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Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation

Abstract

In obesity, nutrient excess and altered adipocyte secretory profiles reprogram cell-intrinsic metabolism, leading to the activation of immune cells within metabolically active tissues such as adipose tissue. This obesity-associated chronic low-grade metabolic inflammation (often referred to as metaflammation) is a well-established driver of insulin resistance and metabolic dysfunction. However, several lines of emerging evidence suggest that metaflammation is not merely a pathologic process, but may also serve as an adaptive response that supports metabolic homeostasis, particularly at the early stages of obesity. This Essay discusses immunometabolic mechanisms underlying the dual nature of metaflammation in obesity, highlighting how its initially beneficial effects can transition into detrimental outcomes.

Citation: Lee YS (2026) Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation. PLoS Biol 24(1): e3003620. https://doi.org/10.1371/journal.pbio.3003620

Academic Editor: Claudio Mauro, University of Birmingham, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND

Published: January 21, 2026

Copyright: © 2026 Yun Sok Lee. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) (DK124298, DK063491, and DK120515), the National Heart, Lung, and Blood Institute (HL142214), and a UCSD Health Sciences Research Grant (RG084153) to Y.S.L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The author has declared that no competing interests exist.

Abbreviations: ACh, acetylcholine; ATMs, adipose tissue macrophages; ChAM, acetylcholine-synthesizing ATM; ER, endoplasmic reticulum; FFA, free fatty acid; HFD, high-fat diet; IKKβ, IκB kinase β; LAMs, lipid-associated ATMs; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; MMe, metabolic activation state; M-IR, insulin resistance-inducing macrophage; NE, norepinephrine; NK, natural killer cells; NO, nitric oxide; ROS, reactive oxygen species; SAMs, sympathetic neuron-associated macrophages; SAT, subcutaneous adipose tissue; SNS, sympathetic nervous system; SPMs, specialized pro-resolving mediators; T2D, type 2 diabetes mellitus; Treg, regulatory T

Introduction

The incidence of obesity is rapidly increasing across the globe and has now reached epidemic proportions [1]. Obesity is a major risk factor for metabolic syndrome, a cluster of conditions that increase the risk of cardiovascular disease and type 2 diabetes mellitus (T2D). Therefore, the ongoing global obesity epidemic can be seen as the primary driver behind the increasing prevalence of metabolic disorders [2]. Although several pathways have been proposed to explain how obesity contributes to the development of metabolic syndrome, the underlying mechanisms remain incompletely understood. A critical factor in this link is insulin resistance. Obesity is the most prevalent cause of insulin resistance in humans. As insulin resistance develops, the pancreatic beta cells typically compensate by increasing insulin secretion to maintain blood glucose levels within a normal range. However, when beta cells can no longer sustain hyperinsulinemia, blood glucose levels are persistently increased (i.e., in T2D). Multiple mechanisms have been proposed for the cause of obesity-associated insulin resistance and beta cell dysfunction [3–12]. In this Essay, I focus on chronic metabolic inflammation (often referred to as metaflammation), with a particular focus on the mechanisms by which obesity triggers metaflammation and how these processes subsequently influence insulin sensitivity and glucose and lipid metabolism, processes that are collectively encompassed by the concept of immunometabolism [13].

One of the seminal studies suggesting a direct effect of chronic inflammation in glycemic control was conducted by Grunfeld and Feingold. Their research demonstrated that administration of TNF induces hyperglycemia without altering plasma insulin levels in rodents [14]. The connection between obesity-induced insulin resistance and inflammation was first suggested in other early landmark studies by Hotamisligil and Spiegelman, showing that TNF levels are elevated in the adipose tissue of obese mice and that neutralizing TNF ameliorates insulin resistance [15,16]. These findings established a foundational understanding that inflammation can directly contribute to the development of insulin resistance and impaired glycemic control in obesity. In 2003, two studies published concurrently demonstrated that obesity-induced inflammation is associated with increased macrophage accumulation in adipose tissue [17,18]. This was seen in both mouse and human adipose tissue. To date, numerous studies have revealed that chronic obesity is associated with increased levels of various immune cell types (including macrophages), cytokines, chemokines (such as CCL2/MCP-1 and IL-1β), as well as other molecules within proximal pro-inflammatory signaling pathways (including JNK and IKKβ). Chronic increases in these pro-inflammatory mediators can impair insulin signaling in classical insulin target tissues, such as the liver, skeletal muscle, and adipose tissue [13,19–26]. While these concepts are largely derived from studies in rodents, studies in human adipose tissue [27–29], liver [30,31], primary adipocytes [32], skeletal muscle [33], pancreatic islets [34], and organoids [35] also support these concepts [36]. Plasma levels of pro-inflammatory cytokines, chemokines, and other related soluble factors (such as TNF, CCL2, IL-6, and PAI-1) are elevated in obese individuals compared with lean individuals. Levels of some of these factors, in particular PAI-1, can predict the severity of insulin resistance and the development of metabolic dysfunction-associated steatotic liver disease (MASLD) among obese individuals [37–39]. Intriguingly, however, emerging evidence also suggests that acute inflammatory responses may paradoxically support metabolic adaptation during the early stages of obesity. This Essay explores these seemingly dichotomous facets of metaflammation.

The dual facets of metaflammation

Because inflammatory responses are detected at an early stage during the development of obesity and are typically associated with insulin resistance in obese individuals and in animal models of obesity, previous studies have mostly focused on how inflammation affects insulin resistance and metabolic dysfunction [13,40,41]. The proposed mechanisms are largely associated with proximal pro-inflammatory pathways, including TNF, IL-1β, and the CCL2–CCR2 system. However, clinical studies of agents targeting these pathways have raised safety concerns and shown disappointing efficacy, although some showed positive metabolic effects [19,42–47]. Indeed, inflammation is a physiological process necessary for defending the body against infection and tissue injury and for promoting tissue repair [48]. Moreover, although inflammation contributes to the development of insulin resistance and glucose intolerance in the context of chronic obesity, at the early stages of obesity, inflammation is not necessary for the development of these metabolic abnormalities [49,50]. For example, while depletion of macrophages, loss of lymphocytes (via Rag1 deficiency), or inhibition of pro-inflammatory immune cell activation (via hematopoietic cell-specific JNK deficiency) all protect mice from insulin resistance and glucose intolerance in the context of chronic obesity, these same strategies do not prevent the development of insulin resistance and glucose intolerance in mice fed a short term 1 week) high-fat diet (HFD) [49]. Furthermore, in humans, acute weight gain from one week of high-calorie intake leads to the development of insulin resistance without inflammation [50]. Instead, evidence indicates that certain acute inflammatory pathways activated at an early stage during the development of obesity contribute to maintaining vascular density and integrity, regulating local iron levels and lipolysis, clearing extracellular lipids and dead cell debris, supporting adipose tissue expandability, healthy remodeling of adipose tissue, and safe storage of excess lipids [51–55]. For example, although inhibiting TNF signaling using a neutralizing antibody after the onset of obesity improves metabolic abnormalities (at least, in rodents) [15], blocking early TNF or NF-κB signaling in adipocytes restricts adipose tissue expansion (by reducing adipogenesis) during HFD and exacerbates adipocyte hypertrophy, liver steatosis, glucose, and insulin intolerance in mice [54,56]. Likewise, adipocyte-specific depletion of TLR4 worsens insulin resistance and glucose intolerance in obese mice [55], although global or hematopoietic cell-specific TLR4 depletion, or global depletion of a TLR4 coreceptor CD14, ameliorates adipose tissue inflammation and insulin resistance in chronically obese mice [57,58–61]. These results suggest that while metaflammation generally has a key role in the development of insulin resistance in chronic established obesity, it is dispensable for triggering insulin resistance and metabolic dysfunction in the early stages of obesity. And specific inflammatory pathways (particularly within adipocytes) support the maintenance of metabolic homeostasis [62].

