestyle Factors and Their Interactions on Adiponectin: The BCAMS Study

Yunpeng Wu, Ling Zhong, Ge Li, Lanwen Han, Junling Fu, Yu Li, Lujiao Li, Qian Zhang, Yiran Guo, Xinhua Xiao, Lu Qi, Ming Li, Shan Gao, Steven M Willi, Yunpeng Wu, Ling Zhong, Ge Li, Lanwen Han, Junling Fu, Yu Li, Lujiao Li, Qian Zhang, Yiran Guo, Xinhua Xiao, Lu Qi, Ming Li, Shan Gao, Steven M Willi

Abstract

Background: Hypoadiponectinemia has been associated with various cardiometabolic disease states. Previous studies in adults have shown that adiponectin levels were regulated by specific genetic and behavioral or lifestyle factors. However, little is known about the influence of these factors on adiponectin levels in children, particularly as mitigated by pubertal development.

Methods: We performed a cross-sectional analysis of data from 3,402 children aged 6-18 years from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. Pubertal progress was classified as prepubertal, midpuberty, and postpuberty. Six relevant single nucleotide polymorphisms (SNPs) were selected from previous genome-wide association studies of adiponectin in East Asians. Individual SNPs and two weighted genetic predisposition scores, as well as their interactions with 14 lifestyle factors, were analyzed to investigate their influence on adiponectin levels across puberty. The effect of these factors on adiponectin was analyzed using general linear models adjusted for age, sex, and BMI.

Results: After adjustment for age, sex, and BMI, the associations between adiponectin levels and diet items, and diet score were significant at prepuberty or postpuberty, while the effect of exercise on adiponectin levels was more prominent at mid- and postpuberty. Walking to school was found to be associated with increased adiponectin levels throughout puberty. Meanwhile, the effect of WDR11-FGFR2-rs3943077 was stronger at midpuberty (P = 0.002), and ADIPOQ-rs6773957 was more effective at postpuberty (P = 0.005), while CDH13-rs4783244 showed the strongest association with adiponectin levels at all pubertal stages (all P < 3.24 × 10-15). We further found that effects of diet score (Pinteraction = 0.022) and exercise (Pinteraction = 0.049) were stronger in children with higher genetic risk of hypoadiponectinemia, while higher diet score and exercise frequency attenuated the differences in adiponectin levels among children with different genetic risks.

Conclusions: Our study confirmed puberty modulates the associations between adiponectin, and genetic variants, lifestyle factors, and gene-by-lifestyle interactions. These findings provide new insight into puberty-specific lifestyle suggestions, especially in genetically susceptible individuals.

Trial registration: ClinicalTrials.gov NCT03421444.

Keywords: adiponectin; diet items; gene-by-lifestyle interaction; genetic variants; puberty.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Wu, Zhong, Li, Han, Fu, Li, Li, Zhang, Guo, Xiao, Qi, Li, Gao and Willi.

Figures

Figure 1
Figure 1
Changes in ln-adiponectin levels during puberty according to sex. Data were shown as mean and SE. Puberty status was reclassified into prepuberty (Tanner stage I), midpuberty (Tanner stage II-III) and postpuberty (Tanner stage ≥ IV). Difference between boys and girls in the same pubertal group was indicated *P

Figure 2

Genetic and lifestyle associations with…

Figure 2

Genetic and lifestyle associations with adiponectin levels according to the different puberty stages.…

Figure 2
Genetic and lifestyle associations with adiponectin levels according to the different puberty stages. Figure (A) shows the effect (histograms) and SEs (error bar) of SNPs on adiponectin levels (% change in adiponectin levels per effect allele) at different puberty stages. Figure (B) shows the effect (histograms) and SEs (error bar) of lifestyle factors on adiponectin levels (% change in adiponectin levels when walking to school for the transportation variable and % change in adiponectin levels per assigned score increase for other variables) at different puberty stages. The results were adjusted for age, sex, and BMI. *P < 0.05; ** P < 0.05/6 = 0.008 (after Bonferroni correction); *** P < 0.001.

Figure 3

Effects of the interactions of…

Figure 3

Effects of the interactions of the weighted genetic score with lifestyle factors on…

Figure 3
Effects of the interactions of the weighted genetic score with lifestyle factors on the % change in adiponectin levels according to the different puberty stages. The figure shows the effect and 95% CI of the interactions of wGPSall and wGPSno CDH13 with lifestyle factors on adiponectin levels (% change in adiponectin levels per wGPSall or wGPSno CDH13 per diet score or per lifestyle factors assigned score increase) in the entire population of children at different puberty stages. The results for the diet items were adjusted for age and sex. The results for the diet score were adjusted for age, sex, and activities (including exercise and transportation type). The results for the activities were adjusted for age, sex, and diet score; * P < 0.05.

