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. 2024 May 15;629(8014):1133–1141. doi: 10.1038/s41586-024-07419-8

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 3 — a-c, Treatment of DIO mice with once-daily s.c. injections of 100 nmol kg⁻¹ MK-801 (n = 7 mice and n = 4 cages), 100 nmol kg⁻¹ GLP-1 (n = 6 mice and n = 3 cages), 100 nmol kg⁻¹, GLP-1–MK-801 (n = 6 mice and n = 3 cages), co-administration of 100 nmol kg⁻¹ GLP-1 and 100 nmol kg⁻¹ MK-801 (n = 6 mice and n = 3 cages) or vehicle (isotonic saline, n = 7 mice and n = 4 cages) for 14 days. a, Schematic. b, Change in body weight. c, Cumulative food intake. d-g and o-s, Treatment of DIO mice in metabolic cages with once-daily s.c. injections of 100 nmol kg⁻¹ MK-801 (n = 7-8 mice), 100 nmol kg⁻¹ GLP-1 (n = 8 mice), 100 nmol kg⁻¹ GLP-1–MK-801 (n = 8 mice) or vehicle (isotonic saline, n = 8 mice) for 14 days. d, Schematic. e, Change in body weight. f, Change in fat mass. For MRI, two values were not registered from MK-801 group, two values were not registered from GLP-1 group and two values were not registered from GLP-1–MK-801 group due to MRI instrumental error. g, Change in lean mass. h-m, GLP-1–MK-801 corrects body weight and fat mass relative to age-matched chow-fed control mice. Treatment of DIO mice with once-daily s.c. injections of 100 nmol kg⁻¹ GLP-1–MK-801 (n = 8 mice and n = 4 cages), 300 nmol kg⁻¹ GLP-1–MK-801 (n = 8 mice and n = 4 cages) or vehicle (isotonic saline, n = 7 mice and n = 4 cages) in comparison with vehicle-treated age-matched chow-fed C57BL/6 J mice (n = 16 mice and n = 8-11 cages) for 14 days. Three double-housed cages with age-matched control animals were split on day 7 of the experiment due to fighting. One mouse was found dead in vehicle group. h, Schematic. i, Change in body weight. j, Body weight on day 14. k, Cumulative food intake. l, Fat mass on day 14. m, Lean mass on day 14. n, Total locomotor activity of mice from indirect calorimetry study in Fig. 1i–p. o, Energy expenditure. One mouse in MK-801 group excluded due to sensor related deviation. p, Regression-based analysis of energy expenditure relative to body weight on day 14. q, Respiratory exchange ratio (RER). r, Average respiratory exchange ratio. s, Total locomotor activity. Data analysed by one-way ANOVA, multiple comparison, Bonferroni post hoc test (f, g, j, l-n, r and s), two-way repeated measures ANOVA to assess main effects of treatment (b, c, e and k), and ANCOVA computed with calR using body weight as a covariate (p). Data represents mean ± SEM; ^*P < 0.05, ^**P < 0.01, ^***P < 0.001, ^****P < 0.0001. Detailed statistics are in Supplementary Table 1. The diagrams in a, d and h were created using BioRender.

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