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Hepatic NADH reductive stress underlies common variation in metabolic traits 期刊论文
NATURE, 2020, 583 (7814) : 122-+
作者:  Skov, Laurits;  Coll Macia, Moises;  Sveinbjoernsson, Gardar;  Mafessoni, Fabrizio;  Lucotte, Elise A.;  Einarsdottir, Margret S.;  Jonsson, Hakon;  Halldorsson, Bjarni;  Gudbjartsson, Daniel F.;  Helgason, Agnar;  Schierup, Mikkel Heide;  Stefansson, Kari
收藏  |  浏览/下载:45/0  |  提交时间:2020/07/03

The cellular NADH/NAD(+) ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX1, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD(+) ratio in mice. By combining this genetic tool with metabolomics, we identify circulating alpha-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD(+) ratio, also known as reductive stress. In humans, elevations in circulating alpha-hydroxybutyrate levels have previously been associated with impaired glucose tolerance(2), insulin resistance(3) and mitochondrial disease(4), and are associated with a common genetic variant in GCKR(5), which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD(+) ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of '  causal metabolism'  .


The authors identify an increased hepatic NADH/NAD(+) ratio as an underlying metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases.


  
Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis 期刊论文
NATURE, 2020, 579 (7798) : 279-+
作者:  Liu, Xiaomeng;  Gao, Hongyan;  Ward, Joy E.;  Liu, Xiaorong;  Yin, Bing;  Fu, Tianda;  Chen, Jianhan;  Lovley, Derek R.;  Yao, Jun
收藏  |  浏览/下载:28/0  |  提交时间:2020/07/03

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes(1-3), the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.


  
Sex-specific adipose tissue imprinting of regulatory T cells 期刊论文
NATURE, 2020, 579 (7800) : 581-+
作者:  Qureshi, Abdul Aziz;  Suades, Albert;  Matsuoka, Rei;  Brock, Joseph;  McComas, Sarah E.;  Nji, Emmanuel;  Orellana, Laura;  Claesson, Magnus;  Delemotte, Lucie;  Drew, David
收藏  |  浏览/下载:21/0  |  提交时间:2020/07/03

Adipose tissue is an energy store and a dynamic endocrine organ(1,2). In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism(3,4). Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes(5,6). Regulatory T (T-reg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT(7-9). Here we uncover pronounced sexual dimorphism in T-reg cells in the VAT. Male VAT was enriched for T-reg cells compared with female VAT, and T-reg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of T-reg cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of T-reg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T-reg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T-reg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.


Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.


  
Noise exposure during the first trimester and the risk of gestational diabetes mellitus 期刊论文
ENVIRONMENTAL RESEARCH LETTERS, 2017, 12 (7)
作者:  Min, Kyoung-Bok;  Min, Jin-Young
收藏  |  浏览/下载:9/0  |  提交时间:2019/04/09
noise pollution  environmental health  diabetogenic  insulin resistance  pregnancy