Adipokines: A gear shift in puberty

3.1. Fat storage

For the initiation of puberty, the timing of stimulation and/or inhibition of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menarche, which emphasizes the importance of body fat. From an evolutionary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy pregnancy, offspring, and maternal survival.40 An improper level of body fat, sex‐hormones, and neuroendocrine alterations can evolve in menstrual dysfunction, for instance, in women with severe obesity or in women with anorexia nervosa.41, 42, 43 Importantly, body fat distribution, particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than amount of total body fat.44, 45, 46 Blood leptin levels are strongly related to gluteofemoral fat depots suggesting that leptin may convey information on body fat distribution to the hypothalamus during puberty.45

3.2. HPG axis

The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the follicles in the ovaries, and it promotes the secretion of estrogen. LH stimulates the production of androgen hormones and induces ovulation (Figure 1).9, 47 The secretion of estrogen has an inhibitory effect on the release of kisspeptin and neurokinin B, and kisspeptin thereby inhibits the GnRH release from the hypothalamus.48 The expression pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28‐day‐cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovulation. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less inhibition of GnRH. As a consequence, the cycle will start again.48 This whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including thelarche and menarche.9, 47

3.3. Adipokines

According to results from studies reported in Table 1, girls with obesity enter puberty earlier compared with girls with normal weight.13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 49, 50, 51 An explanation for the early onset of puberty in these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, higher leptin concentrations inhibit the intake of food and increases energy expenditure.9, 52, 53, 54

Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both the HPA and HPG axes.33 These axes are functionally integrated during adrenarche. In coherence, in children with obesity, the androgen DHEAS was positively associated with leptin levels.55 Nevertheless, another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI levels.55 In addition, the adipokine adiponectin was negatively associated with androgen levels in girls56; however, it was not related to adrenarche in girls with Prader‐Willi syndrome.57 Interestingly, sex differences of adiponectin seem to develop during the progression of puberty.56 Thus, leptin and adiponectin might be able to influence adrenarche; however, both are not required factors.

In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ovaries (Figure 2).58 In return, estrogen stimulates the expression of the Ob gene in WAT, resulting in the synthesis and secretion of leptin.59 Thus, high levels of leptin promote onset of puberty in girls via secretion of kisspeptin, and estrogen stimulates leptin secretion additionally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary gland, and gonads.2, 60 In detail, adiponectin is a regulator of puberty onset as it inhibits the secretion of kisspeptin and GnRH in the hypothalamus and the release of GH and LH in the pituitary gland, and thereby inhibiting the onset of puberty (Figure 2).2, 60, 61, 62 Individuals with obesity often have low levels of adiponectin.52, 60 Sitticharoon et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in girls with central precocious puberty (CPP).63 Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had positive associations with LH levels and the progression of puberty in girls.63 These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin concentrations in girls.63 In addition, individuals with obesity often develop a chronic low‐grade inflammatory state, which can be indicated by a high level of circulating inflammatory cytokines like TNF‐α and IL‐6.64 TNF‐α alters, and IL‐6 inhibits the expression of adiponectin (Figure 2).8 Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obesity can promote the onset of puberty.

Many more adipokines are secreted by WAT including omentin, visfatin, resistin, and chemerin.52, 65, 66, 67 In women, omentin, chemerin, and visfatin are expressed in the ovaries.65, 66, 67 The expression of these adipokines in the ovaries suggests a role within the reproductive system; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines produced by WAT could be permissive key players during an early onset of puberty in girls with obesity.9, 36, 62, 68 As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral reproductive function as HMW is not able to cross the blood brain barrier.63

4.1. Fat storage

Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of fat.72 Subsequently, a growth spurt follows in which they gain tissue mostly consisting of lean mass, which causes exhaustion of most of their body fat.72 These alterations in amount of body fat indicate that in boys, an adequate amount of body fat is important in the onset of puberty.73

4.2. HPG axis

Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH from the pituitary gland (Figure 1).9, 74 FSH induces spermatogenesis, and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and subsequently GnRH from the hypothalamus.9, 48 Contrarily to women, in men, the release of kisspeptin is more consistent, causing a constant release of LH.29, 48 LH‐induced testosterone levels lead to the development of secondary sex characteristics in boys.9 In more detail, differences between sexes in kisspeptin release are related to a sex‐specific and sex steroid‐dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex‐steroid receptors expressed on KNDy neurons.48 In humans, KNDy neurons in the infundibular nucleus are involved in negative and positive sex‐steroid feedbacks.48 These sexual dimorphisms are induced by perinatal exposure to sex steroids and result in sex‐specific differences in kisspeptin release.75, 76

4.3. Adipokines

The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased BMI,14, 17, 22, 23, 50, 51, 77, 78 while others reported no associations at all20, 49 or a delayed onset of puberty79 (Table 1).16, 80 The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively associated with plasma leptin levels.55 Nevertheless, enhanced adrenal androgen secretion in boys with premature adrenarche was not related with leptin levels.55 Thereby, leptin plausibly has a minor impact in adrenarche in boys.

Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obesity.61, 62 Moreover, inflammatory cytokines, TNF‐α, and IL‐6, inhibit adiponectin, and individuals with obesity often have high levels of circulating inflammatory cytokines.64 High leptin and low adiponectin levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of testosterone from the testes,58 and fat tissue can convert testosterone to estrogen (Figure 3).2, 60, 61, 62 Both processes might result in the delay of the development of secondary sex characteristics in boys.29, 61, 79 Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and expression of the leptin receptor in the testis.81, 82

In men, other adipokines like chemerin are found in the gonads too.65 Thereby, resistin is expressed in the testes of rats, but its exact function and role still have to be examined.83 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional support of spermatogenesis.