Background
Childhood obesity prevalence has increased at an alarming rate globally, and the International Association for the Study of Obesity estimates that up to 200 million school-aged children are either overweight or obese [
1,
2]. This is important because children and adolescents with obesity are at higher risk of obesity during adulthood [
3,
4], which is often linked to serious conditions including cardiovascular disease, type 2 diabetes, metabolic syndrome, and several types of cancer [
3‐
8].
It is well-known that adult individuals with obesity show lower plasma sex hormone-binding globulin (SHBG) levels than normal-weight subjects [
9,
10]. SHBG is a protein produced and secreted into the circulation by the liver that binds androgens and estrogens with high affinity. In blood, SHBG acts as a carrier of these sex steroids and regulates their bioavailability and access to target tissues and cells [
11]. Interestingly, we have previously described that low-grade inflammation occurring in obesity is an important regulator of plasma SHBG levels [
12]. Obesity is associated with higher tumor necrosis factor alpha (TNFα) plasma levels and lower adiponectin levels in adults [
13,
14]. Moreover, we have recently elucidated the molecular mechanisms by which TNFα and adiponectin regulate hepatic SHBG production [
15‐
17]. Low plasma SHBG levels have been also found in children with obesity; however, the reasons for such reduction need to be yet determined.
In the present work, we aimed to study whether these regulatory mechanisms were already present in prepubertal children. For this purpose, we determined several morphometric and biochemical parameters in normal-weight and prepubertal children with obesity, as well as quantified plasma SHBG, TNFα receptor 1 (TNFα-R1), and adiponectin levels.
Discussion
Childhood obesity has become a major health concern in the last decades and has increased its prevalence worldwide, in both developed and developing countries [
21‐
23]. It has been already described that childhood and adolescent obesity is associated with an increase in BMI and excess of adiposity [
5,
24] which was also evident in our study since prepubertal children with obesity showed higher BMI-SDS and waist circumference when compared with lean children. This adiposity increase occurring in obesity is also associated with insulin resistance, hypertension, and dyslipidemia, which in turn increase risk of developing atherosclerotic vascular disease and type 2 diabetes [
5,
24]. Our results corroborated the latter since obese prepubertal children had higher insulin plasma levels together with an increase in HOMA-IR and higher LDL and TAG plasma levels when compared with lean prepubertal children.
An excess of adiposity may also influence various aspects of pubertal development, such as timing of pubertal initiation and hormonal parameters during puberty. How obesity may perturb several hormonal aspects of puberty is currently under debate; however, it may involve sex hormone-binding globulin (SHBG), a liver-produced glycoprotein that binds sex steroids with high affinity in blood regulating their bioavailability [
11]. Interestingly, SHBG plasma levels change through human life-span, remaining high during infancy and decreasing when puberty approaches [
25]. It is important to mention that low plasma SHBG levels are found in children with obesity; this is in agreement with our results showing that prepubertal children with obesity had half the plasma SHBG levels present in normal-weight prepubertal children.
Low plasma SHBG levels are also present in adult subjects with obesity [
9,
10]. The reason why this may occur has been investigated during the last three decades; initially, it was suggested that hyperinsulinemia was the main factor reducing plasma SHBG levels [
26,
27]. In fact, a negative correlation between plasma SHBG and insulin levels has been previously described [
28,
29], which we also found in our study. However, insulin as a major factor downregulating SHBG production does not come along with the fact that obese subjects are characterized by insulin resistance [
30,
31], and, to the best of our knowledge, the molecular mechanism by which insulin reduces SHBG production has not yet been described. In this regard, we have demonstrated that insulin does not regulate hepatic SHBG production [
15,
32]. Nevertheless, we found strong correlations between SHBG and insulin plasma levels when analyzing our study population or children with obesity alone. Furthermore, SHBG was strongly associated with both insulin sensitivity (HOMA-IR and WBISI) and insulin secretory (IGI) indexes in children with obesity.
Accumulated evidence over the last decade points to inflammation as one of the critical processes associated with the development of obesity, insulin resistance, and type 2 diabetes [
33,
34]. In fact, obesity is considered a state of chronic low-grade inflammation [
35,
36]. This is of importance since we have reported that alterations in proinflammatory and anti-inflammatory cytokines occurring in obesity [
37,
38] play an important role in regulating hepatic SHBG production [
12,
15‐
17,
39]. Specifically, using in vitro and in vivo models as well as human samples, we have shown that hepatic SHBG production was reduced by TNFα and increased by adiponectin [
15‐
17]. Mechanistically, we have determined that TNFα decreases SHBG production by reducing the protein levels of hepatocyte nuclear receptor 4 alpha (HNF-4α), the main activator of
SHBG gene expression [
15,
16]. On the other hand, adiponectin increases SHBG production via HNF-4α levels by inhibiting hepatic lipogenesis and stimulating hepatic β-oxidation [
17]. Interestingly, we showed that plasma TNFα-R1 levels correlated inversely with plasma SHBG levels in adult obese subjects [
15]. Remarkably, prepubertal children with obesity from our study had higher TNFα-R1 plasma levels than lean children, as described previously [
40]. Importantly, SHBG plasma levels correlated significantly and negatively with TNFα-R1 plasma levels. However, this correlation was lost after adjusting for BMI-SDS. This is of importance since TNFα levels could be an important factor downregulating SHBG production during early stages of obesity development, but once children reach a certain point of inflammation, TNFα plasma levels may not influence SHBG production.
Plasma adiponectin levels are lower in subjects with obesity, both adult [
41] and children, compared to normal-weight controls [
42]. These findings were corroborated in our study, since prepubertal children with obesity had lower levels of adiponectin when compared with lean subjects. In addition, it has been previously reported that adiponectin levels were inversely associated with SHBG [
43,
44], and this correlation was also found in our prepubertal population. Moreover, this correlation between SHBG and adiponectin was maintained after adjusting for BMI-SDS. More importantly, this SHBG correlation with adiponectin was also found when analyzing only subjects with obesity.
In conclusion, the results obtained in this study show that prepubertal children with obesity had decreased plasma SHBG levels compared to normal-weight controls. Importantly, SHBG plasma levels correlated significantly with TNFα (negatively) and adiponectin (positively), suggesting that adiponectin and TNFα could play a role in determining plasma SHBG levels in prepubertal children. In addition, our results suggest that plasma adiponectin levels may play a more important role than TNFα in influencing plasma SHBG levels in our prepubertal population with obesity.
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