Similar to this concept, the well-known pro-inflammatory IκB kinase β (IKKβ) signaling pathway not only induces insulin resistance and metabolic dysfunction, but can also contribute to metabolic homeostasis, depending on when and where it is activated. For example, systemic haplodeficiency of Ikbkb (the gene encoding IKKβ) protects from the development of insulin resistance and glucose intolerance in obese mice [63]. Moreover, global IKKβ deficiency prevents the onset of muscle insulin resistance in mice infused with lipids [64], indicating that IKKβ is necessary for the development of insulin resistance and glucose intolerance induced by both acute lipid exposure and chronic obesity. Tissue-specific genetic manipulations have delineated the compartmental contributions of IKKβ: myeloid lineage-specific IKKβ depletion attenuates systemic inflammation and ameliorates insulin resistance in obese mice, whereas hepatocyte-specific IKKβ depletion or IKKβ inactivation (via hepatocyte-specific IκB overexpression) selectively improves liver-specific insulin sensitivity [65]. Conversely, hepatocyte-specific overexpression of constitutively active IKKβ impairs hepatic insulin action in lean mice [66], indicating that (sub)chronic baseline IKKβ hyperactivity alone is sufficient to cause hepatic insulin resistance. Notably, however, physiological post-prandial activation of hepatocyte IKKβ phosphorylates and activates XBP1, thereby facilitating adaptive responses to endoplasmic reticulum (ER) stress and maintaining metabolic homeostasis. In obesity, this beneficial hepatic IKKβ–XBP1 axis is attenuated. Genetic manipulation to further increase hepatocyte-specific IKKβ in the liver of obese mice alleviates ER stress and improves glucose metabolism [67]. Furthermore, in adipocytes, IKKβ enhances adipose tissue inflammation, but improves (not worsens) insulin sensitivity in mice fed a HFD by promoting the production of the anti-inflammatory cytokine IL-13 [68]. Therefore, it appears that precise spatiotemporal regulation of IKKβ pro-inflammatory activity is essential for maintaining metabolic homeostasis.

These results suggest that not all facets of metaflammation are pathogenic and that its metabolic impact depends critically on when, where, and how metaflammation occurs, affecting specific tissue functions rather than individual factors that exert a uniform systemic effect. Consistent with this view, although the expression of most pro-inflammatory cytokines is elevated in obese versus lean individuals and they are biologically active within induced tissue sites (e.g., adipose tissue), their systemic plasma concentrations (with the exception of PAI-1) are comparable between metabolically healthy and unhealthy obesity and often remain below the levels required to elicit insulin resistance [69].

It is interesting to note that adipose tissue inflammation is induced not only in the context of obesity but also during weight loss. For example, prolonged calorie restriction and weight loss increase the number of adipose tissue macrophages (ATMs) in nonobese individuals [70,71]. Similarly, the abundance of ATMs displays a transient increase within 3–7 days following weight loss in mice maintained on normal chow diet (lean) or HFD (obese) regimens [71], which gradually declines over time and is eventually normalized [72]. However, this acute increase in the number of ATMs during weight loss does not raise pro-inflammatory cytokine expression in ATMs or adipose tissue [72]. Instead, it accompanies increased lipid uptake by ATMs and upregulates lipid metabolism genes in adipocytes [71]. Depletion of macrophages using clodronate liposomes enhances fasting-induced adipose tissue lipolysis and raises plasma free fatty acid (FFA) levels, suggesting that ATMs are necessary for tempering excess lipid release from adipose tissue during weight loss. These observations align with the perspective that inflammation serves as an adaptive response rather than solely as a pathological process, and also highlights the importance of qualitative rather than merely quantitative alterations in ATM abundance and other inflammation metrics. Probably due to this inherent complexity, although weight loss eventually leads to improvements in metaflammation, depending on the experimental timeline, it is often observed that the numbers of ATMs remain elevated for weeks during weight loss, even when metabolic improvements (e.g., glucose tolerance and insulin sensitivity) manifest [37,73–76]. This is often cited as evidence for questioning the causal role of inflammation in obesity-induced metabolic dysfunction [77,78]. However, specific characteristics of inflammation (including the predominant ATM subtypes and their attendant gene expression profiles) induced during weight gain (obesity) versus weight loss may substantially diverge between these states [79]. Therefore, it is likely that metaflammation is not inherently pathological, but rather its impact on metabolic health is dependent upon contextual determinants, the acuity versus chronicity of the inflammatory response, and the specific constituents of the inflammatory milieu. Delineating the molecular determinants governing the transition from protective to detrimental metaflammation during the development of obesity will be imperative in the future.

Initiation of metaflammation

Metaflammation is characterized by distinct immune cell composition, cytokine profiles, and histologic features compared with classical infection-induced inflammation, despite sharing some common features [13]. Although unique molecular signatures continue to be identified, one of the most widely used indicators of metaflammation is increased expression of pro-inflammatory cytokines and chemokines, accompanied by the accumulation of macrophages in metabolically active tissues, particularly adipose tissue. When these parameters are used to assess metaflammation during the development of obesity, increased expression of pro-inflammatory cytokines and infiltration of macrophages can be detected in visceral adipose tissue (VAT) as early as three days after starting a HFD [49,80–82]. This occurs before other peripheral tissues, including subcutaneous adipose tissue (SAT), liver, and skeletal muscle, show signs of inflammation. As obesity develops, VAT inflammation intensifies, paralleling a progressive decline in insulin sensitivity and glucose tolerance [49]. For example, in lean/healthy mice, macrophages constitute approximately 5%–10% of stromal vascular cells in VAT. After 7 days on a HFD, the proportion of ATMs is increased by 15%−25%, accompanied by a 34% decrease in systemic insulin sensitivity, as measured by glucose infusion rate during hyperinsulinemic-euglycemic clamp studies. This trend continues with prolonged HFD and, once obesity becomes fully established, these changes tend to plateau with ATMs making up as much as 40% of all stromal vascular cells, and systemic insulin sensitivity declining by as much as 77% [49]. Inhibition of adipose tissue inflammation through targeted depletion of adipocyte-specific JNK, HIF-1α, or CCL2 (which promotes immune cell infiltration into adipose tissue and activation) improves insulin resistance in adipose tissue, liver, and skeletal muscle and mitigates glucose intolerance in obese mice [83–88], highlighting the primacy of adipose tissue inflammation in systemic insulin action and glycemic control in chronic obesity.

