Unraveling the complex roles of macrophages in obese adipose tissue: an overview

Abstract

Macrophages, a heterogeneous population of innate immune cells, exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases. The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects, inducing insulin resistance through increased inflammation, impaired thermogenesis, and adipose tissue fibrosis. Meanwhile, adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis, facilitating the clearance of dead adipocytes, and promoting mitochondrial transfer. Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions. Recently, the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology. In this review, we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity, as well as explore the potential of drug delivery systems targeting macrophages, aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.

Keywords

obesity / inflammation / adipose tissue macrophages / adipose tissue homeostasis

1 Introduction

Obesity is a pathological state that results from an energy imbalance—energy intake chronically exceeds consumption—with the manifestation of hypertrophy and hyperplasia of adipocytes [1,2]. Over the past 50 years, the increasing global prevalence of obesity has reached a pandemic proportion, and more than 38.2% (one-third) of the United States population is obese with a body mass index (BMI) ≥ 30 kg/m² [3]. Obesity increases the risk of many metabolic diseases, including type 2 diabetes, high triglyceride levels, high blood pressure, and high cholesterol [4–7], and almost 4 million deaths are related to obesity, which is 7.1% of all deaths [8]. Therefore, obesity has become a threat to public health and increases the economic burden on human society.

It was once considered that adipose tissue only has the function of energy storage, however, adipose tissue also displays the key regulation in whole-body energy homeostasis including glucose control, insulin sensitivity, thermogenesis, and food intake [9]. Two kinds of adipose tissues—the energy-storing adipose tissue (white adipose tissue, WAT) and the thermogenic adipose tissue (brown adipose tissue, BAT, and beige adipose tissue), play pivot roles in energy homeostasis in mammals [9,10]. Morphologically, white adipose tissue has few mitochondria and contains a large unilocular lipid droplet, whereas brown adipose tissue has lots of mitochondrial with multitudinous small multilocular lipid droplets; Functionally, the WAT stores excessive energy in the form of triglycerides under nutrition load and releases free fatty acids (FFA) to meet the energy requirement of other metabolic organs by mobilizing fat, and the BAT and beige adipose tissue can dissipate energy to maintain body temperature in a form of non-shivering thermogenesis through uncoupling protein 1 (UCP-1) [11,12].

The adipose tissue is a mixture of distinct cell populations, where adipocytes and non-adipocytes coordinate to maintain the homeostasis of the adipose tissue and the energy balance of the whole body. Many types of cells, including adipocytes, endothelial cells, and various immune cells reside in the adipose tissue [13]. Among these immune cells, adipose tissue macrophages (ATMs) are extensively studied for their regulation of inflammation and insulin resistance [14–17]. In the lean state, ATMs account for only 10%–15% of the cell population in adipose tissue and a large of ATMs represent the M2-alternative activation, secreting cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), and arginase (ARG) 1 that can maintain the insulin sensitivity in adipose tissue; on the contrary, in an obese state, an increased number of ATMs approximately account for 40%–50% of adipose tissue cells and display a state of pro-inflammatory activation to secrete pro-inflammatory factors, such as monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α), to exacerbate the local insulin resistance in adipose tissue or systematic insulin resistance [18–24]. Based on the regulation of inflammatory response in the adipose tissue, ATMs are considered important targets in the treatment of chronic inflammation-related insulin resistance and metabolic diseases.

Besides the regulation of inflammation in the adipose tissue, an increasing number of functions of ATMs have been found to mediate the development of obesity. In this review, we present an integrated summary of the mechanisms of pro-inflammatory activation of ATMs in obese adipose tissue and the regulatory functions of ATMs to discuss how ATMs influence the homeostasis of adipose tissue.

2 The complex mechanisms of macrophage activation response to obesity

Inflammation in the adipose tissue is a predominant driver of insulin resistance and ATMs are considered the primary source of inflammation [25,26]. Obesity creates a microenvironment with different stimulation, and multiple external and internal factors in the microenvironment of the adipose tissue together orchestrate the pro-inflammatory activation of ATMs to secrete pro-inflammatory factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and TNF-α, resulting in impaired insulin sensitivity (Fig.1). The external factors inducing the pro-inflammatory activation of ATMs comprise a variety of molecules or nutrients, including lipopolysaccharides (LPS), FFA, glucose, and insulin. The content of these molecules increases in the microenvironment of the adipose tissue in an obese state. Similarly, the internal factors mediating the activation of macrophages also exit huge complexity including metabolism and protein post-translational modification. Here, we summarize the most studied external and internal factors contributing to the activation of ATMs to deepen the understanding of the mechanisms that mediate the progression of adipose tissue inflammation.

2.1 External factors that induce macrophage activation

2.1.1 Gut-derived endotoxin (LPS)

Gut microbiota is an integrated part of the human body, residing in the lumen of the gut, which regulates various functions in multiple organs in health and disease [27]. LPS is the major component of the outer membrane of gram-negative bacteria to protect bacteria from attack from the outer environment, and LPS has been used as a classical chemical to induce the activation of macrophages. Gut microbiota-derived LPS is deemed to be an important trigger to induce M1-classical activation to produce typical pro-inflammatory cytokines, mediating the chronic inflammation of adipose tissue in the obese state [28]. Obesity can induce the dysregulation of gut microbiota and increase intestinal permeability to increase the levels of LPS in blood and adipose tissue to induce the pro-inflammatory activation of ATMs through the Toll-like receptor 4 (TLR4) [29–33]. Except for the study in mice, higher-level circulating LPS also has been observed in humans with type 2 diabetes than that in control, which further confirms the relationship between gut microbiota-derived LPS and inflammation-related disease [34].

