1689-P: Macrophage SUCLA2-Coupled Glutamine Metabolism Drives Obesity

Activation and infiltration of macrophages in adipose tissue are closely linked to obesity and are implicated in the pathogenesis of metabolic diseases. Glutamine is an essential energy resource that supports the inflammatory activation of macrophages, however, the underlying mechanism remains unkno...

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Veröffentlicht in:Diabetes (New York, N.Y.) N.Y.), 2023-06, Vol.72 (Supplement_1), p.1
1. Verfasser: JIANG, HAOWEN
Format: Artikel
Sprache:eng
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Zusammenfassung:Activation and infiltration of macrophages in adipose tissue are closely linked to obesity and are implicated in the pathogenesis of metabolic diseases. Glutamine is an essential energy resource that supports the inflammatory activation of macrophages, however, the underlying mechanism remains unknown. We found that AMP-activated protein kinase (AMPK) was the key regulator for mitochondrial glutamine metabolism. Once inflammatory activation of macrophages, increased ATP production from glutaminolysis inhibited the activity of AMPK, then removed its inhibitory effect of glutamine metabolism, resulting in the succinate accumulation derived IL-1β production and secretion. Mechanically, macrophage AMPK phosphorylated at Ser60 of succinyl-CoA synthetase β subunit (SUCLA2) that was responsible for catalyzing the succinate production, decreases its activity resulting in the reduction of the succinate accumulation derived IL-1β production and secretion correspondingly. Moreover, myeloid cell-specific knockout of the α subunit of AMPK exacerbated obesity and insulin resistance through IL-1β production and secretion in macrophages. Both the obstruction of the IL-1β signaling pathway by the neutralizing antibody and the decreasing of IL-1β production and secretion by myeloid cell-specific knockout of IL-1β could repair insulin resistance and obesity derived by AMPK deficiency in macrophages. Our study revealed that AMPK-mediated SUCLA2 phosphorylation drove the mitochondrial glutamine metabolism and the IL-1β production and secretion in macrophages, and targeting macrophage AMPK-SUCLA2 pathway might be a potential strategy for obesity and insulin resistance therapy.
ISSN:0012-1797
1939-327X
DOI:10.2337/db23-1689-P