Induction of Gnrh mRNA expression by the ω-3 polyunsaturated fatty acid docosahexaenoic acid and the saturated fatty acid palmitate in a GnRH-synthesizing neuronal cell model, mHypoA-GnRH/GFP

• Docosahexanoic acid (DHA) increases Gnrh transcription in mHypoA-GnRH/GFP neurons.
• The effect of DHA depends on GPR120, PKC/MAPK, and PI3K signaling.
• Palmitate increases Gnrh transcription in mHypoA-GnRH/GFP neurons.
• The effect of palmitate depends on PI3K signaling and palmitoyl-coA synthesis.
• DHA and palmitate increase Gnrh enhancer-derived RNA (eRNA) levels.

Gonadotropin-releasing hormone (GnRH) neurons coordinate reproduction. However, whether GnRH neurons directly sense free fatty acids (FFAs) is unknown. We investigated the individual effects of the FFAs docosahexaenoic acid (DHA), palmitate, palmitoleate, and oleate (100 μM each) on Gnrh mRNA expression in the mHypoA-GnRH/GFP neuronal cell model. We report that 2 h exposure to palmitate or DHA increases Gnrh transcription. Using the inhibitors AH7614, K252c, U0126, wortmannin, and LY294002, we demonstrate that the effect of DHA is mediated through GPR120 to downstream PKC/MAPK and PI3K signaling. Our results indicate that the effect of palmitate may depend on palmitoyl-coA synthesis and PI3K signaling. Finally, we demonstrate that both DHA and palmitate increase Gnrh enhancer-derived RNA levels. Overall, these studies provide evidence that GnRH neurons directly sense FFAs. This will advance our understanding of the mechanisms underlying FFA sensing in the brain and provides insight into the links between nutrition and reproductive function.