2.1.2 Pro-inflammatory lipid

Adipose tissue can store excessive lipids from the blood when nutrient load, however, the ability to store lipids is limited in the state of obesity. Once the ability to store lipids reaches its peak, lipolysis occurs to release FFA into the microenvironment in adipose tissue or blood to result in lipotoxicity, and these FFA are natural chemicals to trigger inflammation [35]. Suganami and colleagues discovered that adipose-derived FFA (palmitate) can activate macrophages to produce TNF-α, using a model of adipocytes and macrophages coculture, which first established a relationship between FFA and macrophage activation [36]. A previous study hypothesized long-chain saturated fatty acids (lcSFAs) can activate macrophages through the TLR4 receptor, a typical receptor for LPS, to promote downstream NF-кB signaling because the principal component of LPS for macrophage activation is the lipid A region which possesses lots of saturated fatty acyl chains [37]. However, a recent study discovered that inflammatory fatty acid palmitate is not a TLR4 agonist and found that TLR4 is required for palmitate-induced macrophage pro-inflammatory activation through TLR4-dependent priming and altered cellular metabolism [38]. Even so, the way that palmitate induces macrophage inflammatory activation is still a classical method to stimulate the macrophage into inflammatory activation in obesity [39,40].

2.1.3 Hypoxia

Hypoxia occurs in the development of obesity because of increased oxygen consumption and relatively reductive blood perfusion in adipose tissue, which is sufficient to induce the expression of hypoxia inducible factor-1 (HIF-1α) to trigger inflammation and adipose tissue dysfunction when obesity [41–44]. In the rodent model, high fat diet (HFD) can significantly reduce interstitial oxygen tension (from 3.4% to less than 1.8%, almost half) in adipose tissue and researchers discovered that HFD did not change the O₂ supply but reduced functional capillary density profoundly. In the human samples, compared to metabolically normal lean participants, the subcutaneous abdominal adipose tissue oxygen tension was significantly reduced in metabolically abnormal obesity participants, although the adipose tissue interstitial oxygen tension was almost 2- to 3-fold in humans than mice [45–47]. Numerous studies have confirmed that HIF-1α is a key regulatory factor in the pro-inflammatory activation of macrophages. HIF-1α knockout in myeloid cells reduces the mortality of mice induced by LPS, which suggests the pivot role HIF1-α plays in inflammation-related diseases [48]. After stimulation by LPS, glutamine-derived succinate accumulates in mitochondria to stabilize HIF-1α which can bind the upstream transcription site of Il1b to augment the mRNA expression [49]. HIF-1α also interacts with the dimeric form of pyruvate kinase isoform M2 (PKM2) that translocates to the nucleus following LPS stimulation, to promote the expression of downstream target genes [50]. In addition, citrate export that increases when macrophages are activated can supply substrate to maintain histone acetylation to promote the transcription of HIF-1α dependent genes and HIF-1α can transcriptionally upregulate immune-responsive gene 1 (Irg1) to regulate the metabolites leakage of the mitochondrial TCA cycle [51]. In conclusion, obesity-induced hypoxia is a key factor in the regulation of inflammation from macrophage mediating by HIF-1α.

2.1.4 Hyperinsulinemia

Obesity-induced adipose tissue inflammation is linked to peripheral or systemic insulin resistance that requires more insulin to be secreted into the blood to maintain the physical functions of tissues, leading to hyperinsulinemia in obese rodents and humans [26]. Although the insulin response reduces in the adipose tissue in an obese state due to insulin resistance, multiple pieces of evidence found insulin can regulate the inflammatory response of macrophages directly. Patients with type 2 diabetes mellitus who got insulin therapy promote the influx of macrophages into the subcutaneous adipose tissue [52]. Boutens and colleagues found that the level of circulating insulin correlates positively with adipose tissue inflammation. Streptozotocin treatment reduced the circulating insulin level and the macrophage content in adipose tissue in obese mice, moreover, insulin infusion can increase the inflammation in adipose tissue even in lean mice [53]. A study discovered that insulin receptor deficiency in myeloid cells protects against obesity-induced inflammation and insulin resistance [54]. These in vivo studies confirmed the positive relationship between circulating insulin and inflammation in adipose tissue. Moreover, numerous studies found insulin can increase the inflammatory activation of macrophages directly. Exposure to insulin can increase LPS-induced inflammatory response in macrophages [55,56]. Above all, hyperinsulinemia in obese individuals is another factor to trigger the inflammatory activation of macrophages in adipose tissue even in a state of insulin resistance in adipose tissue.

2.1.5 Hyperglycemia

Obesity and diabetes usually have the phenotype of hyperglycemia that results from impaired insulin secretion from β cells in the pancreas and insulin action in target tissues [26,57]. Glucose is essential nutrition to maintain the survival and activation of macrophages and glucose can be used to generate energy in mitochondria in the resting state and to provide substrate for glycolysis in the activated state [58]. Exposure to high glucose promotes pro-inflammatory activation in macrophages. In human studies, inflammation is associated with hyperglycemia even after the adjustment for obesity, fat distribution, and other inflammation-related conditions, which suggests hyperglycemia is an independent factor in inducing inflammation [59]. This result can be observed in the rodent diabetes model induced by streptozotocin which disrupts pancreatic β cells directly. Streptozotocin-induced diabetes tends to exhibit the phenotype of reduced insulin levels in the blood, lower bodyweight, and classical hyperglycemia, under this condition, increased expression of pro-inflammatory cytokines in blood and pro-inflammatory genes in adipose tissue can be observed [60–62]. Moreover, clamped setting-induced acute short-term periods of hyperglycemia trigger the pro-inflammatory responses in adipose tissue as well [63]. Similar data have been generated using in vitro experiments which discovered that exposure to high glucose promotes macrophages into a pro-inflammatory state as well [64,65]. Therefore, obesity-induced hyperglycemia is another factor to trigger the inflammatory response in ATMs.