The mechanism by which obesity induces adipose tissue inflammation involves the accumulation of cellular stress (such as metabolic stress, oxidative stress, or hypoxia) and the activation of stress response pathways (such as increased expression of HIF-1α and unfolded protein response; Fig 1). As the earliest change that can trigger metaflammation, adipose tissue hypoxia can be detected as early as 1 day after starting a HFD. The decrease in oxygen tension occurs selectively in adipose tissue and is not observed in skeletal muscle (when measured at a sedentary condition), kidney, or the liver (albeit the liver develops a relatively moderate hypoxia at the later stages of obesity) [89–91]. At the molecular level, elevated levels of FFAs (from either chylomicrons or increased lipolysis) induce an ANT2-dependent increase in mitochondrial oxygen consumption in adipocytes. In addition, as adipose tissue expands, its growth outpaces the development of new blood vessels (vascularization) required to deliver sufficient oxygen [62,92–96]. Furthermore, increased infiltration of immune cells and (myo)fibroblasts in chronic obesity can further raise adipose tissue oxygen demand. These changes collectively lead to the decreases in adipose tissue oxygen tension (hypoxia) and a subsequent increase in HIF-1α expression [84,90]. HIF-1α induces the expression of genes that facilitate adaptation to low oxygen concentration, including those involved in anaerobic metabolism (e.g., Slc2a1 and Pdk1) and angiogenesis (e.g., Vegf and various chemokines). While acute increases in VEGF, pro-inflammatory cytokines (IL-6), chemokines (CCL2), and lipokines (leukotriene B4) mediated by HIF-1α promote endothelial cell recruitment and angiogenesis, chronic increases therein drive the recruitment of circulating monocytes, which differentiate into pro-inflammatory ATMs [25,84,87,97,98]. Moreover, CCL2 promotes ATM proliferation [99]. HIF-1α further elicits fibrogenic gene expression, leading to adipose tissue fibrosis and endotrophin production, which in turn amplifies inflammation [88,100–102]. Concomitantly, HIF-1α upregulates Nos2, Slc2a1, and Pdk1, thereby augmenting nitric oxide (NO) and lactate production. Elevated NO levels induce S-nitrosylation of critical insulin signaling components, impairing their functionality and contributing to insulin resistance in adipose tissue. Furthermore, lactate generated by hypoxic adipocytes in obesity is released into the systemic circulation, where it serves as a substrate for hepatic gluconeogenesis, ultimately contributing to hyperglycemia. Adipocyte-specific overexpression of a constitutively active form of HIF-1α is sufficient to induce adipose tissue inflammation and fibrosis in mice fed a normal chow diet [103]. Conversely, pharmacological inhibition of HIF-1α, genetic deletion of adipocyte-specific Hif1a, or adipocyte-specific overexpression of a dominant-negative form of HIF-1α ameliorates adipose tissue inflammation, as well as insulin resistance and glucose tolerance, in obese mice [84–86,88,104]. These effects are predominantly mediated by HIF-1α, but not HIF-2α [84,105–107], although HIF-1α shares structural similarities and several common target genes with HIF-2α. Taken together, these results suggest that adipose tissue hypoxia and HIF-1α have a central role in triggering metaflammation, and that metaflammation begins as an adaptive response to increased oxygen demand and metabolic stress, although it eventually leads to metabolic dysfunction.

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Fig 1. Initiation of metaflammation in adipose tissue.

Early during the development of obesity, metaflammation first emerges in visceral adipose tissue as an adaptive response to increased oxygen demand, relative hypoxia, and metabolic stress (e.g., ER stress and oxidative stress). While these changes primarily accumulate within adipocytes, prolonged nutrient excess and resulting alterations in adipocyte secretory profiles promote changes in immune cell populations (including macrophages), thereby amplifying the inflammatory response.

https://doi.org/10.1371/journal.pbio.3003620.g001

Expansion and propagation of metaflammation

Adipose tissue hypoxia persists throughout chronic obesity in both mice [84,90,91,101,108,109] and humans [90,110–113] (although some studies in humans have reported contradictory findings [114,115]). Adipose tissue oxygenation correlates with insulin sensitivity in obese individuals [113]. Moreover, as obesity progresses in a (sub)chronic manner, sustained nutrient excess disrupts lipid metabolism, increasing the phosphatidylcholine/phosphatidylethanolamine ratio in the ER membrane [116–118]. This imbalance impairs sarco/ER calcium ATPase function, resulting in ER Ca2+ depletion and defective protein folding, thereby triggering ER stress in adipocytes and hepatocytes. Additionally, prolonged nutrient overload elevates mitochondrial reactive oxygen species (ROS) production and induces cytosolic pro-oxidant enzymes (e.g., Nox4, Nos2, and G6pd), while simultaneously downregulating antioxidant counterparts (Sod1, GPx1, GPx3, and Cat) in adipose tissue [119–122], resulting in enhanced oxidative stress. While hypoxia, ER stress, and oxidative stress likely accumulate primarily in metabolically active cell types, including adipocytes and hepatocytes, and initiate inflammatory responses, prolonged nutrient excess and soluble factors released from hypoxic/stressed adipocytes (e.g., altered adipocytokine and exosome secretion profiles and increased FFAs and ceramide release) also trigger alterations in the number (growth and trafficking) and function of various immune cells, including macrophages, neutrophils, eosinophils, natural killer (NK) cells, regulatory T (Treg) cells, natural killer T (NKT) cells, CD8+ T cells, and B cells, thereby contributing to the amplification of inflammation [13,40,41,48]. Changes in the secretory profiles of adipocytes, hepatocytes, and infiltrating immune cells collectively disrupt both inter-organ and intra-organ communication by altering paracrine and endocrine signaling, as well as sympathetic innervation, ultimately leading to adipose tissue dysfunction, systemic insulin resistance, and metabolic dysfunction [123]. For example, FFAs activate the TLR4 and ANT2/HIF-1α pathways within ATMs, leading to pro-inflammatory ATM activation [124–126]. Additionally, factors released from hypoxic adipocytes in obesity (e.g., increased leptin and FFAs and decreased adiponectin levels in the plasma) promote liver inflammation and metabolic dysfunction by causing liver pseudohypoxia (increased HIF-1α and HIF-2α expression in liver macrophages and hepatocytes). Increased HIF-1α and HIF-2α expression promotes pro-inflammatory activation of hepatic macrophages [107,127]. Furthermore, increased hepatocyte HIF-1α upregulates membrane-bound DPP4 expression and promotes sinusoidal vasoconstriction (which increases sinusoidal flow resistance), leading to increased first-pass inactivation of incretin hormones [89,128,129].

It is interesting to note that, while metaflammation propagates from adipocytes to infiltrating immune cells, depletion of adipocyte-specific TNF and NF-κB signaling at the early stages of obesity impairs insulin sensitivity and glucose tolerance [54,56,68], whereas inhibiting immune cell infiltration and pro-inflammatory activation (through adipocyte-specific depletion of HIF-1α or CCL2, or suppression of global or hemopoietic cell-specific TNF, JNK, and IKKβ/NF-κB signaling) improves insulin resistance and glucose intolerance in obese mice [15,63–65,83–88]. These findings raise the possibility that an acute inflammatory response within adipocytes at the early phase of obesity is metabolically beneficial (as far as it is contained in adipocytes); however, as obesity progresses, sustained immune activation and metaflammation become detrimental, causing adipose tissue dysfunction and systemic metabolic impairment.

