Rodríguez-Vázquez Elvira, Aranda-Torrecillas Álvaro, López-Sancho María, Jiménez-Puyer Manuel, Daza-Dueñas Silvia, Barroso Alexia, Sobrino Verónica, Gaytan Francisco, Obis Elia, Castellano Juan M, Tena-Sempere Manuel
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
Am J Physiol Endocrinol Metab. 2025 May 1;328(5):E675-E694. doi: 10.1152/ajpendo.00493.2024. Epub 2025 Apr 2.
Childhood obesity, especially in girls, often correlates with advanced puberty and long-term comorbidities. Among the central circuits controlling energy homeostasis, hypothalamic lipid sensing pathways, involving free fatty-acid receptors (FFARs), peroxisome proliferator-activated receptors (PPARs), and the bile-acid (BA) receptor, Takeda G protein-coupled receptor 5 (TGR5), have been recognized as major players, with putative pathogenic roles in obesity and its complications. However, their contribution to pubertal regulation and obesity-induced pubertal alterations remains largely unexplored. We describe herein changes in the hypothalamic profiles of specific lipid species, including certain fatty-acyls, BA derivatives, and several glycerolphospholipids, during the juvenile-pubertal transition and conditions of overweight linked to precocious puberty in female rats. Hypothalamic expression of the FFAR, , as well as and gradually increased during the infantile-prepubertal transition, whereas early overfeeding increased hypothalamic mRNA levels of the FFARs, , and . Expression of , , and was documented in FACS-isolated Kiss1 neurons from juvenile and pubertal female mice. Central pharmacological gain- and loss-of-function manipulations of GPR84-, PPAR-, or TGR5-signaling in prepubertal lean and early overfed female rats resulted in specific changes in pubertal timing. In lean rats, central blockade of PPAR-γ/α delayed puberty onset, whereas in early overfed rats, central stimulation of TGR5 signaling partially prevented obesity-induced advanced puberty; effects that were also marginally observed after GPR84 inhibition. Our results disclose the role of brain lipid-sensing pathways in the control of puberty, with a variable contribution of central FFAR-, PPAR-, and TGR5-signaling depending on the maturational and nutritional status. Puberty is highly sensitive to body energy status, and child obesity is often linked to perturbed puberty. However, whether this comes from excessive energy stores or specific nutrient signals altered in obesity remains largely unexplored. Using suitable preclinical models of early obesity and accelerated puberty, we disclose herein conclusive evidence for altered hypothalamic lipid profiles and the roles of specific lipid-sensing pathways in pubertal control, with a variable contribution depending on the maturational and nutritional status.
儿童肥胖，尤其是女孩的肥胖，通常与青春期提前和长期合并症相关。在控制能量稳态的中枢回路中，下丘脑脂质感应途径，包括游离脂肪酸受体（FFARs）、过氧化物酶体增殖物激活受体（PPARs）和胆汁酸（BA）受体——武田G蛋白偶联受体5（TGR5），已被认为是主要参与者，在肥胖及其并发症中具有潜在的致病作用。然而，它们对青春期调节和肥胖诱导的青春期改变的贡献在很大程度上仍未得到探索。我们在此描述了雌性大鼠在幼年到青春期过渡期间以及与性早熟相关的超重情况下，下丘脑特定脂质种类的变化，包括某些脂肪酰基、BA衍生物和几种甘油磷脂。FFAR、以及在婴儿期到青春期前过渡期间下丘脑的表达逐渐增加，而早期过度喂养会增加下丘脑FFARs、和的mRNA水平。在幼年和青春期雌性小鼠经荧光激活细胞分选分离出的Kiss1神经元中记录到了、和的表达。对青春期前瘦型和早期过度喂养的雌性大鼠进行GPR84、PPAR或TGR5信号通路的中枢药理学功能增强和功能丧失操作，导致青春期时间出现特定变化。在瘦型大鼠中，中枢阻断PPAR-γ/α会延迟青春期开始，而在早期过度喂养的大鼠中，中枢刺激TGR5信号通路可部分预防肥胖诱导的青春期提前；在抑制GPR84后也略微观察到了类似效果。我们的结果揭示了脑脂质感应途径在青春期控制中的作用，中枢FFAR、PPAR和TGR5信号通路的贡献因成熟和营养状态而异。青春期对身体能量状态高度敏感，儿童肥胖常与青春期紊乱有关。然而，这是源于能量储存过多还是肥胖中改变的特定营养信号，在很大程度上仍未得到探索。通过使用合适的早期肥胖和青春期加速的临床前模型，我们在此揭示了下丘脑脂质谱改变以及特定脂质感应途径在青春期控制中的作用的确凿证据，其贡献因成熟和营养状态而异。