2.2 Internal factors that regulate macrophage activation

Besides receiving pro-inflammatory stimulation from the outer environment, the activation of ATMs is also a complex process that undergoes highly precise internal control to meet the demand for swift change from a quiescent state to a pro-inflammatory state [58,66].

2.2.1 Mitochondrial metabolism adaption

Macrophages are the kind of specific cells that have great plasticity to adapt their phenotype not only in the transcription but also in the change of metabolism to support the pro-inflammatory response by LPS stimulation. Briefly, glucose, FFA, and mitochondrial metabolism swift quickly to meet the requirement of pro-inflammatory activation of macrophages: (1) increased glycolysis promotes glucose flux into the pentose phosphate pathway for the production of GAPDH which can be used for the generation of the inflammatory mediators nitric oxide (NO) and reactive oxygen species (ROS); (2) accumulated citrate can export from mitochondria to generate acetyl-CoA which can be used as the substrate of fatty acids synthesis and histone modification; (3) the truncation of mitochondria results in the accumulation of TCA metabolite succinate, mainly derived glutamine, to promote HIF-1α and inflammatory genes [58,67,68]. Metabolic reprogramming is an important feature for the macrophage pro-inflammatory activation in vitro study, however, what is the metabolic characteristic of macrophages in obese adipose tissue and whether the metabolism reprogramming of macrophages is enough to induce inflammation in obesity is unclear due to the technical limitation of time and space. Some studies found similar metabolic reprogramming in vivo models, which is in accord with previous studies in vitro. The impairment of mitochondrial function may be one of the reasons to induce inflammation and insulin resistance in the adipose tissue in obesity. Jung and colleagues found that reduced mitochondrial oxidative phosphorylation (OxPhos) in macrophages is enough to promote pro-inflammatory activation and induce systematic insulin resistance in HFD-induced obesity [69]. Another research found that a small molecular targeting ATMs mitochondria, fluorophore (IR-61), can ameliorate HFD-induced obesity and insulin resistance by increasing mitochondrial complex levels and OxPhos, which indicates mitochondrial metabolic reprogramming in macrophages may be a key factor in causing inflammation and insulin resistance [70]. The mechanism that links the reduced mitochondrial metabolism in macrophages and obesity remains unclear, scientists have unveiled some of the potential regulations of mitochondrial function. (1) AMP-activated protein kinase (AMPK) is a key regulator in cellular metabolism [71], Galic and colleagues found that AMPK can maintain the expression of the mitochondrial electron transport chain in macrophages because AMPK β unite knockout causes the significant reduction of protein in the mitochondrial electron transport chain. AMPK activity is significantly reduced in obese mice indicating the reduction of mitochondrial metabolism and mice receiving the bone marrow from AMPK β unite knockout mice exacerbate the inflammation and insulin resistance in diet-induced obesity [39]. (2) Adenine nucleotide translocase (ANT), a mitochondrial protein that mediates ADP/ATP exchange across the mitochondrial inner membrane, was increased in ATMs in obese mice, which mediates FFA-induced mitochondrial permeability transition, leading to the damage of mitochondria [72]. Above all, the change of mitochondrial metabolism in macrophages may be an important cause of regulating macrophage activation in obesity, and the method of improving mitochondrial oxidative phosphorylation of macrophages has a potential therapeutic effect for obesity-related disorders. Except for mitochondrial metabolism, many other metabolic pathways are involved in cellular metabolism and obesity-induced inflammation including glycolysis, cholesterol, and phosphatidylcholine, but the contribution and regulatory mechanism of these metabolic pathways in the activation of macrophages in obesity remain further exploration [73–76].

Even though the state of macrophage activation is associated with a significant alteration in metabolism, the contribution of intracellular ATP to the inflammatory activation of macrophages in obese conditions remains unclear at present. The in vitro test demonstrates that macrophages in a state of inflammatory activation exhibit enhanced glycolysis and reduced OxPhos [77,78], however, the ultimate outcome of metabolic changes does not appear to be reflected in ATP levels, as there is no significant alteration observed in intracellular ATP content or the ATP/ADP ratio, suggesting that ATP content may not serve as the determining factor for macrophage inflammatory activation [79]. The profound alteration in metabolism can generate many metabolites that elicit pro-inflammatory signals. The impaired mitochondrial oxidative phosphorylation, for instance, leads to the accumulation of succinate, which in turn activates HIF-1α and IL-1β [49,80]. Meanwhile, glycolysis-derived one-carbon metabolism contributes to the generation of S-adenosylmethionine, which drives the epigenetic reprogramming necessary for IL-1β expression during LPS-induced activation [77,81]. The release of extracellular ATP from apoptotic and necrotic cells as a danger signal to stimulate inflammation suggests that extracellular ATP may serve as a more direct inflammatory stimulus for macrophages compared to intracellular ATP [82–84]. The causal association between metabolic alterations and ATP levels necessitates further investigation in the context of obesity.

2.2.2 Endoplasmic reticulum (ER) stress

ER is the critical cellular organelle in protein quality control including folding, maturation, and trafficking [85]. The unfolded protein response (UPR) can be activated when protein folding overloads [86]. Inositol-requiring enzyme 1 (IRE1), the most conserved ER stress sensor, is an ER-resident transmembrane protein kinase and endoribonuclease. Activated IRE1α by ER stress can catalyze the unconventional splicing of the mRNA encoding X-box binding protein 1(XBP1) and can selectively degrade mRNA in the form of regulated IRE1-dependent decay (RIDD) [86,87]. HFD-induced obesity in mice increases XBP1 mRNA splicing and decreases known RIDD-target genes in macrophages, suggesting the ER stress can be induced by the nutrient load; moreover, myeloid IRE1α knockout prevents diet-induced obesity with a phenotype of increased energy expenditure, decreased bodyweight and inflammation in adipose tissue; further experiments discovered that IRE1α can regulate the activation of macrophages via an RNAse-dependent mechanism, which links the ER stress and the regulation of macrophage activation in obesity [88]. Another two independent studies also confirmed the importance of ER stress in the pro-inflammatory activation of macrophages in obese adipose tissue. The 78-kDa glucose-regulated protein (GRP78) and glucose-regulated protein 94 (GRP94) are two major endoplasmic reticulum chaperone that modulates UPR, it has been observed that GRP78 or GRP94 knockout in macrophages reduce the inflammation in obese adipose tissue in diet-induced mice [89,90]. In brief, ER stress-induced pro-inflammatory activation of macrophages exacerbates inflammation and disturbs insulin resistance in obese adipose tissue.

