Fig. 8. Neuronal transduction of peripheral lipid signals to regulate longevity.
a, Schematic design using neuron-expressing GBP to detect the uptake of intestine-secreted LBP-3 into neurons. b, In the transgenic line expressing LBP-3–GFP in the intestine and GBP polycistronic mKate in neurons, GFP signals from secreted LBP-3 are detected in neurons (mKate positive). Scale bars, 30 µm and 10 µm in the inset. c, Constitutive expression of lbp-8 (lbp-8 Tg) does not affect the transcription of egl-3, while the induction of either egl-21 or nlp-11 is negligible (<35%). d, lbp-3 Tg and lbp-8 Tg have an additive effect on lifespan extension. e, The loss-of-function mutation of the nuclear receptor nhr-49(lf) fully suppresses the induction of the neuropeptide genes by lipl-4 Tg, while the loss-of-function of nhr-80(lf) only decreases the induction by less than 17%. f, nhr-49(lf) fully suppresses the induction of the neuropeptide genes by lbp-3 Tg, which is rescued by neuronal restoration of nhr-49. g, nhr-49(lf) fully suppresses the lifespan extension in the lbp-3 Tg worms, which is rescued by neuronal restoration of nhr-49. h, In the transgenic line expressing nlp-11 polycistronic GFP and mKate-fused NHR-49 driven by their endogenous promoters, GFP and mKate signals overlap in many neurons. Scale bar, 10 µm. i, Cartoon illustrating the overall model. In c, error bars represent mean ± s.e.m., n = 4 biologically independent samples, *P = 0.034, **P = 0.002 by two-way ANOVA with Holm–Sidak correction, ~2,000 worms per replicate. In d and g, n = 3 biologically independent samples, ***P < 0.001 by log-rank test, 80–101 worms per replicate. See Supplementary Table 4 for full lifespan data. In e, error bars represent mean ± s.e.m., n = 4 biologically independent samples, ***P = 0.0004 and ****P < 0.0001 by two-way ANOVA with Holm–Sidak correction, ~2,000 worms per replicate. In f, error bars represent mean ± s.e.m., n = 4 biologically independent samples, *P = 0.019, **P = 0.009 and ***P = 0.0006 for WT versus lbp-3 Tg, P = 0.0003 for lbp-3 Tg versus lbp-3Tg;nhr-49(lf) and P = 0.0003 for lbp-3Tg;nhr-49(lf) versus lbp-3Tg;nhr-49(lf);neu-nhr-49, ****P < 0.0001 by two-way ANOVA with Holm–Sidak correction, ~2,000 worms per replicate. Source numerical data are available in source data.