In addition to local changes in adipose tissue and the liver, obesity also induces gut dysbiosis and increased intestinal permeability, facilitating the entry of microbiome-derived factors such as bacterial DNA, peptidoglycans, and lipopolysaccharides into the systemic circulation. These microbiome-derived factors promote innate immunity by stimulating Toll-like receptors (TLR4, TLR9) or NOD1 on the surface of macrophages, as well as adipocytes and hepatocytes, and promote metaflammation [57,130–132]. At the neuroendocrine level, central regulation of plasma glucocorticoid levels and autonomic signaling, together with local amplification of glucocorticoid action through increased 11beta-hydroxysteroid dehydrogenase type 1 expression in adipose tissue also contributes to sustaining an inflammatory milieu [133]. Moreover, obesity-associated disruption of circadian clock gene regulation also enhances aberrant pro-inflammatory cytokine production by immune cells [134].

In chronic obesity, these pro-inflammatory changes operate in concert with defective resolution programs. Resolution of inflammation is an active, coordinated process, rather than a passive dissipation of pro-inflammatory signals. It requires the clearance of dead cell debris (efferocytosis) and other inflammatory mediators (phagocytosis), the cessation of pro-inflammatory immune cell recruitment (such as monocytes and neutrophils), and the removal of these cells via lymphatic drainage. These events are orchestrated by a network of signaling molecules such as specialized pro-resolving mediators (SPMs), which are bioactive lipid compounds derived mainly from omega-3 fatty acids (e.g., DHA and EPA), and pro-resolving cytokines such as IL-10 [135,136]. Of interest, beyond terminating inflammation, SPMs can directly contribute to metabolic homeostasis by regulating adipocytes, hepatocytes, and skeletal myocyte function. In obesity, both SPM biosynthesis and signaling are impaired [137,138]. Accordingly, exogenous administration of select SPMs and IL-10 overexpression have both been shown to improve insulin resistance and metabolic profiles in obese mice [139–144].

Thus, the expansion and propagation of metaflammation are likely driven by multifactorial mechanisms. While each of the mechanisms can independently fuel metaflammation, they also reinforce one another, creating a feedforward loop in which the inhibition of one pathway can lead to broader improvements by alleviating others [6,116–119,122,145–158]. Over time, the cumulative burden of these changes drives progressive tissue damage and adipocyte death, reinforcing the self-perpetuating cycle for the expansion of metaflammation. It is important to note, however, that, as discussed earlier, not all facets of metaflammation necessarily lead to metabolic dysfunction. And the relative contribution of individual stressors and defective pro-resolving pathways can vary in determining the intensity, chronicity, and qualitative features of metaflammation. Therefore, each of the metaflammation-driving mechanisms should not be assumed to equally contribute to insulin resistance and metabolic dysfunction. This underscores the importance of delineating how each of these processes contribute to the adaptive versus maladaptive metaflammation and the transition between these states.

Transition from ‘protective’ to ‘detrimental’ metaflammation

While molecular determinants for the transition from protective to detrimental metaflammation remain unclear, since the transition likely occurs as the severity and chronicity of obesity advances, it would be reasonable to assume that the accompanied pathologic changes may be responsible. As obesity progresses, adipose tissue shows a number of pathologic changes, including increased adipocyte death [159–164], adipose tissue fibrosis [62], cellular senescence [165], altered immune cell infiltration and phenotypic switching of the individual infiltrating immune cell types [166], vascular dysfunction [167], adipocyte iron accumulation [168], catecholamine resistance [169], alterations in adipose tissue-derived and circulating exosomes [170], and epigenetic reprogramming [171]. Subsequent adipose tissue dysfunction may also allow changes in the secretory profiles of adipose tissue and the exceeding of a critical lipotoxic threshold [3,172]. As these alterations are highly interconnected, disentangling causality, temporal hierarchy, and directionality among these processes often presents a classic causality dilemma and remains a challenge in the field. Nonetheless, phenotypic switching of immune cells, in particular macrophages, can explain many of these changes. The remainder of this Essay focuses on phenotypic switching of macrophages to obesity-specific phenotypes. This concept has been well-established in murine models through lineage tracing and genetic manipulation, although its translation to humans remains partial and is the focus of ongoing investigation.

Phenotypic switching of ATMs during obesity

Among the various immune cell types involved in systemic and tissue-specific metabolic regulation that show functional shifts, macrophages represent the most abundant immune cells accumulating in adipose tissue, liver, skeletal muscle, and pancreatic islets in obesity [173–175]. Notably, macrophages are the primary cellular source of most pro-inflammatory cytokines and exosomes that regulate insulin sensitivity [18,176–178]. Systemic depletion of macrophages [49,179–181] or macrophage-specific manipulation of molecules within proximal inflammatory pathways (such as IKKβ, JNK, IRF5, CCR2, and HIF-1α) can improve insulin resistance and glucose intolerance in obese mice [25,65,126,182–184], suggesting that macrophages have a key role in the pathogenesis of insulin resistance in obesity. Recently, the importance of macrophages in driving adipose tissue inflammation and hepatic insulin resistance and steatosis was also shown using an interconnected microphysiological system containing adipocytes, hepatocytes, and macrophages derived from an isogenic human iPSC system [35].

In healthy states, the majority of ATMs are developmental yolk sac-derived resident ATMs [185]. Resident ATMs secrete factors that enhance insulin sensitivity, such as IL-10 and insulin-sensitizing exosomes [98,139,178] (Table 1). They also produce PDGFcc, which promotes adipocyte differentiation and lipid storage [186]. Moreover, resident ATMs are enriched in genes associated with endocytosis, lysosomal function, and cholesterol and iron metabolism, reflecting their critical role for sustaining adipose tissue homeostasis. For example, a subset of resident ATMs, characterized by high expression of the cholesterol transporter ABCA1 (Abca+ Lyve1+ Tim4+ ATMs) has a key role in post-prandial reverse cholesterol transport by facilitating high-density lipoprotein cholesterol efflux after a high-fat meal, thereby protecting against dyslipidemia and cardiovascular disease [187]. In addition, resident ATMs take up excessive extracellular iron and buffer local iron levels, preventing excessive iron accumulation in adipocytes, which causes insulin resistance [188,189].