2.2.3 Histone modification

Histone is a kind of highly conservative protein, wrapping around a segment of DNA, with a large amount of covalent posttranslational modifications (PTMs) that can be regulated [91]. Various histone modifications including methylation, acetylation, and ubiquitination have been found to regulate gene expression by changing the structure of chromatin [91]. Recently, an emerging study found histone modifications can regulate macrophage activation and inflammation in the adipose tissue in obesity. Knockout kdm2a, an H3K36me2 demethylation kinase, promotes macrophage M2 activation by regulating fatty acid metabolism. The mice with macrophage-specific deficiency of kdm2a exhibit diminished chronic inflammation in adipose tissue, enhanced insulin sensitivity, and heightened thermogenic capacity in HFD-induced obesity [92]. Another H3K27me3 demethylation kinase, kdm6a displays a similar regulatory function in macrophage activation in obesity. Kdm6a knockout in macrophages upregulates the expression of IL-10 to increase adipocyte differentiation. Myeloid-specific Kdm6a knockout significantly reduces HFD-induced M1 pro-inflammatory activation of macrophages and protects mice from diet-induced obesity [93]. The report about kdm2a and kdm6a confirms the fact that methylation of histone can influence macrophage activation in obesity. Moreover, histone acetylation also controls macrophage activation in obesity. Histone deacetylase 3 (HDAC3) promotes LPS-induced acute inflammation by the NLRP3-dependent caspase-1 activation. Myeloid-specific HDAC3 protects against HFD-induced obesity and inflammation in adipose tissue [94]. However, histone deacetylase 4 (HDAC4) knockout in macrophages exacerbates the diet-induced inflammation in the liver and adipose tissue, which indicates the different regulatory functions of different histone deacetylases [95]. In addition, Sirtuin 6 (Sirt6), the protein that deacetylates histone H3atlysine9 (H3K9) and lysine56 (H3K56), knockout in myeloid cells facilitates pro-inflammatory polarization of bone marrow macrophages [96]. Similarly, Macrophage-specific Sirtuin 3 (Sirt3) knockout gains more bodyweight and inflammation, accompanied by reduced energy expenditure [97]. Undoubtfully, histone modifications have a pivotal role in regulating macrophage M1–M2 balance in obesity, not only methylation and acetylation. Whether the other ways of histone modification can control macrophage activation and how these histone modifications are regulated in the ATMs response to obesity remain further explored.

2.2.4 Membrane receptor response

In vitro studies, pro-inflammatory activation of macrophages needs LPS to bind to the TLR4, which is a classical way to induce the expression of pro-inflammatory genes including IL-1b, IL-6, and TNF-a. LPS-induced pro-inflammatory activation of macrophages has been considered a stable and classical way to study M1 activation [66]. Recently, researchers have discovered multiple receptors except TLR4 involved in the regulation of macrophage pro-inflammatory activation in obesity. Succinate receptor1(SUNCR1), a receptor to sense extracellular succinate, has a critical role inducing anti-inflammatory activation in macrophages. SUCNR1 knockout in the myeloid-specific cell promotes inflammation in adipose tissue and systematic insulin resistance [98]. Shin and colleagues found that the very low-density lipoprotein receptor (VLDLR), a receptor that is involved in lipoprotein uptake and storage, in ATMs can promote adipose tissue inflammation and glucose intolerance in obese mice [99]. GC receptor (GR) knockout in the myeloid-specific cell increases adipose tissue inflammation and obesity-related insulin resistance [100]. CD226, an essential costimulatory receptor on macrophages, T cells, and NK cells, was highly expressed in ATMs and CD226 knockout can also alleviate inflammation induced by obesity [101]. Moreover, a recent study found CD146, an adhesion molecule, can interact with glycoprotein 130 (Gp130) to activate JNK signaling and inhibit the activation of STAT3, therefore promoting the pro-inflammatory activation of ATMs [102]. Besides the receptor that can regulate macrophage activation directly, the protein that interacts with key receptors can regulate macrophage activation. A receptor-related protein, receptor-interacting protein 140 (RIP140), can influence the inflammatory activation of macrophages in obesity, which further confirms the critical role that multiple receptors play in macrophage activation in obesity [103]. The ribosome biosynthesis protein NOC4 (NOC4), can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorating insulin resistance in mice [104]. It is plausible that macrophages need multiple receptors as well as TLR4 to orchestrate its activation because the microenvironment in adipose tissue of obesity is an integrated pool with different stimulates including various proteins and metabolites.

2.2.5 Cellular ROS controlling

Oxidative stress is a major mediator in regulating the activation of macrophages. Oxidative stress is caused because excessive ROS cannot be removed by the natural anti-oxidant defense of the cell timely [105]. ROS promotes macrophages into a pro-inflammatory phenotype in multiple ways including stabilizing HIF-1α, promoting the NF-кB signal pathway and activating NLRP3 inflammosome [106]. Many stimulations induce ROS production such as hyperglycemia, FFA, and LPS induction [107], and these inducible factors usually exist in obese adipose tissue because obesity causes a higher level of glucose, FFA, and LPS in the blood as we said above. Therefore, ROS production may be an important factor that induces the pro-inflammatory activation of macrophages in obese adipose tissue. Recent studies have discovered some of the proteins involved in the regulation of ROS homeostasis and imbalance of ROS production and clearance can influence the pro-inflammatory activation of macrophages in obese adipose tissue [108–111], which indicates ROS is also another driver to induce pro-inflammatory activation of macrophages and targeting macrophage ROS homeostasis may be a potential way to ameliorate obesity-related inflammation and disorders.

