Fig. 5: Effects on the central nervous system.
From: GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice
a–f, DIO mice were treated with a single subcutaneous injection of vehicle or 50 nmol kg−1 GLP-1–GIP, GLP-1–GIP–Lani or Lani. n = 3–4 per group. a,b, Representative image of FOS in brainstem (a) and hypothalamus (b). Scale bars, 100 μm. c–f, Number of FOS-positive neurons in arcuate nucleus (ARC) (c), dorsomedial hypothalamus (DMH) (d), area postrema (AP) (e) and nucleus tractus solitarius (NTS) (f). g, In vitro assessment of blood-brain barrier (BBB) permeability in CD34+ endothelial cells derived from haematopoietic stem cells co-cultured with brain pericytes. n = 3 biological replicates per group. h–m, DIO mice were treated with a single subcutaneous injection of vehicle or 100 nmol kg−1 GLP-1–GIP or GLP-1–GIP–Lani, and brainstem (h–j) and hypothalamus (k–m) were collected 7 h post-injection. n = 9–10 per group. h,l, Venn diagram showing the number of differentially regulated proteins in the brainstem (h) and hypothalamus (l). i,m, PCA of the proteome in brainstem (i) and hypothalamus (m). j,k, Supervised hierarchical clustering of z-scored intensities of significantly changed proteins in the brainstem (j) and hypothalamus (k). n,o, Fibre-photometric assessment of POMC activity in Pomc-cre mice treated with a single subcutaneous injection of vehicle or 10 nmol kg−1 GLP-1–GIP or GLP-1–GIP–Lani. n = 6 per group. n, POMC neuronal activity over time. o, Corresponding area under curve. p, Electrophysiological recording of POMC neuronal activity in Pomc-GFP mice stimulated with 2 nM GLP-1–GIP or GLP-1–GIP–Lani. n = 6 mice per group. Data were analysed using one-way ANOVA with uncorrected Fisher’s least significant difference test (c–f), one-way ANOVA with Bonferroni’s multiple comparisons test (g,o), two-way repeated-measures ANOVA (n), one-way ANOVA (false discovery rate (FDR) < 0.05) with Tukey’s honest significant difference post hoc test (h,l) or one-way ANOVA with FDR < 0.05 and unsupervised hierarchical clustering of z-scored log2 label-free quantification intensities (j,k). Data are mean ± s.e.m. Exact P values, n values and detailed statistics are provided in Supplementary Tables 1 and 3 and Source Data.