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Table 1. Metabolically beneficial vs. detrimental effects of distinct ATM subtypes in health and obesity.

https://doi.org/10.1371/journal.pbio.3003620.t001

In obesity, ATMs undergo phenotypic switching from anti-inflammatory, insulin-sensitizing (M-IS) phenotypes to pro-inflammatory, insulin resistance-inducing (M-IR) phenotypes. Previously, it was suggested that the phenotypes of ATMs in health and obesity are similar to the M2- and M1-polarized bone marrow-derived macrophages, induced by either by IL-4/IL-13 (M2) or LPS/IFNγ (M1) [98] (Box 1). However, recent evidence indicates that ATMs do not exist in these narrow M1/M2 categories. Instead, they represent a highly heterogenous population, with each subtype displaying distinct transcriptomic signatures and functions. Accordingly, the M1/M2 classification system is no longer considered adequate to describe ATM phenotypes. Importantly, the obesity-induced phenotypic switching of ATMs is associated with functional changes in each ATM subtype, as well as with changes in the ratio between different ATMs subtypes. For example, resident ATMs retain some of their metabolically beneficial effects [187–190]; however, their relative abundance declines along with their insulin-sensitizing effects. This decline occurs concomitantly with the accumulation of recruited ATMs, comprising pro-inflammatory M-IR phenotypes, as well as pro-resolving phenotypes (discussed in detail in the following section). In obesity, chemokines and lipokines such as CCL2, CCL5, CCL8, S100, Sema3e, and leukotriene B4 promote monocyte recruitment into adipose tissue [82,97,98,191,192], where they differentiate into pro-inflammatory ATMs. In addition, obesity increases the expression of soluble factors that enhance retention of ATMs within adipose tissue, such as netrin and Sema3e, further sustaining ATM accumulation. Beyond promoting recruitment, CCL2 also stimulates local proliferation of ATMs. Thus, the expansion of the ATM pool arises from increased recruitment of circulating monocytes [98,193] and prolonged ATM retention [192,194,195], as well as enhanced local proliferation [99,196]. Genetic deletion or pharmacological inhibition of each of these ATM recruitment and retention mediators improves metaflammation, insulin sensitivity, and glucose tolerance in obese mice. Moreover, selective depletion of recruited macrophages improves metabolic profiles in obese mice [197], whereas the depletion of Cd169-expressing tissue-resident macrophages induces pathological adipose tissue remodeling and vascular dysfunction in lean mice, resulting in adipocyte hypertrophy and adipose tissue dysfunction [52]. Therefore, it would be reasonable to conclude that the decrease in the beneficial effects of M-IS ATMs, as well as the increase in M-IR ATMs is an etiologic component of insulin resistance and metabolic dysfunction in obesity.

Box 1. M1/M2 macrophage polarization states and obesity-induced ATM activation.

M1 macrophages, often referred to as ‘classically activated’ macrophages, represent a pro-inflammatory phenotype, characterized by the production of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide [198]. By contrast, M2 macrophages, or ‘alternatively activated’ macrophages, display an anti-inflammatory phenotype that is primarily associated with tissue repair, remodeling, and resolution of inflammation [199,200]. Markers typically used to distinguish M1 and M2 macrophages, such as CD11c (M1) and CD206 (M2), are differentially expressed in healthy and obesity-induced adipose tissue macrophages (ATMs). Moreover, most resident ATMs express CD206, whereas recruited pro-inflammatory ATMs express CD11c. However, recent advances in single cell techniques have revealed that in vivo, ATMs do not exist in these narrow categories [29,48,53,201–205,206]. Additionally, in opposition to previous suggestions, CD11c and CD206 are not always reliable indicators for the pro- and anti-inflammatory states of ATMs or for recruited versus resident ATMs. For example, although CD206 is abundantly expressed in resident ATMs, it is also expressed in a subset of CD11c+ pro-inflammatory recruited ATMs. These CD206 and CD11c double-positive ATMs display highly pro-inflammatory phenotypes [207]. Furthermore, myeloid lineage-specific inhibition of IL-4 signaling, which induces M2 polarization in bone marrow-derived macrophages, suppresses adipose tissue inflammation with increased CD11c+ ATMs in mice [208]. In addition, CD206+ ATMs are increased in patients with diabetes and exhibit pro-inflammatory phenotypes in humans [209]. Furthermore, while CD11c+ ATMs represent pro-inflammatory, recruited ATMs in the context of obesity, during weight loss, CD11c+ ATMs exhibit substantially reduced pro-inflammatory gene expression without losing CD11c expression [72]. Therefore, despite some similarities, M2 is not representative of healthy insulin-sensitizing ATMs nor is M1 representative of insulin resistance-inducing ATMs. Instead, ATMs in obesity exhibit unique metabolic gene expression profiles characterized by elevated expression of genes involved in lipid metabolism, as well as mitochondrial and lysosomal activities, which is termed the ‘metabolic activation state (MMe)’ [202–204].

Specific changes in distinct ATM subtypes

Secretion of insulin-sensitizing versus insulin resistance-inducing exosomes.

Exosomes are nano-sized extracellular vesicles that encapsulate diverse bioactive intracellular cargo, including lipids, proteins, mRNAs, microRNAs, long noncoding RNAs, and functional mitochondrial fragments. They are released into extracellular space, where they can subsequently enter systemic circulation [210]. By transferring these intracellular contents from the originating cells, exosomes mediate intercellular communication and modulate recipient cell function [210–214]. Adipose tissue represents a major source of circulating exosomes [170,215]. Treatment with plasma or adipose tissue-derived exosomes from obese individuals with MASLD, but not from lean or obese individuals without MASLD, impairs insulin signaling in cultured human skeletal muscle myotubes and primary mouse hepatocytes [37]. This effect correlates with skeletal muscle and hepatic insulin sensitivity of the donors [69]. While adipocytes are thought to be the major contributors of adipose tissue-derived exosomes [215], ATMs also secrete exosomes that regulate insulin sensitivity in adipocytes, hepatocytes, and skeletal myotubes [178,216,217]. Notably, in healthy mice maintained on a normal chow diet, ATM-derived small extracellular vesicles containing exosomes enhance insulin sensitivity, an effect observed in ATMs from both VAT and SAT. By contrast, in obese mice, VAT ATMs secrete exosomes that promote insulin resistance [178], whereas SAT ATMs largely retain their capacity to secrete exosomes that improve insulin resistance. This VAT-specific phenotypic switching of ATM-derived exosomes is associated with a decrease in resident ATMs, which retain their insulin-sensitizing effect in obesity, as well as the increase in recruited M-IR ATMs. These changes are mediated, at least in part, by CCL26 derived from subcutaneous adipocytes and adipocyte progenitors and by CXCL12 secreted from SAT-resident ATMs [79]. CCL26 increases M-IS and decreases M-IR ATMs by decreasing resident ATM death and blood monocyte chemotaxis. CXCL12 educates recruited ATMs to secret insulin-sensitizing small extracellular vesicles. Notably, treatment with the insulin-sensitizing agent, rosiglitazone, or with CXCL12 reverses this switch, restoring the beneficial effects of ATM-derived exosomes [79,178,190,217]. Although exosomes carry various classes of bioactive molecules, inhibition of microRNA biogenesis in ATMs via Dicer depletion blunts the effect of ATM-derived exosomes on insulin sensitivity, suggesting that microRNAs are the key mediators of this effect. Several microRNAs contained within ATM-derived exosomes have been identified as regulators of insulin sensitivity, including miR-690, miR-155, and miR-210 [178,216–218].

Iron-handling ATMs.