Besides the internal regulations that we have summarized above, other potential regulatory mechanisms have also been discovered in the activation of ATMs in the obese state, including inflammatory signal pathway regulation [112–114], protein post-translational modification [115,116], the regulation of transcription factor [117,118], and iron homeostasis [119,120]. In brief, the activation of ATMs in an obese state is a complex process that involves multiple external signals and internal regulation, and targeting chronic inflammation with pharmacological or anti-inflammatory nutritional interventions in individuals with obesity is a potential strategy for obesity-related disorders.

3 The complex roles of macrophages in obese adipose tissue

3.1 Thermogenic regulation

Functionally, thermogenic adipose tissue, such as brown and beige adipose tissue, has critical roles in maintaining the core temperature through non-shivering thermogenesis [121]. Thermogenic adipose tissue can be activated in multiple ways, such as exercise-related hormones and cold [122–124]. When the body receives a stimulation, such as cold exposure, the sympathetic nervous system (SNS) is activated and the norepinephrine (NE) can be released to the adipose tissue from nerve terminals [125,126]. NE binds to the β3 adrenergic receptor (β3-AR) of adipocytes and activates the downstream cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling. Activated PKA can activate hormone-sensitive lipase (HSL) upon phosphorylation to release fatty acids and glycerol for fueling thermogenesis [127]. In addition, activated PKA can phosphorylate and activate peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PGC1α), a key transcription coactivator for mitochondrial biogenesis, to activate the transcription of UCP-1 [128]. Thus, thermogenic activation is a complex process that involves activation of the SNS, NE release, the binding of NE and receptor, substrate supply, and transcription change in adipocytes, among others, and a strategy that influences any of the facets mentioned above that can influence the thermogenic activity.

Macrophages can regulate the SNS–catecholamine–adipocytes axis to influence thermogenesis mainly in three ways (Fig.2). First, the macrophage-derived pro-inflammatory cytokines inhibit thermogenesis in the adipose tissue. Obesity tends to instruct a microenvironment to induce macrophage activation to release pro-inflammatory cytokines. The pro-inflammatory cytokine, TNF-α, inhibits the expression of UCP-1 mRNA in the adipose tissue by activating the extracellular signal-related kinase (ERK), indicating that the inhibitory effect of thermogenesis of TNF-α is a direct way [129]. Except for the inhibitory effect of UCP-1 expression in the adipose tissue, IL-1β also induces the translocation of IL-1R-associated kinase 2 (IRAK2) in mitochondria to inhibit oxidative metabolism in adipocytes, which may be another mechanism for the suppression of thermogenesis [130,131]. In recent years, an increasing number of studies have discovered the link between the inflammatory regulation of ATMs and thermogenesis in vivo, which confirms the link between the inflammation from macrophages and thermogenesis [92,93,132]. Second, ATMs can modulate thermogenic activity by regulating the concentration of catecholamines. Although the sympathetic nerves are the main source of catecholamines in the adipose tissue, two studies reported that cold exposure promotes the alternative activation of ATMs rapidly to release catecholamines for inducing thermogenic activity [133,134]. However, this conclusion was contested in another study because it was found that the knockout of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, in hematopoietic cells has no effect on the energy expenditure upon cold exposure or browning in the inguinal adipose tissue. Alternatively, IL-4-stimulated macrophages do not release NE into the medium, and conditioned medium from IL-4-stimulated macrophages fail to induce the expression of thermogenic genes in adipocytes [135]. Whether alternatively activated macrophages could regulate thermogenesis in the adipose tissue directly by releasing catecholamines needs confirmation. Besides their role in catecholamine production, ATMs also participate in the clearance of catecholamine, which includes its uptake and degradation [136,137]. A subpopulation of ATMs, which can uptake catecholamine, not by biosynthesis, has been identified to mediate the thermogenic activity [138]. Third, ATMs can regulate thermogenesis by regulating sympathetic activity. In a recent study, it was found that a macrophage-derived cytokine, slit guidance ligand 3 (Slit3), can be secreted from ATMs and that it binds to the roundabout homolog 1 (ROBO1) receptor on sympathetic neurons to activate Ca²⁺/calmodulin-dependent protein kinase II signaling and NE release and then activates the thermogenesis in mice [139]. Recently, another subpopulation of macrophages, named cholinergic adipose macrophages (ChAMs), has been identified to control the thermogenic activity of beige adipocytes in subcutaneous adipose tissue, mediated by acetylcholine [140]. Acute cold exposure activates ChAMs through the β2 adrenergic receptor, and beige adipocytes can sense ChAMs-produced acetylcholine to be activated through cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) to increase the thermogenic activity by UCP-1 and creatine futile cycling [140–142]. Notably, the thermogenic regulation of ChAMs is restricted in beige adipocytes because of the low abundance of ChAT⁺ macrophages in the BAT, and brown adipocytes do not have functional CHRNA2 to sense acetylcholine [140,141].

Most importantly, macrophage activation plays an important part in thermogenesis in mice, not only through the inhibitory effect of pro-inflammatory cytokines but also through the regulation of the SNS–catecholamine–adipocytes axis and the non-neuronal cholinergic system.

