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

Abstract

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.

Impacts of essential amino acids on energy balance

“…Recent studies have shown that the activation of GCN2 signaling in amygdalar protein kinase C (PKC)-δ neurons and macrophages promote WAT browning under Leu deprivation [ 40 , 63 ]. Researchers have found that Leu deficiency-induced WAT browning could be blocked by GCN2 deletion in amygdalar PKC-δ neurons, which is reversed by the over-expression of amino acid-responsive gene activating transcription factor 4 (ATF4) and is mediated by amygdalar PKC-δ neurons activity and the SNS [ 40 ].…”

“…Further analyses revealed that GCN2 activation in macrophages reduces the expression of monoamine oxidase A (MAOA), resulting in increased NE secretion from macrophages to adipocytes, and an enhanced WAT browning. In addition, GCN2 signaling in ATMs similarly mediates Leu deficiency-increased WAT lipolysis [ 63 ].…”

Amino acid sensor GCN2 promotes SARS-CoV-2 receptor ACE2 expression in response to amino acid deprivation

“…Male C57BL/6J wild-type (WT) mice were purchased from the Shanghai Laboratory Animal Co. Ltd (SLAC; Shanghai, China). Gcn2 -floxed mice 56 were intercrossed with Villin -cre mice 48 (Shanghai Biomodel Organism Science & Technology Development Co.,Ltd., Shanghai, China) to generate the IEC-specific Gcn2 IKO mice. All mice were housed in laboratory cages at a temperature of 23 ± 3 °C and humidity of 35 ± 5%, under a 12/12 h dark/light cycle, with free access to a regular chow diet (SLAC) and water.…”

Amino Acid Sensor GCN2 Promotes SARS-CoV-2 Receptor ACE2 Expression in Response to Amino Acid Deprivation

“…Male C57BL/6J wild-type (WT) mice were purchased from the Shanghai Laboratory Animal Co. Ltd (SLAC; Shanghai, China). Gcn2oxed mice 42 were intercrossed with Villin-cre mice (Shanghai Biomodel Organism Science & Technology Development Co.,Ltd., Shanghai, China) to generate the IECspeci c Gcn2 IKO mice. All mice were housed in laboratory cages at a temperature of 23 ± 3°C and humidity of 35 ± 5%, under a 12/12 h dark/light cycle, with free access to a regular chow diet (SLAC) and water.…”