Meta-Inflammation and Metabolic Reprogramming of Macrophages in Diabetes and Obesity: The Importance of Metabolites

Abstract

Diabetes mellitus type II and obesity are two important causes of death in modern society. They are characterized by low-grade chronic inflammation and metabolic dysfunction (meta-inflammation), which is observed in all tissues involved in energy homeostasis. A substantial body of evidence has established an important role for macrophages in these tissues during the development of diabetes mellitus type II and obesity. Macrophages can activate into specialized subsets by cues from their microenvironment to handle a variety of tasks. Many different subsets have been described and in diabetes/obesity literature two main classifications are widely used that are also defined by differential metabolic reprogramming taking place to fuel their main functions. Classically activated, pro-inflammatory macrophages (often referred to as M1) favor glycolysis, produce lactate instead of metabolizing pyruvate to acetyl-CoA, and have a tricarboxylic acid cycle that is interrupted at two points. Alternatively activated macrophages (often referred to as M2) mainly use beta-oxidation of fatty acids and oxidative phosphorylation to create energy-rich molecules such as ATP and are involved in tissue repair and downregulation of inflammation. Since diabetes type II and obesity are characterized by metabolic alterations at the organism level, these alterations may also induce changes in macrophage metabolism resulting in unique macrophage activation patterns in diabetes and obesity. This review describes the interactions between metabolic reprogramming of macrophages and conditions of metabolic dysfunction like diabetes and obesity. We also focus on different possibilities of measuring a range of metabolites intra-and extracellularly in a precise and comprehensive manner to better identify the subsets of polarized macrophages that are unique to diabetes and obesity. Advantages and disadvantages of the currently most widely used metabolite analysis approaches are highlighted. We further describe how their combined use may serve to provide a comprehensive overview of the metabolic changes that take place intracellularly during macrophage activation in conditions like diabetes and obesity.

Polydextrose Alleviates Adipose Tissue Inflammation and Modulates the Gut Microbiota in High-Fat Diet-Fed Mice

“…Previous studies have indicated that gut microbiota dysbiosis is one of the reasons for obesity and related disorders, and fecal microbial transplantation (FMT) is considered a potential source of novel therapeutics (Napolitano and Covasa, 2020;He et al, 2021;Voland et al, 2021). FMT from the obesity-associated human gut microbiota to mice can induce vascular dysfunction and glucose intolerance, and FMT from lean donors to patients with obesity can promote metabolic benefits (Mocanu et al, 2021;Russo et al, 2021). Recent studies over the past decade have revealed that many environmental factors, including diet, antibiotic exposure, energy intake and exercise, can dramatically influence the gut microbiota (Du et al, 2021;Giordan et al, 2021;Shi et al, 2021).…”

“…LPS can recognize toll-like receptor 4 (TLR4) and then activate NF-κB signaling, which promotes the secretion of MCP1 and recruitment of proinflammatory macrophages (Catrysse and van Loo, 2017). Furthermore, obesity leads to release of proinflammatory mediators such as IL-1β, IL-6 and MCP-1, and then causes circulating monocytes recruitment and macrophages accumulation in adipose tissue (Russo et al, 2021). Our results showed that PDX treatment reduced serum LPS and IL6 levels and significantly inhibited NF-κB signaling in the epididymal adipose tissue of HFD-fed mice.…”

“…Macrophages are generally classified into the M1 (expressing high levels of CD11c, TNF-α, IL-1β, IL-6, and Nos2) and M2 (expressing high levels of CD206, CD163, IL-10, IL-4, Arg1, Fizz1, Mrc1, and PPARγ) phenotypes, which represent proinflammatory and anti-inflammatory macrophages, respectively (Shapouri-Moghaddam et al, 2018). M1 macrophages can promote glycolysis to produce lactate instead of metabolizing pyruvate to acetyl-CoA, and M2 macrophages favor beta-oxidation of fatty acids and oxidative phosphorylation to produce energy-rich molecules, which are beneficial to tissue repair and anti-inflammation (Russo et al, 2021). We found that HFD increased infiltration of M1 macrophages and reduced M2 macrophages.…”

Macrophages: shapes and functions

“…Classically activated, proinflammatory M1 macrophages depend to a large extent on glycolysis and produce lactate as the tricarboxylic acid cycle is blocked at two steps. Alternatively activated M2 macrophages prefer β-oxidation and oxidative phosphorylation to synthesize ATP (for an excellent review, see [ 61 ]). It is well established that continuous and excessive inflammatory stimuli, e.g., in various inflammatory and metabolic diseases, including T2DM, lead to macrophage activation.…”

Auricular Transcutaneous Vagus Nerve Stimulation may Increase the Risk of Mild-COVID-19 Infection or of Herpetic Flare: Is there a Role of Microbiota?

“…Many factors favour the occurrence of symptomatic COVID-19, especially aging, diabetes, heart disease or obesity [52][53][54][55]. All these clinical conditions are associated with microglial inflammation (microglial type 1 status) [56,57].…”