Figure 4

The associations of diet and…

Figure 4

The associations of diet and exercise with adiponectin levels according to the categories…

Figure 4
The associations of diet and exercise with adiponectin levels according to the categories of genetic risk. The figure shows the main effects (histograms) and SEs (error bars) of diet score and exercise on adiponectin levels (% change in adiponectin levels per assigned score increase for diet and exercise) according to the genetic risk for decreased adiponectin levels. The data for diet scores were adjusted for age, sex, transportation type and exercise. The data for exercise were adjusted for age, sex and diet score. As we reported an interaction between diet score and wGPSall and an interaction for exercise with wGPSno CDH13, we used wGPSall to identify the genetic modification of diet effect and used wGPSno CDH13 to identify the genetic modification of the exercise effect. Genetic risk was divided into low genetic risk (wGPSno CDH13 or wGPSall > mean +1SD), intermediate genetic risk (wGPSno CDH13 or wGPSall ≥ mean -1SD but ≤ mean+1SD) and high genetic risk (wGPSno CDH13 or wGPSall

Figure 5

Adiponectin levels according to genetic…

Figure 5

Adiponectin levels according to genetic risk and categories of diet and exercise. The…

Figure 5
Adiponectin levels according to genetic risk and categories of diet and exercise. The figure shows multivariable-adjusted means (histograms) and SEs (error bar) of the natural logarithm transformed adiponectin levels according to the categories of lifestyle and genetic risk for decreased adiponectin levels. The P-values are the results of an ANCOVA comparing the adiponectin levels among the genetic risk groups. Data for exercise were adjusted for age, sex, and diet score, while data for diet were adjusted for age, sex, and exercise frequency. As we reported an interaction between diet score and wGPSall and an interaction for exercise with wGPSno CDH13, we used (A) wGPSall to identify genetic risk categories in the diet subgroups and (B) used wGPSno CDH13 to identify genetic risk categories in the exercise subgroups. Genetic risk was divided into low genetic risk (wGPSno CDH13 or wGPSall > mean + 1SD), intermediate genetic risk (wGPSno CDH13 or wGPSall ≥ mean - 1SD but ≤ mean + 1SD) and high genetic risk (wGPSno CDH13 or wGPSall < mean - 1SD). Similarly, diet and exercise were divided into high (diet score> mean + 1SD; exercise frequency ≤ 2 times per week), intermediate (diet score ≥ mean - 1SD but ≤ mean + 1SD; exercise frequency = 3-4 times per week), and low (diet score < mean – 1SD; exercise frequency ≥ 5 times/week). N.S. means the difference is not significant.

Figure 6

Hypothesis for the changes in…

Figure 6

Hypothesis for the changes in adipocyte metabolism during puberty. The figure shows our…

