Neutrophils: Key players in the metabolic syndrome puzzle

Metabolic syndrome (MetS) is a group of metabolic abnormalities associated with an increased risk of getting type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). For many years, MetS has been viewed solely as a metabolic disease. In recent decades, MetS development has been associated with chronic inflammation related to nutrient excess, especially in the adipose tissues (AT). Metabolic stress, arising from the significant metabolic changes in MetS, is known to impact the balance of immune homeostasis. Although multiple immune cells have been investigated in this context, neutrophils, the first responder to inflammation, have only gained increased attention in recent years. Hence, this review aims to summarize the current evidence for the effects of MetS-induced systemic and AT-specific metabolic changes on neutrophils and their functions. We first provide an overview of the metabolic pathways used by neutrophils, with a specific focus on their recently discovered metabolic plasticity. This is followed by a discussion on the impact of MetS-induced alterations on the systemic metabolism and in the AT environment, how these changes may affect neutrophil effector functions, and the main mechanisms involved. Finally, we will examine the roles of neutrophils and their functions in T2DM and CVD that develop due to MetS. We will also provide perspectives on how a deeper understanding of the effects of systemic and site-specific metabolic changes in neutrophils and their effector functions could unlock the therapeutic potential of targeting neutrophils, as the arbiters of innate immunity in the context of MetS.