Abstract
Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.
Highlights
INFLAMMATION IN INSULIN SECRETION, SENSITIVITY AND RESISTANCEType-2 diabetes (T2D) is a disease with dual etiologies, inflammatory, and metabolic
The transcription factor peroxisome proliferator-activated receptor (PPAR)-γ is highly expressed in these cells and controls Adipose tissue macrophage (ATM) oxidative metabolism and capacity to cope with a lipid-rich environment
We demonstrated that macrophage specific knockout of the G Protein Pathway Suppressor 2 (GPS2) subunit exacerbates metabolic inflammation, aggravating glucose homeostasis under metabolic stress [197]
Summary
Lucie Orliaguet 1, Elise Dalmas 1, Karima Drareni 1,2, Nicolas Venteclef 1 and Fawaz Alzaid 1*. Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization.
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