Iron is essential for mitochondrial function and cellular bioenergetics. However, excess iron promotes oxidative stress through metal-catalyzed reaction, in particular the Fenton reaction, which generates ROS. This oxidative burden can drive mitochondrial dysfunction and contribute to damage in vital organs such as the liver, heart, and pancreas. Insulin limits post-prandial increases in circulating iron levels by suppressing intestinal iron absorption and reducing iron export from hepatocytes, macrophages, and adipocytes through upregulating hepcidin expression, which in turn inhibits ferroportin activity [219]. Iron overload is frequently observed in patients with T2D or impaired glucose tolerance. In obesity, adipose tissue iron levels increase. In mice with adipocyte-specific depletion of ferroportin, increased adipocyte iron accumulation worsens insulin resistance and glucose intolerance in obesity [220]. Conversely, reducing adipocyte iron level by adipocyte-specific depletion of transferrin receptor protects from the development of insulin resistance and glucose intolerance with decreased weight gain in mice fed a HFD [221], suggesting that adipocyte iron overload leads to adipose tissue dysfunction and insulin resistance. Of note, adipocyte iron levels are critically regulated by a subset of resident ATMs, termed MFehi ATMs. MFehi ATMs exhibit high expression of iron storage and metabolism genes and prevent adipocyte iron overload by sequestering excess extracellular iron [188,189]. In obesity, the number of MFehi ATMs is reduced along with decreased expression of genes involved in iron metabolism, facilitating iron accumulation in adipocytes [188,222,223].

Of interest, although ATM labile iron content is decreased, total intracellular iron content is generally increased in ATMs along with increased oxidative stress [222]. Genetic manipulation that increases iron content in the mitochondrial matrix of macrophages exacerbates pro-inflammatory ATM activation, adipocyte iron accumulation, insulin resistance, and glucose intolerance in obese mice [222]. Conversely, reducing macrophage mitochondrial matrix iron content improves insulin sensitivity and glucose tolerance together with attenuated metaflammation, increased anti-inflammatory ATM activation, and decreased adipocyte iron accumulation. Therefore, it is likely that aberrant iron accumulation in ATMs also causes pro-inflammatory ATM activation and insulin resistance in obesity. As a possible explanation for the obesity-induced decrease in MFehi resident ATMs and iron-induced pro-inflammatory ATM activation, we recently observed that obesity induces ferroptosis in resident ATMs [190], which may contribute to the relative depletion of MFehi iron-handling ATM subset and the replacement of them with pro-inflammatory recruited ATMs.

ATMs that clear dead adipocyte debris and extracellular lipids.

In healthy adult humans, adipocytes exhibit a slow turnover rate with ~10% of the adipocyte pool renewed annually through apoptosis [161,224]. Macrophages are among the best-known professional phagocytes. Like other tissue macrophages, ATMs engulf and degrade extracellular debris (such as dead adipocytes; i.e., efferocytosis) and foreign particles [161,204]. Resident ATMs in lean adipose tissue are characterized by high expression of genes involved in lysosomal activity and phagocytosis. They aggregate around dead adipocytes, forming histologically distinctive crown-like structures for effective efferocytosis. In obesity, however, the rate of (pre)adipocyte death increases through a combination of programmed and nonprogrammed cell death mechanisms, including pyroptosis, necrosis, apoptosis, and ferroptosis [159–164]. Dying adipocytes release damage-associated molecular patterns, such as ATP, uric acid, and nucleic acids, which are recognized by pattern recognition receptors such as TLRs and NOD-like receptors on macrophages and other immune cells. This recognition triggers local inflammatory responses that alter the secretory profile of white adipocytes (adipocytokines) and impair adaptive thermogenesis in brown/beige adipocytes [225]. Furthermore, lipids released in an uncontrolled manner from dead adipocytes can enter the systemic circulation and be deposited ectopically in nonadipose organs such as the liver, skeletal muscle, and heart, inducing mitochondrial stress, ER stress, insulin resistance, and broader metabolic dysfunction (lipotoxicity). However, in obesity, the abundance and phagocytic activities of resident ATMs decline due to HIF-2α-dependent activation of the mTOR pathway, which suppresses lysosome gene expression, thereby impairing phago-/efferocytic activities while enhancing lysosomal cell death [107]. Instead, a distinct subset of recruited ATMs specialized in clearing extracellular lipids derived from increased lipolysis or dead adipocytes emerges. These ATMs express high levels of genes involved in lipid metabolism (such as Pparg, p62, Trem2, Cd9, and Cd36), mitochondrial oxidative phosphorylation, and lysosomal activity (such as Lamp2, Acp5, and Ctsk), equipping them for efficient lipid uptake, degradation, and clearance. These ATMs take up fatty acids through caveolae-dependent endocytosis mediated by scavenger receptors, such as CD36. They also perform exophagy, a process by which lysosomes are released via exocytosis to degrade apoptotic adipocytes [226].

Several independent studies have described these obesity-induced, circulating monocyte-derived ATMs with largely overlapping phenotypes under different names, including MMe ATMs (Box 1) and lipid-associated ATMs (LAMs) [29,53,202,203]. scRNA-seq data analyses indicate that these populations are largely identical (or, at a minimum, extensively overlapping). Despite variations in the specific markers or criteria used across studies, for convenience and consistency, we hereafter refer to this population as LAMs. LAM phenotypes are likely shaped by excess fatty acids (notably, palmitic acid) and adipocyte-derived factors, such as lipid-laden small extracellular vesicles [202,227]. In obesity, LAMs accumulate, particularly around crown-like structures (marking sites of dead adipocytes) [53]. Moreover, increased lipolysis during weight loss leads to transient accumulation of LAMs in adipose tissue [71]. Functional studies using mice with global or myeloid lineage-specific depletion of LAM-specific regulators/markers, such as Trem2 [53], TFEB [228], or PPARγ [229], suggest that LAMs protect against the development of insulin resistance and glucose tolerance in obesity. For example, global Trem2-deficient mice develop adipocyte hypertrophy, increased body fat accumulation, and glucose intolerance [53,230], although other studies failed to confirm metabolic beneficial effects of global or macrophage-specific Trem2 [231,232].

Although increased in obesity, the effect of LAMs on clearing dead adipocytes and extracellular lipids is likely not sufficient to rescue from metaflammation, insulin resistance, and metabolic dysfunction. Thus, obesity increases the expression of the lysosomal protein TM4SF19 in ATMs, which represses acidification through its interaction with vacuolar ATPase. TM4SF19 inactivation elevates lysosomal acidification and increases the clearance of dead adipocytes. Mice lacking TM4SF19 show improved insulin sensitivity in obesity [233]. Similarly, boosting ATM lysosomal activity by myeloid lineage-specific overexpression of the lysosomal master transcription factor TFEB protects against adipose tissue inflammation and insulin resistance in obese mice, whereas myeloid lineage-specific TFEB depletion worsens adipose tissue inflammation and insulin resistance [228]. Furthermore, suppressing mTOR-dependent inhibition of TFEB via antisense oligonucleotides targeting Folliculin ameliorates metaflammation and metabolic dysfunction-associated steatohepatitis (MASH) in obese mice [107]. Therefore, although it may not be sufficient to fully prevent metaflammation and adipose tissue dysfunction, increased lysosomal activity in LAMs likely helps suppress them by clearing dead adipocytes and excess extracellular lipids. Since autophagy is increased in ATMs in obesity [234], blocks pro-inflammatory ATM activation, and protects against insulin resistance and glucose intolerance in obese mice [235], lysosomal activity in ATMs in obesity may help limit metaflammation by enhancing autophagy and inhibiting pro-inflammatory ATM activation.