3.2 Mitochondria transfer

Mitochondria are important cellular organelles, considered the “powerhouse” of cells for generating ATP via OxPhos, which is the common oxidative pathway of glucose, lipid, and protein metabolism and is involved in the functions of many cells [143]. In a pathological state, such as hypoxia, aging, oxidative stress, and starvation, mitochondria are damaged, leading to ROS generation, energy exhaustion, and apoptosis that damage normal functions in cells [144–147]. Under these conditions, the damaged mitochondria need to be cleared quickly to meet the metabolic demand in cells. Previously, mitophagy, a process of cargo-specific autophagy within cells, was considered an acute and effective way to clear damaged mitochondria and regulate the quality and quantity of mitochondria [148]. Recently, it has been found that mitochondrial clearance does not happen only within a cell but also happens between cells—mitochondria transfer from one cell to another cell. The transfer of mitochondria occurs in physiologic or pathological conditions to maintain tissue homeostasis and the transferred mitochondria could either be healthy or damaged [149]. For example, healthy mitochondria can be released from astrocytes and can be taken up by neurons to promote the viability of neurons under conditions of stroke [150–152]. Moreover, macrophages also can transfer mitochondria to sensory neurons to control the resolution of inflammatory pain when inflammation happens [153]. In brief, the transfer of mitochondria between cells is important in maintaining homeostasis in cells and tissues.

Transfer of mitochondria can happen between adipocytes and ATMs in the adipose tissue (Fig.3) [154–156]. In the WAT, numerous types of cells, including macrophages, eosinophils, and neutrophils, can be the recipient of mitochondria from the adipose tissue, and macrophages are the main cells to take up mitochondria [154]. A study on adipocyte-specific mitochondria reporter mice model showed that 40% of macrophages in gonadal WAT contain mitochondria derived from adipocytes, confirming the existence of adipocyte–macrophage mitochondria transfer in the WAT in a lean state [154]. It was subsequently discovered that intercellular transfer of mitochondria to macrophages is impaired in diet-induced obesity and that pro-inflammatory macrophages have an impaired ability to phagocytize the beads with a size similar to that of mitochondria, suggesting that the impaired transfer of mitochondria from adipocytes to macrophages may impair the homeostasis of the adipose tissue [154]. Except in the WAT, adipocyte–macrophage mitochondria transfer also plays an important role in the regulation of thermogenesis in BAT. Rosina and colleagues discovered that thermogenic activity can induce adipocytes to release extracellular vesicles (EVs), containing damaged mitochondria, to the microenvironment in the BAT, and that these EVs exert a negative action on the thermogenesis if they are not timely cleared [155]. BAT-resident macrophages can remove the EVs containing damaged mitochondria derived from brown adipocytes and maintain the thermogenic activity in the BAT of mice [155]. In conclusion, adipocyte–macrophage mitochondria transfer is critical in maintaining the physiologic function of the adipose tissue, and targeting this transfer in the adipose tissue may be another potential therapeutic strategy to improve obesity-related disorders [155]. As of date, a comprehensive understanding of the mechanisms underlying the adipocyte–macrophage mitochondria transfer is limited; for example, it is not clear whether each EV released from adipocytes contains mitochondria and what is the function of other cells besides macrophages in the uptake of mitochondria from adipocytes. Furthermore, whether the adipocyte–macrophage mitochondria transfer has the same role in human metabolic homeostasis needs to be determined in further studies.

3.3 Adipose tissue fibrosis

Obesity-induced extracellular matrix (ECM) remodeling increases the fibrosis of adipose tissue, which can lead to a dysfunctional process and ultimately organ failure [157]. In a healthy state, ECM acts as a basic component involved in the maintenance of the tissue architecture and is essential for tissue homeostasis; however, obesity-induced fibrosis restricts the hypertrophy and hyperplasia of adipocytes, increasing the risk of insulin resistance and type 2 diabetes [158,159]. Obesity-induced fibrosis of adipose tissue is a chronic pathological process that involves numerous types of cells, including adipocyte progenitors and immune cells. PDGFRα⁺ progenitors are the main source of ECM components and fibrosis [160]. In addition, ATMs are the main cell population involved in regulating fibrosis in obese adipose tissue (Fig.4). The TLR4 signaling pathway is critical in the development of obesity-associated fibrosis of adipose tissue in bone marrow transplantation (BMT) and continuous LPS perfusion models [161]. During the development of obesity, the activation of macrophages induced by endogenous ligands released from dying adipocytes in the crownlike structure (CLS) increases the expression of C-type lectin (Mincle) to induce the expression of fibrosis-related genes, leading to the formation of myofibroblast and aggravating fibrosis in the adipose tissue [162]. Besides Mincle, thrombospondin 1 (TSP1) in macrophages can activate the transforming growth factor beta 1 (TGF-β1) signaling to induce the fibrosis of adipose tissue in obese mice [163]. Moreover, obesity induces macrophages to acquire a senescence-associated secretory phenotype and activate the expression of fibrosis-related genes in adipocyte progenitors [164]. Recently, a new regulator of fibrosis has been reported in obese adipose tissue. It has been discovered that obesity induces a reduced enzymatic activity in the adipose tissue and increases the release of peptidase D (PEPD), a homodimer cytosolic protein that can degrade proline-containing dipeptides (Xaa-Pro or Xaa-hyp) to regulate the degradation and turnover of collagen [165]. Further experiments found that ATMs are the main resource of PEPD and the enzymatic activity and release are related to the proinflammatory activation of macrophages, which confirms the link between macrophage activation and the fibrosis of adipose tissue [165]. Besides the role in the fibrogenesis of adipose tissue, macrophages can also reduce the content of ECM through the uptake and degradation of collagen. The clearance of collagen can happen in M2-like macrophages that uptake collagen in a receptor-dependent pathway [166]; however, whether obesity-induced pro-inflammatory activation of ATMs impairs the ability to uptake collagen is unclear.

