Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue

Lee, Jae Ho; Go, Younghoon; Kim, Do Young; Lee, Sun Hee; Kim, Ok Hee; Jeon, Yong Hyun; Kwon, Taeg Kyu; Bae, Jae Hoon; Song, Dong Hyun; Rhyu, Im Joo; Lee, In Kyu; Shong, Minho; Oh, Byung Chul; Petucci, Christopher; Park, Jeen Woo; Osborne, Timothy F.; Im, Seung Soon

doi:10.1038/s12276-020-0379-z

Cited by 37 publications

(27 citation statements)

References 36 publications

(37 reference statements)

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“…IDH2 is a mitochondrial localised enzyme within the TCA cycle that catalyses the oxidative decarboxylation of isocitrate to alpha-ketoglutarate and a reduction in NADP to NADPH + levels 40 , 41 . Consequently, IDH2 is required for efficient energy substrate metabolism and redox signalling 40 . Considering our observations that muscles with reduced Yap levels display impaired fatty acid oxidation, features of lipotoxicity and lower alpha-ketoglutarate levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

et al. 2021

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Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

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Section: Resultsmentioning

confidence: 99%

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

et al. 2021

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“…In contrast, under chronic metabolic-thermogenic conditions such as obesity, excessive levels of ROS are produced which promotes mitochondrial damage in the BAT (Cui et al, 2019;Kazak et al, 2017;Lee et al, 2020) , . However, it is largely unknown whether and how NO bioactivity, another key redox mediator, modulates BAT function in health and disease.…”

Section: Discussionmentioning

confidence: 99%

“…This redoxmediated modulation leads to activation of UCP1-dependent uncoupling (Chouchani et al, 2016). In contrast, studies have shown that excessive ROS and RNS impairs BAT mitochondrial function (Cui et al, 2019;Lee et al, 2020). We then determined whether UCP1 is targeted by SNO using immunohistochemistry and biotin switch analyses.…”

Section: Obesity Elevates Protein S-nitrosylation and Decreases Cellumentioning

confidence: 99%

“…This redox-mediated modulation leads to activation of UCP1-dependent uncoupling (Chouchani et al, 2016). In contrast, studies have shown that excessive ROS and RNS impairs BAT mitochondrial function (Cui et al, 2019;Lee et al, 2020). GPS-SNO prediction tool (Xue et al, 2010) predicted that Cys25 and Cys305 are potential SNO sites on mouse UCP1, and cys305 as a potential SNO site on human UCP1 (Fig.…”

Section: Obesity Elevates Protein S-nitrosylation and Decreases Cellumentioning

confidence: 99%

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ADH5-mediated NO Bioactivity Maintains Metabolic Homeostasis in Brown Adipose Tissue

Sebag

Zhang

Qian

et al. 2020

Preprint

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Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status but the molecular mechanisms underlying this regulation are incompletely understood. Protein S-nitrosylation, the nitric oxide-mediated cysteine thiol modification of proteins, plays important roles in cellular redox regulation. Here we show that both diet-induced obesity (DIO) and acute cold exposure elevates protein S-nitrosylation of BAT proteins, including UCP1, to regulate thermogenesis. This effect in BAT is regulated largely by S-nitrosoglutathione reductase (GSNOR, ADH5), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 specifically in BAT impairs UCP1-dependent thermogenesis during acute cold challenge and worsens metabolic dysfunction during diet-induced obesity. Mechanistically, we demonstrate that Adh5 expression in BAT is controlled by the transcription factor heat shock factor 1 (HSF1) and administration of an HSF1 activator to the BAT of mice with DIO increased Adh5 expression and significantly improved UCP1-mediated mitochondrial respiration. Together, these data demonstrate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis which may be therapeutically targeted to improve metabolic health.

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“…Western blot analysis was performed as described previously [21]. Briefly, protein samples were collected from the liver tissues of 24 h-fasted and fed WT and LKO mice, as well as from LRH-1 agonist-treated HepG2 cells.…”

Section: Western Blot Analysismentioning

confidence: 99%

LRH-1 Ameliorates Hepatic Triglyceride Accumulation via Regulation of Perilipin 5 in the Liver

Pantha¹,

J²,

Bae³

et al. 2021

Preprint

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Liver receptor homolog-1 (LRH-1) has emerged as a regulator of hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect of LRH-1 on lipid mobilization has not been addressed. This study investigated the regulatory function of LRH-1 in lipid metabolism during fasting. The wild-type (WT) and LRH-1 liver-specific knockout (LKO) mice were either fed or fasted for 24 h, and the liver and serum were isolated. During fasting, the LRH-1 LKO mice showed greater accumulation of triglycerides in the liver compared to that in WT mice. Interestingly, LRH-1 LKO liver decreased the perilipin 5 (PLIN5) expression and genes involved in β-oxidation. Additionally, the LRH-1 agonist dialauroylphosphatidylcholine also enhanced PLIN5 expression in human cultured HepG2 cells. To identify new target genes of LRH-1, these findings directed to analyze the PLIN5 promoter sequence, which revealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immuno-precipitation assays. Moreover, fasted WT primary hepatocytes showed increased co-localization of PLIN5 in lipid droplets (LDs) compared to that in fasted LRH-1 LKO primary hepatocytes. Overall, these findings suggest that PLIN5 might be a novel target of LRH-1 to mobilize LDs and manage the cellular needs.

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Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue

Cited by 37 publications

References 36 publications

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

ADH5-mediated NO Bioactivity Maintains Metabolic Homeostasis in Brown Adipose Tissue

LRH-1 Ameliorates Hepatic Triglyceride Accumulation via Regulation of Perilipin 5 in the Liver

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