Abstract
Inflammation plays a key role in the development and progression of type-2 diabetes (T2D), a disease characterised by peripheral insulin resistance and systemic glucolipotoxicity. Visceral adipose tissue (AT) is the main source of inflammation early in the disease course. Macrophages are innate immune cells that populate all peripheral tissues, including AT. Dysregulated AT macrophage (ATM) responses to microenvironmental changes are at the root of aberrant inflammation and development of insulin resistance, locally and systemically. The inflammatory activation of macrophages is regulated at multiple levels: cell surface receptor stimulation, intracellular signalling, transcriptional and metabolic levels. This review will cover the main mechanisms involved in AT inflammation and insulin resistance in T2D. First, we will describe the physiological and pathological changes in AT that lead to inflammation and insulin resistance. We will next focus on the transcriptional and metabolic mechanisms described that lead to the activation of ATMs. We will discuss more novel metabolic mechanisms that influence macrophage polarisation in other disease or tissue contexts that may be relevant to future work in insulin resistance and T2D.
Highlights
Physiology and Pathology of Adipose TissueThe physiological role of adipose tissue (AT) is long-term energy storage in the form of fat, and depending on the AT depot, this fat provides protection and insulation
Throughout the development of obesity, insulin resistance and type-2 diabetes (T2D), AT macrophage (ATM) increase in number to represent up to 50% of cells in AT [1]
Mice with a myeloid-deficiency of IRF5 have improved metabolic homeostasis upon high-fat feeding, lower AT inflammation and redistribution of AT from the visceral depot towards the subcutaneous depot. This phenomenon is mediated by alternatively activated macrophages that restrict adipocyte growth and promote a hyperplasic and metabolically protective response upon diet-induced obesity. This phenotype is comparable to that of TLR4-deficient mice, indicating that the TLR4–IRF5 axis of macrophage polarisation may be conserved in metabolic inflammation [72]
Summary
The physiological role of adipose tissue (AT) is long-term energy storage in the form of fat, and depending on the AT depot, this fat provides protection and insulation. Macrophages represent one of the most dynamic cells in this fraction of adipose tissue and are key actors of inflammation and the development of insulin resistance. Whilst progress has been made in defining cell lineages and differentiation trajectories, single-cell analyses and high density in situ analytical methods have only started to unravel the metabolic and transcriptional specificities of ATM subsets relative to other macrophages (monocyte-derived, peritoneal, Kupffer or red pulp). In this light, the current review brings together the established transcriptional and metabolic mechanisms that dictate macrophage effector functions and inflammatory polarisation in contexts relevant to insulin resistance and T2D
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