ESPE Yearbook of Paediatric Endocrinology

Am J Physiol Endocrinol Metab. 2025 May 1;328(5):E675-E694. doi: 10.1152/ajpendo.00493.2024. PMID: 40172224.

Brief summary: This study highlights the involvement of brain lipid sensing pathways in the central regulation of puberty, depending on pubertal maturation stages and nutritional conditions.

Hypothalamic lipid-sensing pathways are central regulators of energy homeostasis. 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 roles in obesity and its complications. However, their contribution to pubertal regulation and obesity-induced pubertal alterations remains largely unexplored(1,2), and the specific role of brain lipid-sensing pathways in the metabolic control of puberty remains poorly characterized.

The authors identified 299 lipid species differentially expressed in the mediobasal hypothalamus of female rats, depending on pubertal maturation or nutritional status (lean vs. early overfed). These lipid species were categorized into fatty acyls, glycerolipids, sterol lipids, and glycerophospholipids. Hypothalamic mRNA expression of various lipid-sensing receptors changed progressively during pubertal maturation: Ffar2, Ffar3, and Lpl expression decreased, while Pparg expression increased with pubertal maturation. Obesity was associated with increased mRNA expression of Ffar2 and Gpr84, and decreased expression of Lpl at the time of pubertal onset.

Using fluorescence-activated cell sorting (FACS), expression of Gpr84, Ppara, Lpl, and Cd36 was detected in Kiss1 neurons from both the arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV) of the hypothalamus. Notably, Tgr5 expression was restricted to Kiss1 neurons in the ARC. Under conditions of obesity, Gpr84 and Lpl mRNA levels were increased in ARC Kiss1 neurons at PND 32 (peripubertal), while in the AVPV, obesity had a more limited effect, illustrated by suppression of Lpl mRNA levels at PND 25 only (prepubertal).

Central blockade of Gpr84 during pubertal transition did not affect pubertal onset in either lean or obese females. In contrast, central blockade of Pparg/a delayed pubertal timing in lean females but not in obese ones. Furthermore, central activation of Tgr5 prevented the advancement of puberty in obese female rats.

This study highlights a novel role for brain lipid-sensing pathways in the regulation of puberty by nutritional status. The findings reveal differential involvement of central FFAR, PPAR, and TGR5 signalling depending on maturational stage and the presence of early-onset obesity.

Reference: 1. Heras V, Castellano JM, Fernandois D, Velasco I, Rodríguez-Vazquez E, Roa J, Vazquez MJ, Ruiz-Pino F, Rubio M, Pineda R, Torres E, Avendaño MS, Paredes A, Pinilla L, Belsham D, Diéguez C, Gaytán F, Casals N, López M, Tena-Sempere M. Central Ceramide Signaling Mediates Obesity-Induced Precocious Puberty. Cell Metab. 2020 Dec 1;32(6):951-966.e8.2. Vanden Brink H, Vandeputte D, Brito IL, Ronnekleiv OK, Roberson MS, Lomniczi A. Changes in the Bile Acid Pool and Timing of Female Puberty: Potential Novel Role of Hypothalamic TGR5. Endocrinology. 2024 Jul 26;165(9):bqae098.