It is interesting to note that, while LAMs are generally considered to be a pro-resolving, protective ATM subtype, they are not quiescent ATMs. Thus, LAMs express higher levels of pro-inflammatory genes compared with resident ATMs [53,79,204], although they exhibit relatively lower expression of pro- inflammatory genes compared with other Cd9-expressing, recruited ATMs [53,230–232]. Indeed, LAMs show substantial overlap with previously defined CD11c+ pro-inflammatory, M-IR ATMs in visceral white adipose tissue from obese mice [53,79,125]. One study in mice identified NOX2 as a key driver of both pro- inflammatory and adipocyte-clearing properties of LAMs and showed that depletion of NOX2 attenuates pro-inflammatory ATM activation and improves glucose tolerance after 8 weeks of a HFD while, paradoxically, it worsens insulin resistance with the accumulation of dead adipocytes after 16 weeks of a HFD [204]. These results suggest that although LAMs are generally considered to be a pro-resolving, protective ATM subtype, they may also mediate metabolically detrimental effects during the development of obesity. Interestingly, a recent study showed that LAMs can transition into pro-inflammatory ATMs during the progression of obesity [79], mirroring their phenotypic shift in atherosclerosis [236]. Therefore, it is possible that LAMs may represent an intermediate state, in which persistent metabolic stress (or failure to adequately control extracellular lipid and dead adipocyte accumulation) drives their conversion into pro-inflammatory ATMs. To date, most funtional studies have investigated the effects of LAM-specific molecules (e.g., Trem2), instead of the role of LAMs themselves. Additionally, Trem2 and Nox2 are not exclusively expressed in LAMs, but are also expressed in other macrophage subtypes, such as resident ATMs, although they are more abundant in LAMs. Therefore, future studies are required to define the specific effects of this ATM subpopulation on the development of metaflammation and insulin resistance, and to understand how the protective effects of LAMs decline to favor pro-inflammatory phenotypes.

ATMs that metabolize catecholamine and acetylcholine and regulate lipolysis and adaptive thermogenesis.

One of the primary functions of adipose tissue is to store excess lipids during periods of caloric surplus and to release them in accordance with metabolic demands. For example, during fasting or cold exposure, activation of the sympathetic nervous system (SNS) in adipose tissue triggers the release of norepinephrine (NE) from local sympathetic nerves. Acting through beta adrenergic receptors on adipocytes, NE promotes lipolysis in white adipocytes and drives adaptive thermogenesis in brown and beige adipocytes. In addition, NE inhibits adipose tissue expansion by suppressing the proliferation and differentiation (adipogenesis) of preadipocytes, while it enhances sympathetic innervation by stimulating the recruitment of eosinophils, which secrete nerve growth factor [237]. A specialized subset of resident ATMs, known as sympathetic neuron-associated macrophages (SAMs), resides in close proximity to sympathetic nerves within adipose tissue. These ATMs take up and catabolize catecholamines (including NE) [238], which may help limit excessive energy expenditure and enable rapid recovery of the capacity to expand adipose tissue. However, in the context of obesity and aging, an increased number of or activity of SAMs leads to reduced adaptive thermogenic capacity [238,239].

In addition to SAMs, a Cx3cr1-expressing ATM subtype that resides in brown adipose tissue has an essential role in sympathetic innervation into interscapular brown adipose tissue in mice [240]. In contrast to the function of SAMs, it has also been suggested that anti-inflammatory M2-like polarized ATMs can directly generate catecholamines, and that treatment with IL-4 promotes adaptive thermogenesis by inducing M2-like polarization of ATMs [241,242]. However, this latter hypothesis has been challenged by subsequent studies [243].

Similar to catecholamines, acetylcholine (ACh), the primary neurotransmitter of the parasympathetic nervous system, also enhances thermogenesis. Of note, adipose tissue lacks parasympathetic innervation [244]. Instead, adipose tissue ACh is produced from a distinct subset of ATMs, called acetylcholine-synthesizing ATMs (ChAMs). ChAMs constitute a minor fraction (~0.17%) of stromal vascular cells in inguinal adipose tissue [245,246]. They release ACh in response to NE stimulation and enhance the cAMP–PKA pathway and adaptive thermogenesis in beige adipocytes in subcutaneous adipose tissue [245,246]. Myeloid lineage-specific genetic deletion of choline acetyltransferase (Chat), the rate-limiting enzyme for acetylcholine synthesis, impairs cold-induced adaptive thermogenesis and reduces cold tolerance in lean, healthy mice. Although it is not known whether obesity affects the abundance or functional activity of ChAMs, depletion of cholinergic receptor nicotinic alpha 2 subunit (Chrna2) in Ucp1-expressing brown/beige adipocytes exacerbates diet-induced obesity in mice fed a HFD. Therefore, local cholinergic signaling in adipose tissue (likely mediated by ChAMs) may exerts an anti-obesogenic role under conditions of nutrient excess.

In support of the concept that ATMs regulate local catecholamine and ACh availability, systemic depletion of tissue macrophages using clodronate liposomes, but not sympathetic denervation, abolished beiging of subcutaneous adipose tissue in adipocyte-specific Fasn knockout mice [247]. Of note, although both NE and ACh promote thermogenic responses in brown/beige adipocytes and ChAMs are activated by NE, ACh suppresses TNF-induced pro-inflammatory gene expression while increasing Glut4 expression in adipocytes [248], whereas NE promotes acute inflammation by increasing lipolysis and FFA levels [249]. Moreover, ACh enhances efferocytosis by macrophages and the resolution of inflammation [250]. Therefore, it is likely that distinct subsets of ATMs actively regulate lipolysis, adaptive thermogenesis, and adipose tissue mass by regulating sympathetic innervation and local NE and ACh levels.

It remains unclear how these macrophage-mediated regulation of local NE and ACh levels and their downstream effects are coordinated in obesity. Central regulation of sympathetic innervation of adipose tissue is decreased in obesity due to leptin resistance in the paraventricular nucleus of the hypothalamus, which can be reversed by chronic leptin treatment [251]. Given that obesity also reduces adipose eosinophil infiltration while increasing SAMs, these local immune changes may further decrease sympathetic innervation, lower local NE levels, and suppress ChAM activation, which can collectively enhance catecholamine resistance and impair adaptive thermogenesis.

ATMs that regulate angiogenesis and tissue remodeling during adipose tissue expansion.

In order to store excess lipids and release them according to metabolic demand, mature adipocytes can adjust their volume by up to 100-fold [224,252,253]. In addition, both adult humans and mice retain the capacity for de novo adipogenesis throughout life, which is increased in obesity. To maintain adequate perfusion and efficient delivery of oxygen and nutrients, adipose tissue expansion is coordinated with angiogenesis and vascular remodeling [62]. Macrophages secrete VEGF, PDGF, matrix metalloproteinases, TNF, and other cytokines. These factors facilitate not only endothelial cell migration, proliferation, and new blood vessel formation, but also degradation of extracellular matrix to allow vessel sprouting and remodeling [254,255]. Resident ATMs abundantly express these factors and the depletion of tissue-resident macrophages causes vascular dysfunction [52]. In obesity, the resident ATM population declines, whereas a subset of ATMs expressing LYVE-1 accumulates preferentially around the dense vascular network located at the leading edge of expanding adipose tissue [256–258]. These LYVE-1+ ATMs serve as an important source of PDGF, necessary for angiogenic remodeling. The depletion of macrophages using clodronate liposomes reduces the formation of a dense vascular network, underscoring the role of ATMs in adipose tissue expansion. LYVE-1+ ATMs are recruited from bone marrow (i.e., recruited ATMs) by local hypoxia-induced CXCL12 expression, independent of the CCR2–CCL2 system [256]. Similar to these LYVE-1+ ATMs, scRNA-seq analyses revealed that a subset of recruited ATMs expressing a monocyte marker, Lyc6, most abundantly express pro-angiogenic genes compared with other ATM subtypes including Trem2+ and/or CD9+ populations [29]. These ATMs are located outside of the crown-like structure and also enhance adipocyte differentiation, consistent with their role in adipose tissue expansion. A subset of ATMs displaying pro-angiogenic gene signatures was also identified in humans [259].

