Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet.
OBJECTIVE
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.
Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
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F
Sheedfar
Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
M
M
Vermeer
Gastroenterology Unit, Department of Medical Sciences, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo (FG), Italy.
V
V
Pazienza
1] Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain [2] CIBER Fisiopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III, Madrid, Spain.
J
J
Villarroya
Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy.
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F
Rappa
1] Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy [2] Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.
F
F
Cappello
Division of Internal Medicine and Chronobiology Unit, Department of Medical Sciences, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo (FG), Italy.
G
G
Mazzoccoli
Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.
F
F
Villarroya
Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
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H
van der Molen
Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
M H
MH
Hofker
Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
D P
DP
Koonen
1] Gastroenterology Unit, Department of Medical Sciences, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo (FG), Italy [2] Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy [3] Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), UCL Medical School, Royal Free Hospital, London, UK.
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M
Vinciguerra
D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D013851:Thinness / Q000378:metabolism*
D006657:Histones; C120756:macroH2A histone