{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:04:34Z","timestamp":1789391074900,"version":"build-2803163510"},"reference-count":150,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2013pituitary\u2013gonadal (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\u2014consistently 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 IKK\u03b2\/NF-\u03baB 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\u2014of hypothalamic oxidative stress, glial activation, Nrf2 dysfunction, SIRT1 remodeling, or microbiome-mediated activation\u2014remains 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.<\/jats:p>","DOI":"10.3390\/ijms27188159","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Obesity, Oxidative Stress, and Inflammation in Precocious Puberty: Do All Roads Lead to the Hypothalamus?"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-5579","authenticated-orcid":false,"given":"Teofana-Otilia","family":"Bizerea-Moga","sequence":"first","affiliation":[{"name":"Department XI of Pediatrics, First Pediatric University Clinic, Center for Research on Growth and Developmental Disorders in Children, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, Eftimie Murgu Sq No. 2, 300041 Timi\u0219oara, Romania"},{"name":"1st Pediatric Clinic, \u2018Louis \u021aurcanu\u2019 Children\u2019s Clinical and Emergency Hospital, Iosif Nemoianu 2, 300011 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Chi\u0219avu","sequence":"additional","affiliation":[{"name":"Nephrology University Clinic, Centre for Molecular Research in Nephrology and Vascular Disease, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, Eftimie Murgu Sq No. 2, 300041 Timi\u0219oara, Romania"},{"name":"4th Pediatric Clinic, \u2018Louis \u021aurcanu\u2019 Children\u2019s Clinical and Emergency Hospital, Iosif Nemoianu 2, 300011 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-1945","authenticated-orcid":false,"given":"Laz\u0103r","family":"Chi\u0219avu","sequence":"additional","affiliation":[{"name":"Nephrology University Clinic, Centre for Molecular Research in Nephrology and Vascular Disease, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, Eftimie Murgu Sq No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Nephrology Clinic, \u2018Pius Br\u00eenzeu\u2019 County Emergency Clinical Hospital, Liviu Rebreanu 156, 300723 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5991-6203","authenticated-orcid":false,"given":"Laura","family":"Pitulice","sequence":"additional","affiliation":[{"name":"Department of Chemistry, West University of Timi\u015foara, Pestallozi 16, 300115 Timi\u015foara, Romania"},{"name":"Institute of Advanced Environmental Research, Oituz 4c, 300086 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8978-1856","authenticated-orcid":false,"given":"Tudor Voicu","family":"Moga","sequence":"additional","affiliation":[{"name":"Department VII of Internal Medicine, Gastroenterology University Clinic, Advanced Regional Research Center in Gastroenterology and Hepatology, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, Eftimie Murgu Sq No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Gastroenterology and Hepatology Clinic, \u2018Pius Br\u00eenzeu\u2019 County Emergency Clinical Hospital, Liviu Rebreanu 156, 300723 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meda-Ada","family":"Bugi","sequence":"additional","affiliation":[{"name":"1st Pediatric Clinic, \u2018Louis \u021aurcanu\u2019 Children\u2019s Clinical and Emergency Hospital, Iosif Nemoianu 2, 300011 Timi\u0219oara, Romania"},{"name":"Department of Pharmacy, University of Medicine and Pharmacy \u2018Vasile Goldis\u2019, 310025 Arad, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4621-274X","authenticated-orcid":false,"given":"Cornel Flavius","family":"Foghi\u0219","sequence":"additional","affiliation":[{"name":"Department XI of Pediatrics, First Pediatric University Clinic, Center for Research on Growth and Developmental Disorders in Children, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, Eftimie Murgu Sq No. 2, 300041 Timi\u0219oara, Romania"},{"name":"1st Pediatric Clinic, \u2018Louis \u021aurcanu\u2019 Children\u2019s Clinical and Emergency Hospital, Iosif Nemoianu 2, 300011 Timi\u0219oara, Romania"},{"name":"Ph.D. School Department, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, Eftimie Murgu Sq No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1478-9797","authenticated-orcid":false,"given":"Raluca","family":"Isac","sequence":"additional","affiliation":[{"name":"4th Pediatric Clinic, \u2018Louis \u021aurcanu\u2019 Children\u2019s Clinical and Emergency Hospital, Iosif Nemoianu 2, 300011 Timi\u0219oara, Romania"},{"name":"Department XI of Pediatrics, Third Pediatric University Clinic, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, Eftimie Murgu Sq No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2313-7643","authenticated-orcid":false,"given":"Otilia","family":"M\u0103rginean","sequence":"additional","affiliation":[{"name":"Department XI of Pediatrics, First Pediatric University Clinic, Center for Research on Growth and Developmental Disorders in Children, \u2018Victor Babe\u0219\u2019 University of Medicine 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