Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

Kanzleiter, Timo; Schneider, T.R.; Walter, Isabel; Bolze, Florian; Eickhorst, Christoph; Heldmaier, Gerhard; Schimrigk, К.; Klingenspor, Martin

doi:10.1152/physiolgenomics.00204.2005

Cited by 60 publications

(44 citation statements)

References 61 publications

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“…Conversely, our MINOR skeletal muscle tissue specific transgenic mice presented very similar results with reduced body weight, improved insulin and glucose intolerances, reduced plasma levels of triglyceride, cholesterol and free fatty acid as well as enhanced expression of genes which are related to insulin action and its signaling pathways. Interestingly, in these Nur77 knockout mice there were the dramatic compensatory increases in MINOR expression detected [20,21], however, we have not observed detectable changes of Nur77 or Nurr1 genes in the MINOR transgenic mice when compared to WT mice, probably due to the differences between global knockout and tissue specific overexpression. Whichever, these studies have indicated that expression and function of MINOR and Nur77 nuclear receptors are strongly associated with metabolic activities in skeletal muscle.…”

Section: Discussioncontrasting

confidence: 66%

MINOR (NR4A3) Overexpression in Mouse Skeletal Muscle Enhances Insulin Action

Zhang¹,

Garvey²,

Luo

et al. 2014

J Mol Genet Med

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MINOR (Mitogen-Inducible Nuclear Orphan Receptor) is one member of the NR4A3 nuclear orphan receptor family which are immediate early gene products involved in neuroendocrine regulation, neural differentiation, liver regeneration, cell apoptosis, and mitogenic and inflammatory stimulation in different cell types. We have found that MINOR can modulate insulin action and the glucose transport system in 3T3-L1 adipocytes; however, MINOR is highly expressed in skeletal muscle and its function in vivo is not well understood.To determine the role of MINOR in vivo, we have generated a mouse model that has the MINOR gene specifically expressed in the skeletal muscle using a muscle creatine kinase (MCK) promoter, and investigated whether the gene functions of MINOR would be linked to insulin action in vivo since skeletal muscle is one of the primary target tissues for insulin action.We demonstrate that these MCK-MINOR transgenic mice have reduced body weight due to a reduction of fat mass inside the body. Mice with MINOR overexpression also have improved insulin and glucose tolerances, reduced plasma levels of triglyceride, cholesterol and free fatty acid as well as enhanced expression of genes which are related to insulin action and its signaling pathways. Thus, MINOR functions in skeletal muscle act to improve insulin sensitivity and glucose intolerances and regulate insulin action and lipid and energy expenditure process.

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Section: Discussioncontrasting

confidence: 66%

MINOR (NR4A3) Overexpression in Mouse Skeletal Muscle Enhances Insulin Action

Zhang¹,

Garvey²,

Luo

et al. 2014

J Mol Genet Med

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“…NUR77 (nuclear receptor subfamily 4, group A, member 2, Nr4a1) was found to be an adrenergic stimulation-induced orphan nuclear receptor by the comparison of gene expression in immortalized HIB-1B brown adipocytes incubated with or without an adrenergic agonist. 73) This report suggests that NUR77 would inhibit expression of the UCP1 gene. In addition, in vivo investigation showed that the expression of NUR77 gene is transiently up-regulated by short-term cold exposure and that prolonged exposure causes rapid downregulation of this gene.…”

Section: Transcription Factors and Their Co-activatorsmentioning

confidence: 85%

Cold-Induced Changes in Gene Expression in Brown Adipose Tissue: Implications for the Activation of Thermogenesis

Watanabe

Yamamoto

Mori

et al. 2008

Biological & Pharmaceutical Bulletin

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Brown adipose tissue (BAT) is the site of heat production (thermogenesis). This unique function is performed by uncoupling protein 1 (UCP1) specifically expressed in mitochondria of BAT. UCP1 dissipates the driving force of ATP synthesis, and thus causes heat production followed by energy expenditure. The thermogenic function of BAT has the role of maintaining body temperature under cold conditions. When animals are exposed to cold, the expression of UCP1 gene is increased to activate thermogenesis. To date, functional analysis of BAT has been focused on UCP1, because it plays an indispensable role in thermogenesis. However, the gene expression of not only UCP1 but also that of other genes in BAT is expected to be regulated to achieve effective thermogenesis. Our previous investigations showed increased expression of genes that encode several energy metabolic enzymes in the BAT of rats kept in the cold. These changes in gene expression imply that the enhancement of energy metabolism is needed to activate thermogenesis. Furthermore, various reports from studies focused on genes whose expression is changed in response to cold stimulation have provided new insights into the function of BAT. In this review, to understand the thermogenic function of BAT systematically, we have provided an overview of previous findings on changes in the expression of genes thought to be related to the activation of thermogenesis in BAT.

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“…These results might initially seem contradictory to the findings of Maxwell et al [16], who used C2C12 cells with a stable knockdown of Nur77 and identified differentially expressed genes linked to lipid and glucose metabolism. However, the loss of Nur77 expression in Nur77-knockout mice results in a compensatory increase of another member of nuclear receptor subfamily 4, group A (NR4A), Nor1 (also known as Nr4a3) [15,29]. This partial redundancy between NR4A receptors makes it difficult to study the direct effects of gene deletion.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

et al. 2010

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Aims/hypothesis A hallmark feature of the metabolic syndrome is abnormal glucose metabolism which can be improved by exercise. Recently the orphan nuclear receptor subfamily 4, group A, member 1 (NUR77) was found to be induced by exercise in muscle and was linked to transcriptional control of genes involved in lipid and glucose metabolism. Here we investigated if overexpression of Nur77 (also known as Nr4a1) in skeletal muscle has functional consequences for lipid and/or glucose metabolism. Methods L6 rat skeletal muscle myotubes were infected with a Nur77-coding adenovirus and lipid and glucose oxidation was measured. Nur77 was also overexpressed in skeletal muscle of chow-and fat-fed rats and the effects on glucose and lipid metabolism evaluated. Results Nur77 overexpression had no effect on lipid oxidation in L6 cells or rat muscle, but did increase glucose oxidation and glycogen synthesis in L6 cells. In chow-and high-fat-fed rats, Nur77 overexpression by electrotransfer significantly increased basal glucose uptake and glycogen synthesis, but no increase in insulin-stimulated glucose metabolism was observed. Nur77 electrotransfer was associated with increased production of GLUT4 and glycogenin and increased hexokinase and phosphofructokinase activity. Interestingly, Nur77 expression in muscle biopsies from obese men was significantly lower than in those from lean men and was closely correlated with bodyfat content and insulin sensitivity. Conclusions/interpretation Our data provide compelling evidence that NUR77 is a functional regulator of glucose metabolism in skeletal muscle in vivo. Importantly, the diminished content in muscle of obese insulin-resistant men suggests that it might be a potential therapeutic target for the treatment of dysregulated glucose metabolism.

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Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

Abstract: Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis.

Cited by 60 publications

References 61 publications

MINOR (NR4A3) Overexpression in Mouse Skeletal Muscle Enhances Insulin Action

MINOR (NR4A3) Overexpression in Mouse Skeletal Muscle Enhances Insulin Action

Cold-Induced Changes in Gene Expression in Brown Adipose Tissue: Implications for the Activation of Thermogenesis

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

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