Exercise and PGC-1α-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERRγ

Narkar, Vihang A.; Fan, Weiwei; Downes, Michael; Yu, Ruth T.; Jonker, Johan W.; Alaynick, William A.; Banayo, Ester; Karunasiri, Malith; Lorca, Sabina; Evans, Ronald M.

doi:10.1016/j.cmet.2011.01.019

Cited by 156 publications

(241 citation statements)

References 77 publications

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“…Muscle ERRγ expression levels correlate with exercise performance in humans (36). Moreover, mice lacking ERRβ and ERRγ in skeletal muscle have decreased running capacity whereas mice overexpressing ERRγ in muscle show increased exercise capacity (36)(37)(38). We speculate that p38-mediated activation of ERRβ and ERRγ may link exercise to adaptive metabolic changes in skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

GADD45γ regulates the thermogenic capacity of brown adipose tissue

Gantner

Hazen

Conkright

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Brown adipose tissue (BAT) specializes in converting stored chemical energy into heat. When activated in response to cold, BAT increases the body’s metabolic rate and promotes fat loss. The recent identification of BAT in humans makes activation of this tissue an attractive target for counteracting obesity. However, our understanding of the intracellular pathways that regulate the response to cold is limited. Here, we identify a previously unknown regulator of BAT activation, growth arrest and DNA-damage-inducible protein 45 γ, which is induced in response to cold and works via the MAPK p38 and the transcription factor estrogen-related receptor γ to enhance the expression of genes important for thermogenesis. Our findings may provide new avenues for the stimulation of energy expenditure.

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Section: Discussionmentioning

confidence: 99%

GADD45γ regulates the thermogenic capacity of brown adipose tissue

Gantner

Hazen

Conkright

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, the observed hyperactivation of ERRα when FLCN is repressed was shown to be AMPK-dependent, as deletion of AMPK in MEFs abrogated ERRα activity. Interestingly, modulation of ERRα or ERRγ expression in mouse muscle cells also affects AMPK activity, indicating that ERRs themselves can activate the AMPK pathway, possibly underlying a positive feedback loop between AMPK and the ERRs (Dufour et al 2007;Narkar et al 2011). …”

Section: Discussionmentioning

confidence: 99%

Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

et al. 2016

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The tumor suppressor folliculin (FLCN) forms a repressor complex with AMP-activated protein kinase (AMPK). Given that AMPK is a master regulator of cellular energy homeostasis, we generated an adipose-specific Flcn (Adipoq-FLCN) knockout mouse model to investigate the role of FLCN in energy metabolism. We show that loss of FLCN results in a complete metabolic reprogramming of adipose tissues, resulting in enhanced oxidative metabolism. Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. Importantly, FLCN ablation leads to chronic hyperactivation of AMPK, which in turns induces and activates two key transcriptional regulators of cellular metabolism, proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and estrogen-related receptor α (ERRα). Together, the AMPK/PGC-1α/ERRα molecular axis positively modulates the expression of metabolic genes to promote mitochondrial biogenesis and activity. In addition, mitochondrial uncoupling proteins as well as other markers of brown fat are up-regulated in both white and brown FLCN-null adipose tissues, underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure. These findings identify a key role of FLCN as a negative regulator of mitochondrial function and identify a novel molecular pathway involved in the browning of white adipocytes and the activity of brown fat.

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“…The putative Myh7 ERR binding site is located well upstream of the well-described proximal promoter elements known to respond to the thyroid receptor, MCAT, and Sox6 (20,21). Notably, ERRγ has been shown recently to activate oxidative muscle fiber programs in a manner similar to that of PPARβ/δ (14,22). We found that ERRγ (Esrrg) mRNA and protein levels were increased in MCK-PPARβ/δ muscle but not in MCK-PPARα muscle ( Figure 4B and data not shown).…”

Section: The Nuclear Receptor Errγ Functions Downstream Of Pparβ/δ Tomentioning

confidence: 99%

Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism

Gan¹,

Rumsey²,

Hazen³

et al. 2013

J. Clin. Invest.

172

226

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The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

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Exercise and PGC-1α-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERRγ

Cited by 156 publications

References 77 publications

GADD45γ regulates the thermogenic capacity of brown adipose tissue

GADD45γ regulates the thermogenic capacity of brown adipose tissue

Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism

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