SignificanceAdipose tissue macrophages (ATMs) maintain adipose tissue homeostasis. However, during obesity ATMs become inflammatory, resulting in impaired adipose tissue function. Oxidative stress increases during obesity, which is thought to contribute to adipose tissue inflammation. To date, the connection between oxidative stress and adipose tissue inflammation remain unclear. In this study, we identify two classes of phospholipid oxidation products in lean and obese adipose tissue, which polarize macrophages to an antioxidant or proinflammatory state, respectively. Furthermore, we show that these phospholipids differently affect macrophage cellular metabolism, reflecting the metabolisms of ATMs found in lean and obese adipose tissue. Identification of pathways controlling ATM metabolism will lead to novel therapies for insulin resistance.

ObjectiveMacrophages control tissue homeostasis and inflammation by sensing and responding to environmental cues. However, the metabolic adaptation of macrophages to oxidative tissue damage and its translation into inflammatory mechanisms remains enigmatic.MethodsHere we identify the critical regulatory pathways that are induced by endogenous oxidation-derived DAMPs (oxidized phospholipids, OxPL) in vitro, leading to formation of a unique redox-regulatory metabolic phenotype (Mox), which is strikingly different from conventional classical or alternative macrophage activation.ResultsUnexpectedly, metabolomic analyses demonstrated that Mox heavily rely on glucose metabolism and the pentose phosphate pathway (PPP) to support GSH production and Nrf2-dependent antioxidant gene expression. While the metabolic adaptation of macrophages to OxPL involved transient suppression of aerobic glycolysis, it also led to upregulation of inflammatory gene expression. In contrast to classically activated (M1) macrophages, Hif1α mediated expression of OxPL-induced Glut1 and VEGF but was dispensable for Il1β expression. Mechanistically, we show that OxPL suppress mitochondrial respiration via TLR2-dependent ceramide production, redirecting TCA metabolites to GSH synthesis. Finally, we identify spleen tyrosine kinase (Syk) as a critical downstream signaling mediator that translates OxPL-induced effects into ceramide production and inflammatory gene regulation.ConclusionsTogether, these data demonstrate the metabolic and bioenergetic requirements that enable macrophages to translate tissue oxidation status into either antioxidant or inflammatory responses via sensing OxPL. Targeting dysregulated redox homeostasis in macrophages could therefore lead to novel therapies to treat chronic inflammation.

Highlights d Identification of MCU as a major regulator of phagosomal killing by macrophages d Mice lacking Mcu in myeloid cells are highly susceptible to in vivo candidiasis d Fungal pathogens elicit mCa 2+ elevations using a fast twophase Ca 2+ relay d mCa 2+ signaling activates pyruvate dehydrogenase during phagocytosis

Insulin secretion from β-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of β-cells elicit secretory defects associated with type-1 or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics. We show that this behavior is correlated with two subpopulations of insulin granules whose relative abundance is differentially shifted depending on diabetic model condition. The two types of granules have different release characteristics, distinct lipid and protein compositions, and package different secretory contents alongside insulin. This complexity of β-cell secretory physiology establishes a direct link between granule subpopulation and type of diabetes and leads to a revised model of secretory changes in the diabetogenic process.