Loss of Imprinting of Cdkn1c Protects against Age and Diet-Induced Obesity

被引:7
作者
Van de Pette, Mathew [1 ,2 ]
Tunster, Simon J. [1 ]
John, Rosalind M. [1 ]
机构
[1] Cardiff Univ, Sch BioSci, Cardiff CF10 3AX, S Glam, Wales
[2] Hammersmith Hosp, MRC London Inst Clin Sci, London W12 0NN, England
基金
英国生物技术与生命科学研究理事会;
关键词
Cdkn1c; imprinting; BACs; adipose; aging; high fat diet; methylation; BECKWITH-WIEDEMANN-SYNDROME; STEM-CELLS; MOUSE; P57(KIP2); GENE; EXPRESSION; METHYLATION; INHIBITOR; QUIESCENCE; MECHANISMS;
D O I
10.3390/ijms19092734
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cyclin dependent kinase inhibitor 1c (Cdkn1c) is a maternally expressed imprinted gene with roles in embryonic development, post-natal metabolism and behaviour. Using mouse models with altered dosages of Cdkn1c, we have previously identified a role for the gene in promoting brown adipose tissue formation. Here, we use these transgenic mouse lines to model the loss of imprinting of Cdkn1c in adulthood. We demonstrate that only a two-fold increase in the expression of Cdkn1c during development is sufficient to protect against age-related weight gain in addition to glucose and insulin intolerance. Further to this, we show that the loss of imprinting of Cdkn1c protects against diet-induced obesity. Bisulphite sequencing was performed to test the stability of the two differentially methylated regions that regulate Cdkn1c imprinting, and both were found to be unaltered in aged or diet-challenged adipose tissue, despite drastic reductions in Cdkn1c expression. These data demonstrate a critical role for Cdkn1c in regulating adult adipose tissue, with modest changes in expression capable of protecting against both age and diet-induced obesity and metabolic syndrome, with a natural decline in Cdkn1c expression observed that may contribute to less healthy metabolic aging. Finally, we have observed a post-natal insensitivity of the imprint to environmental factors, in contrast to recent observations of an in utero sensitivity.
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页数:14
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