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Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals with obesity, liver lesions in steatosis and steatohepatitis, and the intestinal lamina propria. LAMs can also emerge in the metabolically demanding microenvironment of certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, and self-renewal, and, ultimately, their acute and chronic functional impact on the development of metabolic diseases. Further studies need to clarify whether and under which circumstances LAMs drive disease progression or resolution and how their phenotype can be modulated to ameliorate metabolic disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB-mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases., Competing Interests: The authors declare no competing interest.

Macrophages are cells of the innate immune system that play myriad roles in the body. Macrophages are known to reside in endocrine glands, and a body of evidence now suggests that these cells interact closely with endocrine cells. Immune-endocrine interactions are important in the development of endocrine glands and their functioning during physiological states, and also become key players in pathophysiological states. Through gene expression profiling, diverse subpopulations of tissue macrophages have been discovered within endocrine organs; this has important implications for disease pathogenesis and potential pharmacotherapy. The molecular basis for the crosstalk between macrophages and endocrine cells is being unraveled, and allows the identification of multiple points for pharmacologic intervention. Macrophages in adipose tissue and pancreatic islets are key players in the process of metaflammation (metabolic inflammation) that underlies the development of insulin resistance, metabolic syndrome, diabetes mellitus, and non-alcoholic fatty liver disease. In the ovary, they play important roles in ovarian folliculogenesis and ovulation, whereas in the male reproductive tract they regulate spermatogenesis through the regulation of steroidogenesis by Leydig cells. We summarize the diverse roles played by macrophages in the endocrine system and identify potential targets for pharmacotherapy in endocrine disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Metaflammation is responsible for several metabolic syndromes, such as type 2 diabetes. However, the mechanisms by which metabolic disorders trigger metaflammation remain unclear. We identified a cell type-specific downregulation of CD1d expression in M2 macrophages during the progression of obesity prior to the onset of inflammation in visceral adipose tissues. A reduction in CD1d expression influenced the ability of M2 macrophages to present antigens and caused a change in antigen-presenting cells from M2 macrophages to M1 macrophages. With CD1d conditional knockout (KO) mice, we further demonstrated that natural killer T (NKT) cell activation by M2 macrophages inhibited metaflammation and insulin resistance by promoting Th2 responses and M2 polarization in visceral adipose tissues of obese mice, whereas NKT cell activation by M1 macrophages exacerbated metaflammation and insulin resistance by promoting Th1 responses and inhibiting M2 polarization. Our results suggest that an M2-specific reduction of CD1d is an initiating event that switches NKT cell-mediated immune responses and disrupts the immune balance in visceral adipose tissues in obese mice.

Macrophage differentiation and signal responses are coordinated by closely linked transcriptional and epigenomic mechanisms that trigger gene expression. In contrast to well-characterized transcriptional activation pathways in response to diverse metabolic and inflammatory signals, we just begin appreciating that transcriptional repression is equally important. Here, we will highlight macrophage pathways that are controlled by multifaceted repression events, along with a discussion of underlying regulatory mechanisms and components. We will particularly discuss pro- versus anti-inflammatory action of a fundamental corepressor complex, transcription factor cross-talk, repression at enhancers and during elongation, and diverse corepressor knockout mouse models. We will finally emphasize how alterations of macrophage repression pathways in humans contribute to, or even cause, metabolic inflammatory diseases such as obesity and type 2 diabetes., (© 2017 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The steadily increasing obesity epidemic affects currently 30% of western populations and is causative for numerous disorders. It has been demonstrated that immune cells such as macrophages reside in or infiltrate metabolic organs under obese conditions and cause the so-called low-grade inflammation or metaflammation that impairs insulin action thus leading to the development of insulin resistance. Here, we report on data that specifically address macrophage biology/physiology in obesity-induced inflammation and insulin resistance.

Overnutrition triggers obesity and metabolic dysregulation, causing metaflammation. D-allulose, exhibits anti-obesity and hypoglycemic benefits. However, its involvement in metaflammation remains incompletely understood. In this study, high-fat diet-fed mice were supplemented with 300 mg/kg of D-allulose for 60 days. Levels of inflammation in various tissues, changes in intestinal barrier function, and gut microbiota composition, which serve as key markers of metaflammation, were analyzed. We foud that D-allulose significantly attenuated HFD-induced metaflammation, evidenced by a reduction in inflammation levels and in the activation of proinflammatory macrophages in adipose tissue. Additionally, D-allulose effectively restored impaired intestinal barrier function in HFD-fed mice by enhancing the expression of tight junction proteins, replenishing goblet cell populations, and modulating intestinal flora composition, which improved intestinal barrier integrity and contributed to the attenuation of metaflammation. Our findings highlight the potential of D-allulose in obesity and metaflammation management and provide new directions for future applications and advancements of D-allulose.

