Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation

Yuan, Feixiang; Jiang, Haizhou; Yin, Hanrui; Jiang, Xiaoxue; Jiao, Fangfang; Chen, Shanghai; Ying, Hao; Chen, Yan; Zhai, Qiwei; Guo, Feifan

doi:10.1038/s41467-020-16662-2

Cited by 34 publications

(37 citation statements)

References 62 publications

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“…Similarly, we found that Ucp1 expression was increased in mice and rats fed with a valine‐deficient diet, and Guo and colleagues showed that both valine and isoleucine deficiency increase lipid mobilization and energy expenditure suggesting that hypermetabolism is a conserved response to amino acid imbalance 68,85 . Other investigators demonstrated that leucine deprivation induced the induction of Ucp1 and other markers of thermogenic activation (generally known as ‘browning’) in WAT, via a CNS pathway and activation of sympathetic outflow 92 . The evolutionary benefit of this increase in metabolic rate and metabolic reprogramming of adipose tissue in an undernourished animal is not immediately clear, but may be important to balance the energy demands of foraging, via SNS‐mediated activation of lipolysis 90 …”

Section: Protein Malnutritionsupporting

confidence: 68%

“…68,85 Other investigators demonstrated that leucine deprivation induced the induction of Ucp1 and other markers of thermogenic activation (generally known as 'browning') in WAT, via a CNS pathway and activation of sympathetic outflow. 92 The evolutionary benefit of this increase in metabolic rate and metabolic reprogramming of adipose tissue in an undernourished animal is not immediately clear, but may be important to balance the energy demands of foraging, via SNS-mediated activation of lipolysis. 90…”

Section: Resting Metabolic Ratementioning

confidence: 99%

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Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

Olson

Marks

Grossberg

2020

J cachexia sarcopenia muscle

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Background Our evolutionary history is defined, in part, by our ability to survive times of nutrient scarcity. The outcomes of the metabolic and behavioural adaptations during starvation are highly efficient macronutrient allocation, minimization of energy expenditure, and maximized odds of finding food. However, in different contexts, caloric deprivation is met with vastly different physiologic and behavioural responses, which challenge the primacy of energy homeostasis. Methods We conducted a literature review of scientific studies in humans, laboratory animals, and non-laboratory animals that evaluated the physiologic, metabolic, and behavioural responses to fasting, starvation, protein-deficient or essential amino acid-deficient diets, and cachexia. Studies that investigated the changes in ingestive behaviour, locomotor activity, resting metabolic rate, and tissue catabolism were selected as the focus of discussion. Results Whereas starvation responses prioritize energy balance, both protein malnutrition and cachexia present existential threats that induce unique adaptive programmes, which can exacerbate the caloric insufficiency of undernutrition. We compare and contrast the behavioural and metabolic responses and elucidate the mechanistic pathways that drive state-dependent alterations in energy seeking and partitioning. Conclusions The evolution of energetically inefficient metabolic and behavioural responses to protein malnutrition and cachexia reveal a hierarchy of metabolic priorities governed by discrete regulatory networks.

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Section: Protein Malnutritionsupporting

confidence: 68%

Section: Resting Metabolic Ratementioning

confidence: 99%

Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

Olson

Marks

Grossberg

2020

J cachexia sarcopenia muscle

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“…21 GCN2 activation in amygdalar PKC-δ neurons facilitates WAT browning under leucine deprivation. 14 These findings suggest that macrophage GCN2 may play a role in leucine deprivation-induced other metabolic effects, such as WAT browning and lipolysis. In this study, we aimed to investigate whether ATMs are involved in leucine deprivation-induced WAT browning and lipolysis and whether GCN2 in ATMs contribute to this regulation.…”

Section: Introductionmentioning

confidence: 90%

“…The sections were subjected to hematoxylin and eosin (H&E) staining after deparaffinization and rehydration. 14 For UCP1 immunohistochemistry (IHC), the WAT sections were subjected to antigen retrieval in citrate acid buffer (pH 6.0) at 95°C for 20 minutes after deparaffinization and rehydration. After blocking with 5% goat serum in 0.1 M phosphate buffer and 0.2% Triton X-100 for 1 hour at room temperature, the WAT sections were incubated overnight at 4°C with anti-UCP1 antibody (1:500; ab10983, Abcam, Cambridge, UK) 22 and then incubated with HRP-conjugated secondary antibodies (1:1000; Jackson ImmunoResearch, PA, USA).…”

