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Animal Models

Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet

Abstract

Background/objectives:

In the context of obesity, epigenetic mechanisms regulate cell-specific chromatin plasticity, perpetuating gene expression responses to nutrient excess. MacroH2A1, a variant of histone H2A, emerged as a key chromatin regulator sensing small nutrients during cell proliferation and differentiation. Mice genetically ablated for macroH2A1 (knockout (KO)) do not show overt phenotypes under a standard diet. Our objective was to analyse the in vivo role of macroH2A1 in response to nutritional excess.

Methods:

Twelve-week-old whole-body macroH2A1 KO male mice were given a high-fat diet (60% energy from lard) for 12 weeks until being killed, and examined for glucose and insulin tolerance, and for body fat composition. Energy expenditure was assessed using metabolic cages and by measuring the expression levels of genes involved in thermogenesis in the brown adipose tissue (BAT) or in adipogenesis in the visceral adipose tissue (VAT).

Results:

Under a chow diet, macroH2A1 KO mice did not differ from their wild-type (WT) littermates for body weight, and for sensitivity to glucose or insulin. However, KO mice displayed decreased heat production (P<0.05), and enhanced total activity during the night (P<0.01). These activities related to protection against diet-induced obesity in KO mice, which displayed decreased body weight owing to a specific decrease in fat mass (P<0.05), increased tolerance to glucose (P<0.05), and enhanced total activity during the day (P<0.05), compared with WT mice. KO mice displayed increased expression of thermogenic genes (Ucp1, P<0.05; Glut4, P<0.05; Cox4, P<0.01) in BAT and a decreased expression of adipogenic genes (Pparγ, P<0.05; Fabp4, P<0.05; Glut4, P<0.05) in VAT compared with WT mice, indicative of augmented energy expenditure.

Conclusions:

Genetic eviction of macroH2A1 confers protection against diet-induced obesity and metabolic derangements in mice. Inhibition of macroH2A1 might be a helpful strategy for epigenetic therapy of obesity.

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Acknowledgements

We appreciate Dr Bastiaan Moesker, Paulina Bartuzi and Dr Marcela Aparicio-Vergara for their technical helps. FS is supported by a PhD scholarship from the Graduate School for Drug Exploration (GUIDE), University of Groningen. DPK and MHH are supported by the Center for Translational Molecular Medicine (http://www.ctmm.nl), project PREDICCt (Grant 01C-104) and by the Dutch Heart Foundation, Dutch Diabetes Research Foundation and Dutch Kidney Foundation. MV is a recipient of a My First AIRC Grant (MFAG) from Associazione Italiana per la Ricerca sul Cancro, Italy. FC is funded by Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.

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Correspondence to M Vinciguerra.

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Sheedfar, F., Vermeer, M., Pazienza, V. et al. Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet. Int J Obes 39, 331–338 (2015). https://doi.org/10.1038/ijo.2014.91

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