Independent phenotypic plasticity axes define distinct obesity sub-types.
Independent phenotypic plasticity axes define distinct obesity sub-types.
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DOI：
10.1038/s42255-022-00629-2
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发表时间：
2022-09
影响因子：
20.8
通讯作者：
Pospisilik, J. Andrew
中科院分区：
文献类型：
--
作者：
Yang, Chih-Hsiang;Fagnocchi, Luca;Apostle, Stefanos;Wegert, Vanessa;Casani-Galdon, Salvador;Landgraf, Kathrin;Panzeri, Ilaria;Dror, Erez;Heyne, Steffen;Woerpel, Till;Chandler, Darrell P.;Lu, Di;Yang, Tao;Gibbons, Elizabeth;Guerreiro, Rita;Bras, Jose;Thomasen, Martin;Grunnet, Louise G.;Vaag, Allan A.;Gillberg, Linn;Grundberg, Elin;Conesa, Ana;Korner, Antje;Pospisilik, J. Andrew
对基因“相同”个体的研究表明，多达50%的复杂性状变异无法追溯到遗传或环境。产生这种“无法解释的”表型变异（UPV）的机制在很大程度上仍然未知。在这里，我们确定神经元蛋白（NNAT）作为一个保守的因素，对UPV的缓冲。我们发现，Nnat缺乏症在同基因小鼠触发出现双稳定的多型性，在那里出生的成年人出现“正常”或“过度生长”。从机制上讲，这是由胰岛素依赖性过度生长介导的，胰岛素依赖性过度生长是由组蛋白脱乙酰酶（HDAC）依赖性β细胞过度增殖引起的。对同卵双生子不一致性的多维分析揭示了人类UPV存在两种模式，其中一种（B型）表型模仿了在小鼠中鉴定的NNAT缓冲多型性。具体而言，B型单卵双胞胎表现出全身脂肪和瘦体重的协调增加; NNAT表达降低; HDAC响应基因特征增加;以及与胰岛素血症相关的临床结果。重要的是，B型UPV特征将儿童和成人队列分为四种代谢状态，包括两种表型和分子上不同的肥胖类型。Yang等人表明，神经元蛋白（NNAT）可以解释复杂性状的部分表型变异，而与遗传或环境无关。这种NNAT依赖性变化可以将人类群组分层为四种代谢亚型，包括两种不同类型的肥胖。
Studies in genetically ‘identical’ individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this ‘unexplained’ phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either ‘normal’ or ‘overgrown’. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent β-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity. Yang et al. show that neuronatin (NNAT) can explain part of the phenotypic variation of complex traits, independently of genetics or the environment. Such NNAT-dependent variations can stratify human cohorts into four metabolic sub-types, including two distinct types of obesity.
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DOI：
10.1152/ajpendo.00463.2012
发表时间：
2013-04-15
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
--
作者：
Gburcik V;Cleasby ME;Timmons JA
通讯作者：
Timmons JA
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.2
作者：
Yokoi N
通讯作者：
Yokoi N
影响因子：
4.6
作者：
Cimino I;Rimmington D;Tung YCL;Lawler K;Larraufie P;Kay RG;Virtue S;Lam BYH;Fagnocchi L;Ma MKL;Saudek V;Zvetkova I;Vidal-Puig A;Yeo GSH;Farooqi IS;Pospisilik JA;Gribble FM;Reimann F;O'Rahilly S;Coll AP
通讯作者：
Coll AP
影响因子：
6.5
作者：
Elder, Sonya J.;Lichtenstein, Alice H.;Neale, Michael C.
通讯作者：
Neale, Michael C.