Childhood obesity, especially in girls, is frequently bound to earlier puberty, which is linked to higher disease burden later in life. The mechanisms underlying this association remain elusive. Here we show that brain ceramides participate in the control of female puberty and contribute to its alteration in early-onset obesity in rats. Postnatal overweight caused earlier puberty and increased hypothalamic ceramide content, while pharmacological activation of ceramide synthesis mimicked the pubertal advancement caused by obesity, specifically in females. Conversely, central blockade of de novo ceramide synthesis delayed puberty and prevented the effects of the puberty-activating signal, kisspeptin. This phenomenon seemingly involves a circuit encompassing the paraventricular nucleus (PVN) and ovarian sympathetic innervation. Early-onset obesity enhanced PVN expression of SPTLC1, a key enzyme for ceramide synthesis, and advanced the maturation of the ovarian noradrenergic system. In turn, obesity-induced pubertal precocity was reversed by virogenetic suppression of SPTLC1 in the PVN. Our data unveil a pathway, linking kisspeptin, PVN ceramides, and sympathetic ovarian innervation, as key for obesity-induced pubertal precocity.

儿童肥胖，尤其是女孩，往往与青春期过早有关，这与以后生活中更高的疾病负担有关。这种关联背后的机制仍然难以捉摸。在这里，我们表明脑神经酰胺参与女性青春期的控制，并有助于其改变大鼠早发性肥胖。产后超重导致青春期提前和下丘脑神经酰胺含量增加，而神经酰胺合成的药理学激活模拟了肥胖引起的青春期进展，特别是在女性中。相反，中央封锁从头神经酰胺合成延迟了青春期并阻止了青春期激活信号kisspeptin的作用。这种现象似乎涉及一个包含室旁核 (PVN) 和卵巢交感神经支配的回路。早发性肥胖增强了 SPTLC1（神经酰胺合成的关键酶）的 PVN 表达，并促进了卵巢去甲肾上腺素能系统的成熟。反过来，肥胖引起的青春期早熟被 PVN 中 SPTLC1 的病毒抑制逆转。我们的数据揭示了一条连接kisspeptin、PVN神经酰胺和交感卵巢神经支配的通路，这是肥胖引起的青春期早熟的关键。