Section: Histopathology and Ucp1 Immunohistochemistrymentioning

confidence: 99%

“…21 Norepinephrine (NE) level of serum, tissue, and medium was assessed using the ELISA kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) in accordance with the manufacturer's instructions. 14 NE level of adipose tissue macrophages (ATMs) isolated by fluorescence activated cell sorting was measured using an ELISA kit (ml063805-X, Shanghai Enzyme-linked Biotechnology, Shanghai, China). BMDMs were grown in leucine deprivation medium for 12 hours, and the intracellular leucine content was measured by ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (LC-MS) (AB SCIEX, Singapore).…”

Section: Metabolic Parameter Measurementsmentioning

confidence: 99%

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Activation of GCN2 in macrophages promotes white adipose tissue browning and lipolysis under leucine deprivation

Wang

Xiao

et al. 2021

The FASEB Journal

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We have previously shown that leucine deprivation stimulates browning and lipolysis in white adipose tissue (WAT), which helps to treat obesity. Adipose tissue macrophages (ATMs) significantly influence WAT browning and lipolysis. However, it is unclear whether ATMs are involved in leucine deprivation-induced browning and lipolysis in WAT; the associated signals remain to be elucidated. Here, we investigated the role of ATMs and the possible mechanisms involved in WAT browning and lipolysis under leucine-deprivation conditions. In this study, macrophages were depleted in mice by injecting clodronate-liposomes (CLOD) into subcutaneous white adipose tissues. Then, mice lacking general control nonderepressible 2 kinase (GCN2), which is a sensor of amino acid starvation, specifically in Lyz2-expressing cells, were generated to investigate the changes in leucine deprivation-induced WAT browning and lipolysis. We found leucine deprivation decreased the accumulation and changed the polarization of ATMs. Ablation of macrophages by CLOD impaired WAT browning and lipolysis under leucine-deprivation conditions. Mechanistically, leucine deprivation activated GCN2 signals in macrophages. Myeloid-specific abrogation of GCN2 in mice blocked leucine deprivation-induced browning and lipolysis in WAT. Further analyses revealed that GCN2 activation in macrophages reduced the expression of monoamine oxidase A (MAOA), resulting in increased norepinephrine (NE) secretion from macrophages to adipocytes, and this resulted in enhanced WAT browning and lipolysis. Moreover, the injection of CL316,243, a β3-adrenergic receptor agonist, and inhibition of MAOA effectively increased the level of NE, leading to the enhancement of browning and lipolysis of WAT in myeloid GCN2 knockout mice under leucine deprivation. Collectively, our results demonstrate a novel 2 of 16 | WANG et Al.

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Trim21 Regulates the Postnatal Development and Thermogenesis of Brown Adipose Tissue

Hu,

Xu,

Xiao

et al. 2023

Advanced Biology

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Brown adipose tissue undergoes rapid postnatal development to mature and plays a crucial role in thermoregulation and energy expenditure, which protects against cold and obesity. Herein, it is shown that the expression of Trim21 mRNA level of interscapular brown adipose tissue elevates after birth, and peaks at P14 (postnatal day 14). Trim21 depletion severely impairs the maturation of interscapular brown adipose tissue, decreases the expression of a series of thermogenic genes, and reduces energy expenditure. Consistently, the loss of Trim21 also leads to a suppression of white adipose tissue “browning”, in response to cold exposure and a β‐adrenergic agonist, CL316,243. In addition, Trim21−/− mice are more prone to high‐fat diet‐induced obesity compared with the control littermates. Taken together, the study for the first time reveals a critical role of Trim21 in regulating iBAT postnatal development and thermogenesis.

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Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation

Cited by 34 publications

References 62 publications

Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

Activation of GCN2 in macrophages promotes white adipose tissue browning and lipolysis under leucine deprivation

Trim21 Regulates the Postnatal Development and Thermogenesis of Brown Adipose Tissue

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