Figure 6
Hypothesis for the changes in adipocyte metabolism during puberty. The figure shows our hypothesis, which is that the modification effect of puberty on the SNP-adiponectin association is based on the development of adipose tissue during puberty. The SNPs shown in this figure are SNP1: ADIPOQ-rs10937273; SNP2: ADIPOQ-rs6773957; SNP3: CDH13-rs4783244; SNP4: WDR11-FGFR2-rs3943077; and SNP5: PEPD-rs889140. The puberty categories that we used in the current study were as follows: prepuberty (Tanner stage I), midpuberty (Tanner stage II-III), and postpuberty (Tanner stage ≥ IV). Prepuberty is a period during which the processes of puberty have not yet been activated completely. Midpuberty is the phase during which puberty has been activated but is not finished. Postpuberty is the stage at which the processes of puberty are nearly completed, and adolescents at postpuberty are similar to adults. The development of adipose tissue includes hyperplasia, related to WDR11-FGFR2-rs3943077, and the hypertrophy of adipocytes. The number of adipocytes increases quickly at midpuberty but remains relatively consistent after postpuberty. The size of adipocytes increases during puberty, which makes them secrete lower amounts of adiponectin. The process of hypertrophy is suppressed by the function of collagen, which might be related to PEPD-rs889140. ADIPOQ-rs10937273 and ADIPOQ-rs6773957 are SNPs located at different regulation sites of the adiponectin gene. They are activated at different puberty stages. Adiponectin is bound by T-cadherin encoded by CDH13, which is a high-molecular-weight adiponectin receptor expressed on target cells. Sex steroids decrease adiponectin levels by taking part in the regulation of both the distribution and differentiation of adipocytes.
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References
    1. Blüher M. Obesity: Global Epidemiology and Pathogenesis. Nat Rev Endocrinol (2019) 15(5):288–98. doi: 10.1038/s41574-019-0176-8 - DOI - PubMed
    1. Pan XF, Wang L, Pan A. Epidemiology and Determinants of Obesity in China. Lancet Diabetes Endocrinol (2021) 9(6):373–92. doi: 10.1016/s2213-8587(21)00045-0 - DOI - PubMed
    1. Zeng Q, Li N, Pan XF, Chen L, Pan A. Clinical Management and Treatment of Obesity in China. Lancet Diabetes Endocrinol (2021) 9(6):393–405. doi: 10.1016/s2213-8587(21)00047-4 - DOI - PubMed
    1. Rosen E, Spiegelman B. What We Talk About When We Talk About Fat. Cell (2014) 156(1-2):20–44. doi: 10.1016/j.cell.2013.12.012 - DOI - PMC - PubMed
    1. Kershaw EE, Flier JS. Adipose Tissue as an Endocrine Organ. J Clin Endocrinol Metab (2004) 89(6):2548–56. doi: 10.1210/jc.2004-0395 - DOI - PubMed
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Figure 2
Figure 2
Genetic and lifestyle associations with adiponectin levels according to the different puberty stages. Figure (A) shows the effect (histograms) and SEs (error bar) of SNPs on adiponectin levels (% change in adiponectin levels per effect allele) at different puberty stages. Figure (B) shows the effect (histograms) and SEs (error bar) of lifestyle factors on adiponectin levels (% change in adiponectin levels when walking to school for the transportation variable and % change in adiponectin levels per assigned score increase for other variables) at different puberty stages. The results were adjusted for age, sex, and BMI. *P < 0.05; ** P < 0.05/6 = 0.008 (after Bonferroni correction); *** P < 0.001.
Figure 3
Figure 3
Effects of the interactions of the weighted genetic score with lifestyle factors on the % change in adiponectin levels according to the different puberty stages. The figure shows the effect and 95% CI of the interactions of wGPSall and wGPSno CDH13 with lifestyle factors on adiponectin levels (% change in adiponectin levels per wGPSall or wGPSno CDH13 per diet score or per lifestyle factors assigned score increase) in the entire population of children at different puberty stages. The results for the diet items were adjusted for age and sex. The results for the diet score were adjusted for age, sex, and activities (including exercise and transportation type). The results for the activities were adjusted for age, sex, and diet score; * P < 0.05.
Figure 4
Figure 4
The associations of diet and exercise with adiponectin levels according to the categories of genetic risk. The figure shows the main effects (histograms) and SEs (error bars) of diet score and exercise on adiponectin levels (% change in adiponectin levels per assigned score increase for diet and exercise) according to the genetic risk for decreased adiponectin levels. The data for diet scores were adjusted for age, sex, transportation type and exercise. The data for exercise were adjusted for age, sex and diet score. As we reported an interaction between diet score and wGPSall and an interaction for exercise with wGPSno CDH13, we used wGPSall to identify the genetic modification of diet effect and used wGPSno CDH13 to identify the genetic modification of the exercise effect. Genetic risk was divided into low genetic risk (wGPSno CDH13 or wGPSall > mean +1SD), intermediate genetic risk (wGPSno CDH13 or wGPSall ≥ mean -1SD but ≤ mean+1SD) and high genetic risk (wGPSno CDH13 or wGPSall

Figure 5

Adiponectin levels according to genetic…

Figure 5

Adiponectin levels according to genetic risk and categories of diet and exercise. The…

Figure 5
Adiponectin levels according to genetic risk and categories of diet and exercise. The figure shows multivariable-adjusted means (histograms) and SEs (error bar) of the natural logarithm transformed adiponectin levels according to the categories of lifestyle and genetic risk for decreased adiponectin levels. The P-values are the results of an ANCOVA comparing the adiponectin levels among the genetic risk groups. Data for exercise were adjusted for age, sex, and diet score, while data for diet were adjusted for age, sex, and exercise frequency. As we reported an interaction between diet score and wGPSall and an interaction for exercise with wGPSno CDH13, we used (A) wGPSall to identify genetic risk categories in the diet subgroups and (B) used wGPSno CDH13 to identify genetic risk categories in the exercise subgroups. Genetic risk was divided into low genetic risk (wGPSno CDH13 or wGPSall > mean + 1SD), intermediate genetic risk (wGPSno CDH13 or wGPSall ≥ mean - 1SD but ≤ mean + 1SD) and high genetic risk (wGPSno CDH13 or wGPSall < mean - 1SD). Similarly, diet and exercise were divided into high (diet score> mean + 1SD; exercise frequency ≤ 2 times per week), intermediate (diet score ≥ mean - 1SD but ≤ mean + 1SD; exercise frequency = 3-4 times per week), and low (diet score < mean – 1SD; exercise frequency ≥ 5 times/week). N.S. means the difference is not significant.