3.4 Exosome secretion

Exosomes are EVs (50–200 nm) surrounded by a phospholipid bilayer. They play an important role in cell communication by carrying a variety of molecular components, including mRNA, microRNA (miRNA), and protein [167]. miRNAs are small noncoding RNAs that regulate the expression of target mRNAs by binding to them and leading to their recruitment to the RNA-induced silencing complex (RISC) and eventual degradation [168,169]. Recently, ATM-derived exosomes containing miRNA were reported to be secreted into the circulation and to modulate systematic insulin action (Fig.5). Ying and colleagues discovered that treatment of lean mice with obese ATM-derived exosomes causes insulin resistance and treatment of obese mice with lean ATM-derived exosomes improves insulin resistance, indicating that the exosomes derived from ATMs are important in modulating the insulin action in mice [170,171]. Further cell experiments identified more than 500 miRNAs in the exosomes derived from ATMs and obesity could significantly change the expression of some of these miRNAs, such as miR-149, miR-155, and miR-690. Among the identified miRNAs, the effect of miR-155 and miR-690 was further confirmed. In the lean state, ATM-derived exosomes containing miR-690 improve the insulin action in the skeletal muscle, liver, and adipose tissue [170,171]. However, obesity induces ATMs into a pro-inflammatory state. The expression of some miRNAs changes significantly with an increase in the expression of miR-155 and decreases in that of miR-690 in the exosomes derived from ATMs and the increase in miR-155 from ATMs in the obese state could cause insulin resistance [170,171]. Thus, exosomes are a treasure trove waiting to be explored; Ying and colleagues discovered more than 500 miRNAs in exosomes derived from ATMs but explored the functions of only miR-155 and miR-690. In other studies, the regulatory functions of other miRNAs in exosomes derived from ATMs have been demonstrated. For example, miR-210 in exosomes derived from ATMs suppresses the expression of NADH dehydrogenase ubiquinone 1 alpha subcomplex 4 (NDUFA4) in the adipose tissue and promotes the pathogenesis of diabetic obesity in mice [172]. MiR-143-5p in the exosomes from bone marrow-derived macrophages contributes to insulin resistance in hepatocytes by repressing mitogen-activated protein kinase phosphatase-5 (MKP5) [173]. MiR-212-5p in the exosomes from pro-inflammatory macrophages can inhibit the secretion of insulin by beta-cells in mice [174]. However, there are many unanswered questions regarding ATM-derived exosomes. Some pertinent questions are as follows: (1) What are the functions of other miRNAs, besides the ones that have been explored, in the ATM-derived exosomes? (2) What are the functions of other cellular components in the exosomes derived from ATMs, considering exosomes contain a complex mixture of mRNAs, miRNAs, proteins, and other cellular components? (3) Whether macrophages in different organs involved in metabolisms, such as the liver, adipose tissue, and skeletal muscle, express the same miRNAs in exosomes? (4) Whether there are other regulatory mechanisms for the expression of miRNAs in the exosomes? Undoubtedly, a brand new regulatory pathway between macrophages and adipocytes or distal tissues has been found, and targeting ATMs derived exosomes may be an effective way to improve obesity-related disorders.

3.5 T cell activation

Besides macrophages, T cells also accumulate in the adipose tissue in an obese state and contribute to the generation of inflammation and insulin resistance [33]. Nishimura and colleagues found increasing numbers of CD8⁺ effector T cells infiltrating the adipose tissue in HFD-fed mice and these infiltrated CD8⁺ T cells accumulate in the adipose tissue, preceding the accumulation of macrophages [175]. Genetic depletion of CD8⁺ T cells reduces the infiltration of macrophages in the adipose tissue and improves systemic insulin resistance, suggesting that the infiltration of T cells may be one of the triggers to induce the inflammation of the adipose tissue in obesity [175]. Although the accumulation of T cells in the adipose tissue precedes that of macrophages, macrophages are essential for maintaining the activation of T cells in the adipose tissue because the study revealed that weight loss in mice does not reduce the frequency of IFN-γ⁺ and TNF⁺ CD8⁺ T cells and IL-17⁺ and IL-22⁺ CD8⁺ T cells in the adipose tissue. However, macrophage depletion significantly reduces the frequency of IFN-γ⁺, TNF⁺, IL-17⁺, and IL-22⁺, CD8⁺ T cells in the adipose tissue, suggesting a critical role for macrophages in activating T cells [176]. ATMs are the most prominent professional antigen-presenting cells (APCs) in mice and humans [177,178], and they can process and present major histocompatibility complex (MHC) class II-restricted antigens to promote the activation of antigen-specific T cells [179]. Macrophage-specific MHC-II knockout is sufficient to prevent the accumulation and maturation of CD4⁺ T cells in the adipose tissue and to attenuate HFD-induced insulin resistance due to improved insulin sensitivity in the adipose tissue [180]. Moreover, macrophages promote the production of interleukin-22 (IL-22) and interleukin-17 (IL-17) from CD4⁺ T cells in the adipose tissue by secreting the pro-inflammatory cytokine IL-1β, and reciprocally, IL-22 can bind to IL-22 receptors and induce the transcription of pro-Il1b in macrophages [181]. In conclusion, macrophages and T cells coordinate to induce inflammation and insulin resistance in the adipose tissue in an obese state (Fig.6).

