Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

Abstract

Puberty is driven by sophisticated neuroendocrine networks that timely activate the brain centers governing the reproductive axis. The timing of puberty is genetically determined; yet, puberty is also sensitive to numerous internal and external cues, among which metabolic/nutritional signals are especially prominent. Compelling epidemiological evidence suggests that alterations of the age of puberty are becoming more frequent; the underlying mechanisms remain largely unknown, but the escalating prevalence of obesity and other metabolic/feeding disorders is possibly a major contributing factor. This phenomenon may have clinical implications, since alterations in pubertal timing have been associated to adverse health outcomes, including higher risk of earlier all-cause mortality. This urges for a better understanding of the neurohormonal basis of normal puberty and its deviations. Compelling evidence has recently documented the master role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine pathways controlling puberty. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. Key cellular metabolic sensors, as the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and the fuel-sensing deacetylase, SIRT1, have been recently shown to participate also in the metabolic modulation of puberty. Recently, we have documented that AMPK and SIRT1 operate as major molecular effectors for the metabolic control of Kiss1 neurons and, thereby, puberty onset. Alterations of these molecular pathways may contribute to the perturbation of pubertal timing linked to conditions of metabolic stress in humans, such as subnutrition or obesity and might become druggable targets for better management of pubertal disorders.

The adverse maternal and perinatal outcomes of adolescent pregnancy: a cross sectional study in Hebei, China

“…The endocrine-regulating system of adolescent women is not in perfect condition [34], with higher risks of obesity or GDM, but we found a lower risk of GDM in older adolescents (18-19 years) and younger adults (20-24 years) compared with women aged 25-34 years. This result was basically consistent with another study on the delivery population in Beijing, China, with aRR (95%CI) was 0.55 (0.39-0.77) [28].…”

Neuropeptide Control of Puberty: Beyond Kisspeptins

“…82 The latter is possibly at the basis of the trends for earlier onset of puberty that has been reported worldwide, especially in girls, but eventually also in boys, in parallel with the escalation of the child obesity epidemics. 2,79,83,84 Both extreme situations illustrate the tight bonding between the mechanisms controlling puberty onset and body energy homeostasis, in which the neuropeptide pathways summarized in previous sections seemingly play a relevant role.…”

“…One of the major modifiers of pubertal timing is the state of body energy reserves, so that extreme changes in body weight during early stages of maturation are associated with detectable alterations in the age of puberty in humans and laboratory animals. 2,79 Thus, situations of persistent energy deficit, such as those seen in chronic malnutrition, anorexia, or even in individuals undergoing strenuous physical exercise, are bound to delayed puberty, whereas conditions of excess of body energy reserves, as seen in early-onset obesity, are commonly linked to advanced puberty onset. 80,81 The former is the reflection of the need to attain a threshold of body energy stores (mainly, as fat depots) to reach pubertal maturation, as initially defined by the so-called critical-fat-mass hypothesis.…”

“…Concerning hormonal regulation, the adipose hormone, leptin, is by far the best characterized. While an exhaustive recapitulation of the roles of leptin in the control of puberty clearly exceeds the scope of this review, and can be found elsewhere, 2,79 it is important to stress that in the last decades leptin has been recognized as an essential gatekeeper of puberty, with a major permissive role that enables puberty to proceed only when conditions of sufficient energy reserves are achieved. This function is conveyed, mainly, through hypothalamic pathways that are, directly or indirectly, sensitive to the regulatory effects of leptin and impinge onto the GnRH neuronal network.…”

Lin28 gene and mammalian puberty

“…Whereas, the GnRH pulsatile secretion is dependent on the coordinated action of the scattered GnRH neurons, controlled by stimulatory and inhibitory inputs, such as neurokinin B, kisspeptins, and gamma‐aminobutyric acid (Plant, 2015). The onset of puberty is also gated by body energy reserves and nutritional cues (Vazquez, Velasco, & Tena‐Sempere, 2019), and in which, the adipose hormone leptin is an essential signal to the hypothalamic GnRH pulse generator that there are sufficient energy stores in the adipose tissue for fertility to commence, which is necessary for the initiation of puberty (Ahmed, Ong, & Dunger, 2009; Biro, Khoury, & Morrison, 2006; Egan, Inglis, & Anderson, 2017). Leptin stimulates GnRH secretion by binding to the leptin receptor to activates several signaling pathways, including the 5′ adenosine monophosphate‐activated protein kinase (Roa et al, 2018; Xie et al, 2018), mammalian target of rapamycin (mTOR; Roa & Tena‐Sempere, 2010; Roa et al, 2009), phosphoinositide 3‐kinase (PI3K; Garcia‐Galiano, Borges, Allen, & Elias, 2019; Garcia‐Galiano et al, 2017; Nelson et al, 2017; Nguyen, Zacchi, Schulz, Moore, & Fortes, 2018).…”