Figure 6

Hypothesis for the changes in…

Figure 6

Hypothesis for the changes in adipocyte metabolism during puberty. The figure shows our…

Figure 6
Hypothesis for the changes in adipocyte metabolism during puberty. The figure shows our hypothesis, which is that the modification effect of puberty on the SNP-adiponectin association is based on the development of adipose tissue during puberty. The SNPs shown in this figure are SNP1: ADIPOQ-rs10937273; SNP2: ADIPOQ-rs6773957; SNP3: CDH13-rs4783244; SNP4: WDR11-FGFR2-rs3943077; and SNP5: PEPD-rs889140. The puberty categories that we used in the current study were as follows: prepuberty (Tanner stage I), midpuberty (Tanner stage II-III), and postpuberty (Tanner stage ≥ IV). Prepuberty is a period during which the processes of puberty have not yet been activated completely. Midpuberty is the phase during which puberty has been activated but is not finished. Postpuberty is the stage at which the processes of puberty are nearly completed, and adolescents at postpuberty are similar to adults. The development of adipose tissue includes hyperplasia, related to WDR11-FGFR2-rs3943077, and the hypertrophy of adipocytes. The number of adipocytes increases quickly at midpuberty but remains relatively consistent after postpuberty. The size of adipocytes increases during puberty, which makes them secrete lower amounts of adiponectin. The process of hypertrophy is suppressed by the function of collagen, which might be related to PEPD-rs889140. ADIPOQ-rs10937273 and ADIPOQ-rs6773957 are SNPs located at different regulation sites of the adiponectin gene. They are activated at different puberty stages. Adiponectin is bound by T-cadherin encoded by CDH13, which is a high-molecular-weight adiponectin receptor expressed on target cells. Sex steroids decrease adiponectin levels by taking part in the regulation of both the distribution and differentiation of adipocytes.
Figure 5
Figure 5
Adiponectin levels according to genetic risk and categories of diet and exercise. The figure shows multivariable-adjusted means (histograms) and SEs (error bar) of the natural logarithm transformed adiponectin levels according to the categories of lifestyle and genetic risk for decreased adiponectin levels. The P-values are the results of an ANCOVA comparing the adiponectin levels among the genetic risk groups. Data for exercise were adjusted for age, sex, and diet score, while data for diet were adjusted for age, sex, and exercise frequency. As we reported an interaction between diet score and wGPSall and an interaction for exercise with wGPSno CDH13, we used (A) wGPSall to identify genetic risk categories in the diet subgroups and (B) used wGPSno CDH13 to identify genetic risk categories in the exercise subgroups. Genetic risk was divided into low genetic risk (wGPSno CDH13 or wGPSall > mean + 1SD), intermediate genetic risk (wGPSno CDH13 or wGPSall ≥ mean - 1SD but ≤ mean + 1SD) and high genetic risk (wGPSno CDH13 or wGPSall < mean - 1SD). Similarly, diet and exercise were divided into high (diet score> mean + 1SD; exercise frequency ≤ 2 times per week), intermediate (diet score ≥ mean - 1SD but ≤ mean + 1SD; exercise frequency = 3-4 times per week), and low (diet score < mean – 1SD; exercise frequency ≥ 5 times/week). N.S. means the difference is not significant.
Figure 6
Figure 6
Hypothesis for the changes in adipocyte metabolism during puberty. The figure shows our hypothesis, which is that the modification effect of puberty on the SNP-adiponectin association is based on the development of adipose tissue during puberty. The SNPs shown in this figure are SNP1: ADIPOQ-rs10937273; SNP2: ADIPOQ-rs6773957; SNP3: CDH13-rs4783244; SNP4: WDR11-FGFR2-rs3943077; and SNP5: PEPD-rs889140. The puberty categories that we used in the current study were as follows: prepuberty (Tanner stage I), midpuberty (Tanner stage II-III), and postpuberty (Tanner stage ≥ IV). Prepuberty is a period during which the processes of puberty have not yet been activated completely. Midpuberty is the phase during which puberty has been activated but is not finished. Postpuberty is the stage at which the processes of puberty are nearly completed, and adolescents at postpuberty are similar to adults. The development of adipose tissue includes hyperplasia, related to WDR11-FGFR2-rs3943077, and the hypertrophy of adipocytes. The number of adipocytes increases quickly at midpuberty but remains relatively consistent after postpuberty. The size of adipocytes increases during puberty, which makes them secrete lower amounts of adiponectin. The process of hypertrophy is suppressed by the function of collagen, which might be related to PEPD-rs889140. ADIPOQ-rs10937273 and ADIPOQ-rs6773957 are SNPs located at different regulation sites of the adiponectin gene. They are activated at different puberty stages. Adiponectin is bound by T-cadherin encoded by CDH13, which is a high-molecular-weight adiponectin receptor expressed on target cells. Sex steroids decrease adiponectin levels by taking part in the regulation of both the distribution and differentiation of adipocytes.

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Source: PubMed

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