A recent study has shed light on the complex interplay between obesity and immune cell metabolism, particularly focusing on the role of macrophages. Researchers have discovered how glutaminolysis, the metabolic conversion of glutamine, influences obesity through the activity of AMP-activated protein kinase (AMPK) and the inflammatory cytokine interleukin-1β (IL-1β).
Obesity is increasingly recognized as more than just excess weight; it is now understood as a chronic inflammatory condition. This research highlights the significance of adipose tissue macrophages (ATMs) as both active participants and regulators of metabolic processes associated with obesity. The central finding of the study indicates glutaminolysis as the predominant metabolic pathway fueling macrophage energy and inflammatory signaling.
The research utilized multiple experimental models, including genetically modified mice and human adipose tissue samples, to explore the immunometabolic reprogramming of ATMs. The activation of AMPK, which is pivotal for maintaining cellular energy homeostasis, was shown to be inhibited by ATP generated from glutaminolysis. This inhibition is significant because it leads to the activation of succinyl-CoA synthetase (SUCLA2), contributes to succinate accumulation, and enhances IL-1β production.
Importantly, the abrogation of AMPKα within myeloid cells was found to promote pro-inflammatory ATMs, which were associated with decreased thermogenesis and higher obesity levels observed in mice fed high-fat diets (HFD). The proinflammatory state caused by the absence of AMPK was directly linked to enhanced IL-1β secretion—a potent inflammatory cytokine known to exacerbate obesity.
Interestingly, the study documents how SUCLA2, as the β subunit of the succinate-producing enzyme complex, is influenced by AMPK activity. Researchers observed reduced phosphorylation of SUCLA2 at Ser60, which is thought to be instrumental for its regulatory function; without AMPK activity, macrophage SUCLA2 becomes hyperactive, leading to more succinate and pro-inflammatory responses.
Through metabolic tracing experiments with [U-13C]-glutamine, it was demonstrated how glutamine-derived metabolites significantly contributed to IL-1β expression. Specific inhibitors targeting glutaminolysis effectively lowered IL-1β secretion from activated macrophages, underlining the pathway's therapeutic potential.
Beyond animal studies, the researchers investigated human adipose tissues and found correlations between SUCLA2 phosphorylation and obesity metrics. Notably, lower phosphorylated SUCLA2 levels correlated with increased inflammation indicators, providing compelling evidence supporting the connection between macrophage metabolism and obesity.
Concluding this multifaceted investigation, the researchers suggest targeting macrophage SUCLA2 could open new avenues for obesity treatment. By manipulating the AMPK-SUCLA2-IL-1β axis, it may be possible to develop therapeutic strategies to mitigate obesity-related inflammation and promote healthier metabolic states.
This research not only deepens our comprehension of obesity as a multifactorial condition involving metabolic and immune mechanisms but also holds promise for developing targeted therapies aimed at mitigating its global health impact.