Central lipid sensing pathways contribute to the control of puberty and its alterations in conditions of obesity.

Abstract

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 (PPAR) and the bile-acid (BA) receptor, 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 glycerol(phospho)lipids, during the juvenile-pubertal transition and conditions of overweight linked to precocious puberty in female rats. Hypothalamic expression of the FFAR, Gpr84, as well as Ppar-γ and Tgr5 gradually increased during infantile-prepubertal transition, while early-overfeeding increased hypothalamic mRNA levels of the FFARs, Gpr43 and Gpr84. Expression of Gpr84, Ppar-α and Tgr5 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, while in early-overfed rats, central stimulation of TGR5 signaling partially prevented obesity-induced advanced puberty; effects marginally observed also 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.