Obesity is associated with copper elevation in serum and tissues

Abstract

Copper misbalance has been linked to fat accumulation in animals and experimental systems; however, information about copper homeostasis in human obesity is limited. In this study, the copper status of obese individuals was evaluated by measuring their levels of copper and cuproproteins in serum, adipose and hepatic tissues. The analysis of serum trace elements showed significant positive and element-specific correlation between copper and BMI after controlling for gender, age, and ethnicity. Serum copper also positively correlated with leptin, insulin, and the leptin/BMI ratio. When compared to lean controls, obese patients had elevated circulating cuproproteins, such as semucarbazide-sensitive amine oxidase (SSAO) and ceruloplasmin, and higher SSAO activity and copper levels in visceral fat. Although hepatic steatosis reduces copper levels in the liver, obese patients with no or mild steatosis have higher copper content in the liver compared to lean controls. In conclusion, obese patients evaluated in this study had altered copper status. Strong positive correlations of copper levels with BMI and leptin suggest that copper and/or cuproproteins may be functionally linked to fat accumulation.

Fig. 1

Cu levels in serum are higher in obese patients and positively correlate with BMI. (A) Serum Cu levels in female and male obese patients and lean controls (Ctrl). (B) Serum Cu concentration plotted against BMI values for both obese and lean patients. (C) Serum Cu levels are plotted against BMI values only for obese individuals. (Pearson’s r and p values were calculated by using a linear regression analysis. Student’s t-test, ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05, ns p > 0.05. The data are presented as mean ± SEM.)

Fig. 2

Correlations between serum Cu content and serum metabolic parameters. The serum concentrations of (A) leptin, (B) insulin, and (C) leptin/BMI levels in a group combining all obese and lean subjects are plotted against their Cu levels. (D) Leptin levels in either obese patients or lean controls (Ctrl) are plotted against their Cu levels. (Pearson’s r and p values were calculated by using a linear regression analysis.)

Fig. 3

Serum ceruloplasmin and SSAO are elevated in obese subjects. A representative Western blot of equal volumes of serum from obese patients (n = 4) and lean controls (n = 4). The copper values and other characteristics of these samples are summarized in Table 3. The Cu-containing enzymes ceruloplasmin and SSAO are elevated in obese individuals, whereas iron-carrying transferrin (Tf) is not elevated.

Fig. 4

SSAO activity and Cu levels in visceral fat. (A) The activity of SSAO in the visceral fat of obese patients is significantly higher than in lean controls. (B) The activity of SSAO is plotted against BMI values. (C) Cu levels measured per tissue weight are lower in obese subjects. (D) Cu levels normalized per protein content of visceral fat are higher in obese patients compared to lean controls. (E) Cu levels normalized to protein are plotted against BMI. (F) SSAO activity is plotted against the visceral fat Cu normalized to protein. (B, E, F, Pearson’s r and p values were calculated by using a linear regression analysis. Student’s t-test, ****p < 0.0001, ***p < 0.001, **p<0.01, *p<0.05, ns p>0.05. The data are presented as mean ± SEM.)

Fig. 5

Relative mRNA levels of CTR1 and ATP7A in visceral fat. Relative mRNA levels of CTR1 (A) and ATP7A (B) in the visceral fat of obese patients are higher than in lean controls. (C) Relative CTR1 mRNA levels positively correlate with BMI. (C, Pearson’s r and p values were calculated by using a linear regression analysis. Student’s t-test, ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05, ns p > 0.05. The data are presented as mean ± SEM.)

Fig. 6

Hepatic Cu is higher in obese patients and positively correlates with Cu in adipose tissue. (A) Hepatic Cu levels grouped based on the degree of liver abnormalities: (1) no steatosis and no fibrosis, (2) mild steatosis and no fibrosis, (2.5) mild steatosis and mild fibrosis, (3) moderate steatosis and no fibrosis, (3.5) moderate steatosis and fibrosis, and (4.5) mild steatohepatitis with fibrosis. (B) Cu levels in the liver of lean controls and obese patients. (C) Hepatic Cu levels are plotted against serum Cu levels (p > 0.05). (D) Cu concentration in adipose tissue (fat) is plotted against serum Cu concentration (p > 0.05). (E) Adipose Cu levels (per protein) are plotted against liver Cu levels (per protein). (A and C–E, Pearson’s r and p values were calculated by using a linear regression analysis. Student’s t-test, **p < 0.01, *p < 0.05. The data are presented as mean ± SEM.)