[Display omitted] • D-allulose significantly reduced metaflammation induced by HFD. • D-allulose alleviated the activation of metabolically activated macrophages (MMe) in adipose tissue. • D-allulose restored the intestinal barrier function and reduce circulating LPS levels. • D-allulose improved the HFD-induced changes in the composition of intestinal flora. Overnutrition triggers obesity and metabolic dysregulation, causing metaflammation. D-allulose, exhibits anti-obesity and hypoglycemic benefits. However, its involvement in metaflammation remains incompletely understood. In this study, high-fat diet-fed mice were supplemented with 300 mg/kg of D-allulose for 60 days. Levels of inflammation in various tissues, changes in intestinal barrier function, and gut microbiota composition, which serve as key markers of metaflammation, were analyzed. We foud that D-allulose significantly attenuated HFD-induced metaflammation, evidenced by a reduction in inflammation levels and in the activation of proinflammatory macrophages in adipose tissue. Additionally, D-allulose effectively restored impaired intestinal barrier function in HFD-fed mice by enhancing the expression of tight junction proteins, replenishing goblet cell populations, and modulating intestinal flora composition, which improved intestinal barrier integrity and contributed to the attenuation of metaflammation. Our findings highlight the potential of D-allulose in obesity and metaflammation management and provide new directions for future applications and advancements of D-allulose. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a classic metaflammatory disease, and the inflammatory states of the pancreatic islet and insulin target organs have been well confirmed. However, abundant evidence demonstrates that there are countless connections between these organs in the presence of a low degree of inflammation. In this review, we focus on cell-cell crosstalk among local cells in the islet and organ-organ crosstalk among insulin-related organs. In contrast to that in acute inflammation, macrophages are the dominant immune cells causing inflammation in the islets and insulin target organs in T2DM. In the inflammatory microenvironment (IME) of the islet, cell-cell crosstalk involving local macrophage polarization and proinflammatory cytokine production impair insulin secretion by β-cells. Furthermore, organ-organ crosstalk, including the gut-brain-pancreas axis and interactions among insulin-related organs during inflammation, reduces insulin sensitivity and induces endocrine dysfunction. Therefore, this crosstalk ultimately results in a cascade leading to β-cell dysfunction. These findings could have broad implications for therapies aimed at treating T2DM. [Display omitted] • T2DM is a systemic metaflammatory disease, including multiple interactions between the immune response and metabolism. • Under normal conditions, islet-resident macrophages make an essential contribution to maintain β-cell mass and proliferation. • Crosstalk between M1-like macrophages and β-cells in the inflammatory condition leads to β-cell apoptosis and dysfunction. • Gut absorbs excess nutrition to cause hypothalamus inflammation and energy imbalance. • Crosstalk among inflammatory insulin-related organs induces insulin resistance and β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.

The steadily increasing obesity epidemic affects currently 30% of western populations and is causative for numerous disorders. It has been demonstrated that immune cells such as macrophages reside in or infiltrate metabolic organs under obese conditions and cause the so-called low-grade inflammation or metaflammation that impairs insulin action thus leading to the development of insulin resistance. Here, we report on data that specifically address macrophage biology/physiology in obesity-induced inflammation and insulin resistance. [ABSTRACT FROM AUTHOR]

Summary Obesity induced inflammation acts as a reflex produced due to altered metabolic homeostasis in accordance to the nutrient overload on the metabolic cells. It involves up-regulation of the genes encoding for cytokines, chemokines and other inflammatory mediators through activated transcription factors – nuclear factor-kB, activator protein-1, nuclear factor of activated T cells and signal transducer and activator of transcription 3. These execute macromolecular innate immune cell sensor – inflammasome to activate caspase-1 pathway resulting in proteolytic maturation. Secretion of pro-inflammatory cytokines including TNF-α, IL-6, CRP, IL-1β, etc. from the M1 macrophages of white adipose tissue is increased, whereas there occurs a steep decline in the production of anti-inflammatory cytokines like IL-10, IL-Ra, adiponectin. Not only the adipose tissue, but also the immune cells, liver, brain, muscles and pancreas suffers from the inflammatory insult during obese condition and are exaggeratedly affected. The inflammatory kinases like JNK and IKK apart from inhibiting insulin action and glucose uptake, down-regulate transcriptional process resulting in increased expression of pro-inflammatory cytokines. Macrophage-like Kupffer cells initiate the inflammatory process in the liver preceding the inflammatory signals produced by the white adipose tissue which may further lead to hepatic-necro-inflammation. The muscle-fibre is affected by the cytokines and therefore results in decreased glycogen synthesis. The triggered hypothalamic–pituitary–adrenal axis further affects the expression of inflammatory cytokines thus altering insulin homeostasis and initiating glucose intolerance. Anti-inflammatory treatment so as to curb the severity of inflammatory responses includes administration of synthetic drugs to target the actual inflammatory molecules and various therapeutic interventions. [ABSTRACT FROM AUTHOR]

Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: to limit inflammasome priming and metaflammation. [ABSTRACT FROM AUTHOR]

Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance. [ABSTRACT FROM AUTHOR]