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Epigenetic germline inheritance of diet-induced obesity and insulin resistance


There is considerable controversy regarding epigenetic inheritance in mammalian gametes. Using in vitro fertilization to ensure exclusive inheritance via the gametes, we show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes in a sex- and parent of origin–specific mode. The epigenetic inheritance of acquired metabolic disorders may contribute to the current obesity and diabetes pandemic.

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Figure 1: F1 body weight trajectories and distributions.
Figure 2: F1 glucose tolerance and insulin levels.

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The authors are grateful for the expert technical assistance of M. Bamberger, A. Bettenbrock, S. Dunst, J. Wörner, M. Brückl, B. Rey and the animal caretakers of the German Mouse Clinic. This work was supported by grants from the Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease' (J.B.), the Helmholtz Alliance 'Imaging and Curing Environmental Metabolic Diseases' (ICEMED; J.B.) and the German Federal Ministry of Education and Research, INFRAFRONTIER grant 01KX1012 (M.H.d.A.).

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Authors and Affiliations



P.H., M.T., M.H.d.A. and J.B. initiated the project and designed experiments. P.H., M.W., D.D. and S.M. performed the experiments. P.H., S.S., F.T. and J.B. analyzed data. P.H. and J.B. wrote the manuscript.

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Correspondence to Peter Huypens or Johannes Beckers.

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The authors declare no competing financial interests.

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Supplementary Figure 1 Experimental design.

Parental mice (F0) were at random allocated to diet treatments. These animals were maintained on an HFD (red), LFD (black) or NC (gray) diet between 9 and 15 weeks of age and subsequently served as gamete donors for IVF. Two-cell embryos were transferred into healthy CD-1 foster mothers that were maintained on an NC diet. All offspring (F1) were weaned and kept on an NC diet until 9 weeks of age. At 9 weeks of age, all F1 offspring were placed on an HFD diet until 15 weeks of age. This experiment was replicated at least three times for each F1 cohort, using sperm and oocytes from independent donors. Parental diets (father × mother) are abbreviated in parentheses, and color codes are consistent throughout the figures.

Supplementary Figure 2 Parental (F0) metabolic phenotype.

(ae) Maternal (fF0) and (fj) paternal (mF0) phenotype measured from at least three independent cohorts of mice. (a,f) Body weight gain from 9 to 15 weeks (mean ± s.e.m.). (b,g) Box-and-whiskers graphs of percent body fat mass relative to body mass at 15 weeks measured by NMR (in b, fF0 LFD n = 15, fF0 NC n = 14 and fF0 HFD n = 17; in g, mF0 LFD n = 13, mF0 NC n = 14 and mF0 HFD n = 14). (c,h) ipGTT at 15 weeks. (d,i) Area under the glucose curve (AUC) (in d, fF0 LFD n = 4, fF0 NC n = 9 and fF0 HFD n = 5; in i, mF0 LFD n = 5, mF0 NC n = 9 and mF0 HFD n = 7). (e,j) Plasma insulin levels during ipGTT (in e, fF0 LFD n = 4, fF0 NC n = 3 and fF0 HFD n = 5; in j, mF0 LFD n = 6, mF0 NC n = 7 and mF0 HFD n = 4). Statistics in b, d, g and i: one-way ANOVA, post-hoc Bonferroni test; statistics in a, c, e, f, h and j: two-way repeated-measurement ANOVA, post-hoc Bonferroni multiple-comparisons test. *P < 0.05, **P < 0.01, ***P < 0.001 versus F0 LFD and F0 NC.

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Supplementary Figure 3 F1 exact cumulative body weight curves and relative fat mass at 15 weeks of age.

(a) Exact cumulative body weight curves of female F1 progeny at 15 weeks of age. (b) Box-and-whiskers graphs of female F1 percentage body fat at 15 weeks of age measured via NMR. (c) Exact cumulative body weight curves of male F1 mice at 15 weeks of age. (d) Box-and-whiskers graphs of male F1 percentage body fat at 15 weeks of age measured via NMR. Statistics in a and c: Kruskal-Wallis test, with Dunn’s multiple-comparisons post-hoc test to assign §P < 0.05, §§P < 0.01, §§§P < 0.001 versus each of both control groups, F1(LFD × LFD) and F1(NC × NC); ΩP < 0.05 versus F1(HFD × NC); statistics in b and d: one-way ANOVA, post-hoc Bonferroni multiple-comparisons test assigning *P < 0.05, **P < 0.01, ***P < 0.001 versus each of both control groups, F1(LFD × LFD) and F1(NC × NC); ΩP < 0.05 versus F1(HFD × NC).

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3. (PDF 592 kb)

Supplementary Table 1

Detailed diet composition. (XLSX 13 kb)

Supplementary Table 2

IVF details. (XLSX 23 kb)

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Huypens, P., Sass, S., Wu, M. et al. Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat Genet 48, 497–499 (2016).

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