Hypothalamic insensitivity to leptin, an adipocyte-derived anorexigenic hormone, has been viewed as a major determinant of adiposity in hyper-alimented rodents and humans. Although it has been suggested that dietary lipids affect leptin sensitivity, comparison of the effect of each fatty acid at cellular level has not been fully addressed. Here we explored the effect of major dietary fatty acids on leptin responsiveness in vitro and further examined the effect using hypothalamic slice cultures.


SH-SY5Y cells stably expressing functional leptin receptor or organotypic hypothalamic slice culture obtained from murine pups were pretreated with each fatty acid solubilized in DMSO followed by stimulation with leptin. Leptin-induced Stat3 phosphorylation (p-Stat3) was measured by western blot analysis or amplified luminescence proximity homogeneous assay in cells and by immunostaining in slice cultures. In BV-2 microglial cells, gene expression for cytokines was analyzed after pretreatment with fatty acids and LPS stimulation.


In SH-SY5Y cells, all fatty acids tested increased leptin-induced p-Stat3. Among these, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) showed the highest potency with dose dependency. Similarly, EPA and DHA augmented p-Stat3 in slice cultures. While palmitic acid increased p-Stat3 in SH-SY5Y, it attenuated p-Stat3 in slice cultures, suggesting that non-neuronal cells within the hypothalamus be responsible for leptin resistance by palmitic acid. Treatment of BV-2 microglial cells with palmitic acid augmented and EPA and DHA suppressed the expression of inflammatory cytokines.


Our data here show that major fatty acids as a whole enhance leptin sensitivity in a cellular model of leptin responsiveness. EPA and DHA potently and directly act on the neurons to enhance leptin sensitivity, while activation of hypothalamic microglial cells is suggested to be involved in palmitic acid-induced leptin resistance in slice cultures.