Extended Data Fig. 2: Verification of IR inactivation in tanycytes, HFD-induced insulin resistance in IR^GFP-Tan-mice, and assessment of insulin signalling in VMH and LH of IR^ΔTan-mice.

a. Microphotographs of smFISH assessing Insr expression in lateral (B’, B’) and basal (B’’) tanycytes of IR^GFP-Tan and IR^ΔTan animals. b. Quantification of Insr positive cells in lateral and basal tanycytes. a-b. p(lateral) = 0.0026, p(basal) = 0.0186, n = 5/IR^GFP-Tan, n = 7/IR^ΔTan. c. Body weight of NCD and HFD fed IR^GFP-Tan animals. Animals were fed a HFD starting at 4 weeks of age, at 12 weeks mice received an i.c.v. injection with the AAV-Dio2-GFP virus. d. ITT of NCD and HFD fed IR^GFP-Tan animals (as in Fig. 3c). e. GTT of NCD and HFD fed IR^GFP-Tan animals (as in Fig. 3c). c-e. n = 13/IR^GFP-Tan (NCD), 14/IR^GFP-Tan (HFD). f-i. Representative images and quantification of pAKT immunostaining in ventromedial hypothalamus (g, h) and lateral hypothalamus (I, j) of unstimulated mice and 5, 10, 20 and 30 min post i.v. injection of 0.5 IU/kg insulin in IR^GFP-Tan (top panel) or IR^ΔTan (bottom panel). n(0 min) = 3/IR^GFP-Tan (NCD), 4/IR^ΔTan(NCD); n(5 min) = 4/IR^GFP-Tan (NCD), 5/IR^ΔTan (NCD); n(10 min, 20 min, 30 min) = 5/IR^GFP-Tan (NCD), 6/IR^ΔTan (NCD). For VMH: p(10 min) = 0.0012, p(20 min) = 0.0058, p(30 min) = 0.023, a-b, f-i. unpaired, two-tailed Student’s t-test. Data are represented as the mean ± SEM. Scale bar: 100 µm.

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