Int. J. Mol. Sci. 2026, 27(18), 8159; https://doi.org/10.3390/ijms27188159 (registering DOI) - 13 Sep 2026
Abstract
Childhood obesity is consistently associated with earlier pubertal timing, particularly in girls, whereas its relationship with true central precocious puberty (CPP), defined by premature activation of the hypothalamic–pituitary–gonadal (HPG) axis, is less clearly established. An increased frequency of CPP diagnoses and referrals was
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Childhood obesity is consistently associated with earlier pubertal timing, particularly in girls, whereas its relationship with true central precocious puberty (CPP), defined by premature activation of the hypothalamic–pituitary–gonadal (HPG) axis, is less clearly established. An increased frequency of CPP diagnoses and referrals was reported during the COVID-19 pandemic, alongside changes in body weight, lifestyle, sleep, and psychosocial exposures. Human studies link excess adiposity to hyperleptinemia, insulin resistance, reduced adiponectin, altered sex-steroid bioavailability, and systemic low-grade inflammation, and associate these features with earlier pubertal development—consistently in girls, less so in boys. However, such associations do not establish that obesity directly induces premature hypothalamic activation. Mechanistic understanding of how these peripheral signals may influence pubertal timing derives predominantly from experimental models. The arcuate nucleus kisspeptin/neurokinin B/dynorphin (KNDy) network, a key component of the gonadotropin-releasing hormone (GnRH) pulse generator, interacts with hypothalamic metabolic circuits. In animal models of obesity and overnutrition, altered leptin and insulin signaling, mitochondrial reactive oxygen species generation, and activation of microglia and astrocytes remodel the mediobasal hypothalamus through inflammatory and stress-responsive pathways, including IKKβ/NF-κB and JNK signaling and altered Nrf2-mediated antioxidant defenses. At the molecular level, metabolic status interacts with the epigenetic machinery governing Kiss1 expression: in rodent models of overnutrition, accelerated loss of SIRT1-mediated repression at the Kiss1 promoter facilitates pubertal activation. Human genetic evidence establishes MKRN3 and DLK1 as causes of familial CPP, but evidence that obesity modifies these pathways to induce sporadic CPP is insufficient. Similarly, gut microbial metabolites have been linked experimentally to pubertal timing, and antioxidant micronutrients such as selenium, zinc, and vitamins C and E may be altered in pediatric obesity, yet a specific role in CPP remains unproven. Collectively, current evidence supports a working model in which metabolic, inflammatory, redox, glial, and epigenetic pathways may converge on hypothalamic reproductive circuits to influence pubertal timing in susceptible children. Direct evidence in children with CPP—of hypothalamic oxidative stress, glial activation, Nrf2 dysfunction, SIRT1 remodeling, or microbiome-mediated activation—remains limited or absent. Lifestyle optimization is appropriate for improving metabolic health in children with obesity, whereas antioxidant, micronutrient, and microbiome-targeted interventions should be considered investigational with respect to CPP. Longitudinal pediatric studies that distinguish earlier pubertal timing from true CPP, and that integrate metabolic phenotyping with validated measures of HPG-axis activation, are needed to test this framework.
Full article
(This article belongs to the Special Issue Latest Advances in Pituitary Endocrinology)
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