While the longitudinal dynamics of pro-angiogenic ATM abundance and function across the full course of obesity remain incompletely defined, it is noteworthy that the expression of pro-angiogenic factors and their activity within adipose tissue acutely increase at an early stage during the development of obesity [84], but eventually decline together with decreased vascular density and function within adipose tissue in chronic obesity [92,93], contributing to adipose tissue hypoxia. Adipocyte-specific overexpression of VEGF-A or VEGF-B improves insulin sensitivity and glucose tolerance with increased vascular density and oxygen tension in adipose tissue in obese mice. Conversely, adipocyte-specific depletion of VEGF-A worsens adipose tissue inflammation, insulin resistance and glucose intolerance [93–96]. Interestingly, although pro-angiogenic stimulation supports healthy adipose tissue remodeling at the early stages of obesity, inhibition of VEGF signaling or angiogenesis after the onset of obesity can also yield metabolic benefits, including reducing adiposity and body weight and improved adipose tissue inflammation and glucose tolerance [93,260–264]. Therefore, it is likely that the metabolic consequences of pro-angiogenic signaling in adipose tissue are context- and timing-dependent. It still remains to be elucidated whether and how pro-angiogenic ATM abundance and activity eventually decline during chronic obesity and the molecular determinants distinguishing the beneficial versus detrimental effects of angiogenic processes on metabolic health.

Conclusions and future directions

In summary, although metaflammation ultimately leads to insulin resistance and metabolic dysfunction in chronic obesity, it likely begins as an adaptive response to increased oxygen demand and metabolic stress rather than as a purely pathological process. During the early stages of obesity, metaflammation does not cause insulin resistance. Instead, metaflammation, with the activation of distinct resident ATM subtypes (including pro-angiogenic ATMs and iron-handling ATMs), appears to support healthy adipose tissue expansion and to restrain the progression of insulin resistance and metabolic dysfunction. In addition, SAMs may contribute to clearing extracellular NE, thereby limiting excessive lipolysis and sustaining adipose tissue expendability. At this stage, recruited ATMs that differentiate into ChAMs and LAMs also promote metabolic homeostasis by enhancing energy expenditure and buffering extracellular lipid accumulation. As obesity progresses, however, the beneficial effects of resident ATMs in secreting insulin-sensitizing exosomes, anti-inflammatory cytokines (such as IL-10), and pro-angiogenic and adipogenic factors (e.g., PDGF) gradually decline, as does the iron-handling capacity of resident ATMs. At the same time, sustained resident SAM activation may suppress adaptive thermogenesis and promote weigh gain, and recruited ATMs such as LAMs can transition into pro-inflammatory M-IR ATMs, which secrete cytokines and exosomes that directly induce insulin resistance. Collectively, these changes likely contribute to the shift of metaflammation from an adaptive process to a chronic, maladaptive, nonresolving state, driving insulin resistance, and metabolic dysfunction. Thus, just as adipose tissue itself is not inherently pathological but is critical for metabolic homeostasis, not all macrophage-mediated or inflammatory responses should be viewed as detrimental. Rather, the failure of beneficial functions of metaflammation to maintain metabolic homeostasis and the pathological reprogramming of ATMs into M-IR phenotypes may represent central etiologic contributors to the development of insulin resistance and metabolic dysfunction in obesity.

Genetic and pharmacologic studies targeting proximal inflammatory pathways have established chronic tissue metaflammation as a key contributor to the pathogenesis of insulin resistance and glucose intolerance. However, most of these studies were conducted in mice. In humans, obesity is associated with increased infiltration of pro-inflammatory immune cells, including macrophages, in adipose tissue, liver, skeletal muscle, and pancreatic islets, and in vitro work in primary human adipocytes, hepatocytes, skeletal myotubes, and organoids is consistent with a causal role for metaflammation. However, because the types of genetic manipulation used in murine models are not feasible in humans, pharmacologic interventions are required to rigorously test whether modifying metaflammation can prevent or reverse metabolic dysfunction.

To date, several anti-inflammatory strategies directed against targets such as TNF, CCL2, and IL-1β have been tested for the treatment of insulin resistance and T2D. Although some have shown positive results, most yielded disappointing efficacy and raised safety concerns [19,48]. While some clinically available insulin-sensitizing agents, including thiazolidinediones and salicylic acid derivatives, can directly suppress inflammatory pathways and improve markers of metaflammation in parallel with better metabolic profiles, it remains unclear to what extent their metabolic benefits are mediated by direct immunomodulation versus other mechanisms. Because not all inflammatory responses during metaflammation are deleterious and acute activation of selected pathways can support healthy adipose tissue expansion and promote resolution of chronic inflammation, future therapeutic strategies should aim to distinguish and selectively modulate adaptive versus pathogenic inflammatory programs. Ideally, interventions would target the molecular determinants governing the transition between these states while minimizing systemic safety concerns. In this context, drug-delivery platforms capable of selectively targeting adipocytes or defined macrophage subsets represent a particularly attractive approach to enhance efficacy and limit off-target (or unwanted on-target) effects.

As obesity is a major risk factor for metaflammation, insulin resistance, and downstream complications including T2D, MASH, and related metabolic disorders, sustained weight loss would be a rational therapeutic goal. However, durable weight reduction through lifestyle interventions alone is difficult to achieve in most cases. Pharmacological interventions such as GLP-1/GIP-based pharmacotherapies provide an effective option for weight reduction and improving metabolic parameters [265]. However, their broader utility can be limited by adverse effects (including gastrointestinal side effects), cost, and access, and the frequent occurrence of rapid weight regain upon discontinuation. Weight regain is often followed by prompt recurrence of metaflammation, insulin resistance, and metabolic dysfunction, suggesting that immunologic and tissue level memory of obesity and metaflammation may persist despite transient weight loss [266]. A detailed mechanistic understanding of how chronic metaflammation remodels metabolic tissues will also be essential to identify durable points of intervention.

Overall, understanding how metaflammation is initiated, expands, propagates, and is ultimately converted into a driver of metabolic disease remains a challenge for the field. Key unresolved questions include: how pro-inflammatory factors and lipid mediators differ in beneficial versus detrimental phases of metaflammation; which novel pathological pathways and cellular players emerge during the transition; by what mechanisms protective inflammation transitions to maladaptive responses; how resolution of inflammation fails and pro-inflammatory signaling persists; and whether these processes are reversible or instead embedded through epigenetic, microenvironmental, or immune memory-related mechanisms. As these mechanisms are elucidated, hopefully, there will be an opportunity to develop more precise tools that can test the causal hypothesis in humans.

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