References of "Cell Metabolism"
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See detailGlutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function
Kurniawan, Henry; Franchina, Davide G.; Guerra, Luana UL et al

in Cell Metabolism (2020), 31(5), 920--9367

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for ... [more ▼]

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine’s functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase ( Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality. [less ▲]

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See detailA Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways.
Molenaars, Marte; Janssens, Georges E.; Williams, Evan UL et al

in Cell metabolism (2020), 31(3), 549-5637

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal ... [more ▼]

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity. [less ▲]

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See detailTurn up the heat: circulating serotonin tunes our internal heating system.
Schneider, Jochen UL; Nadeau, Joseph H.

in Cell metabolism (2015), 21(2), 156-8

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al ... [more ▼]

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al. (2014) find that peripheral serotonin controls thermogenesis in adipose tissue by modulating beta-adrenergic stimulation of UCP-1, thereby affecting glucose homeostasis and weight gain. [less ▲]

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See detailRegulation of steatohepatitis and PPARgamma signaling by distinct AP-1 dimers.
Hasenfuss, Sebastian C.; Bakiri, Latifa; Thomsen, Martin K. et al

in Cell metabolism (2014), 19(1), 84-95

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric ... [more ▼]

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric Activator Protein 1 as a regulator of NAFLD. Fos-related antigen 1 (Fra-1) and Fos-related antigen 2 (Fra-2) prevent dietary NAFLD by inhibiting prosteatotic PPARgamma signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPARgamma expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPARgamma signaling and NAFLD development. This unique antagonistic regulation of PPARgamma by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism, and NAFLD. [less ▲]

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See detailPharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
Pirinen, Eija; Canto, Carles; Jo, Young Suk et al

in Cell metabolism (2014), 19(6), 1034-41

We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the ... [more ▼]

We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function. [less ▲]

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See detailNew hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis
Chakravarthy, M. V.; Pan, Z.; Zhu, Y. et al

in Cell Metabolism (2005), 1(5), 309-22

De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme ... [more ▼]

De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPARalpha-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPARalpha target genes in FASKOL mice were corrected with a PPARalpha agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPARalpha agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPARalpha in adult liver [less ▲]

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