3.6 Clearance of dead adipocytes

ATMs can maintain the homeostasis of the adipose tissue by clearing dead or damaged adipocytes and fragmented cellular contents (Fig.7). The rate of adipocyte death is increased about 30-fold; dead adipocytes exhibit ultrastructural features of necrosis in the development of obesity in mice and humans, and can cause dysfunction and inflammation in the adipose tissue [182,183]. A fat apoptosis mice model that allows for the elimination of adipocytes can induce the infiltration of macrophages into the adipose tissue, which confirms the relationship between adipocyte death and macrophage recruitment [184]. The dead adipocytes and the surrounding macrophages form CLS, where macrophages release lysosomal enzymes to the microenvironment of dead adipocytes through exocytosis to form an extracellular acidic compartment to degrade adipocyte debris, leading to the release of FFA and the formation of foam cells [182,185,186]. Although obesity is considered a chronic inflammatory disease, with the characteristic of an increased number of pro-inflammatory macrophages infiltrating the adipose tissue, apoptosis of adipocytes occurring in the adipose tissue can induce the recruitment of alternatively activated CD206⁺ M2 macrophages into the adipose tissue, which indicates that the death of adipocytes is not the initiating factor in the induction of inflammation in the adipose tissue and that adipocyte death-induced M2 macrophage infiltration may contribute to the repair of tissue damage [184]. Indeed, adipocyte death can contribute to the lipid-related activation of macrophages in the adipose tissue because macrophages surrounding the dead adipocytes exhibit a morphology similar to that of foam cells, which indicates that adipocyte death can induce the activation of macrophages through lipotoxicity [182,187]. Thus, clearance of dead adipocytes is another function of macrophages required to maintain homeostasis of the adipose tissue.

3.7 Angiogenesis

In individuals with obesity, the increased oxygen demand because of expansive adipose tissue contradicts the relatively lower oxygen supply, requiring more neovascularization to provide sufficient oxygen and nutrition [188]. ATMs also regulate the physiologic and pathological remodeling of adipose tissue by mediating angiogenesis because macrophage depletion by clodronate liposomes significantly reduces the capillary density in the adipose tissue, indicating that macrophages are essential for angiogenesis in the adipose tissue [189,190]. ATMs can promote angiogenesis in obese adipose tissue in multiple ways. First, inflammation in adipose tissue can promote angiogenesis. It is widely accepted that obesity is a chronic inflammatory disease accompanied by the accumulation of pro-inflammatory macrophages in the adipose tissue and ATM-derived pro-inflammatory cytokines, such as TNF-α and IL-6, can promote angiogenesis [191–194]. Second, lymphatic vessel endothelial receptor 1-positive macrophages participate in the angiogenic remodeling of the adipose tissue ECM by secreting tissue remodeling factors, such as matrix metalloproteinase (MMP)-7, MMP-9, and MMP-12, which activate vascular endothelial growth factor/vascular endothelial growth factor receptors (VEGF/VEGFR) signaling to promote the formation of new blood vessels [195,196]. In addition, macrophages are the main source of platelet-derived growth factor (PDGF) in the adipose tissue and PDGF mediates capillary maturation by recruiting pericytes [189]. Above all, obese adipose tissue has limited blood vessel that is linked to glucose homeostasis and ATMs can maintain the homeostasis of the adipose tissue by mediating the ECM remodeling and angiogenesis (Fig.7).

4 The complex heterogeneity of adipose tissue macrophages

The correlation between inflammation and insulin resistance has been explored for two decades. Many signal pathways involved in the formation of chronic inflammation including JNK, IKK/NF-κB, JAK/STAT [197–201], and the inflammation derived from macrophages in obese adipose tissue is considered a promising target for the treatment of obesity-related insulin resistance and diabetes even though the causal relationship between inflammation and insulin is still subject to further proof. Current studies attempt to target macrophage-derived inflammatory factors such as IL-1β, IL-6, and TNF-α but the therapeutic effects exit huge heterogeneity. Antibodies targeting IL-1β, IL-6, and TNF-α are the direct methods that can effectively reduce the content of inflammatory factors and inflammatory signals correspondingly. IL-1β neutralizing antibody exert positive effects in the regeneration of β-cells and the improvement of HbA1c, glycemia, and insulinemia for high-risk patients with type 2 diabetes [202,203]. IL-6 neutralizing antibody also have a positive effect for reducing HOMA-IR and insulin resistance in non-diabetic patients with RA [204]. The effect of inhibiting TNF-α for the treatment of insulin resistance shows great controversy. Even though many studies show great therapeutic prospect for the inhibition of TNF-α [205,206], TNF-α neutralizing antibody shows no effect on the improvement in glucose homeostasis and insulin sensitivity in clinical trials [207,208]. Up to now, it is hard to answer the question of why TNF-α neutralizing antibody do not affect insulin sensitivity. Moreover, it seems that focusing on macrophage inflammation alone is not sufficient to fully understand the functions of ATMs.

The contradictoriness of therapeutic effects targeting inflammatory factors forces us to think: (1) whether macrophage-derived inflammation plays the most important role in the induction of insulin resistance compared to other functions. (2) whether all the macrophages in the adipose tissue tend to differentiate into the pro-inflammatory state? Recently, the development of single-cell technologies created a deeper insight into the understanding of the heterogeneity and plasticity of ATMs in obesity (Fig.8). Previously classical theory thought ATMs are the cell population that polarizes toward the pro-inflammatory M1 activation in obesity occurs [177,209], however, a new algorithm (MacSpectrum) for high-resolution macrophage analysis based on single-cell transcriptome data found that ATMs isolated from obese or lean murine visceral adipose tissue have different transcriptome pattern comparing to the M1 or M2 activated macrophage [210]. Recent studies based on scRNA-seq or snRNA-seq reveal the heterogeneity and plasticity of ATMs and found that only a part of ATMs polarizes toward a more pro-inflammatory state and others are more metabolically active [13,211–216]. In a single-cell study of human white adipose tissue, pro-inflammatory factors IL-1β and TNF-α were found primarily expressed in lipid-associated macrophages (LAM) and inflammatory macrophages (IM). Using single-nucleus RNA-seq of epididymal adipose tissue in mice, six different macrophage subpopulations have been found: regulatory macrophages (RM), perivascular-like macrophages (PVM), LAM, non-perivascular-like macrophages (NPVM), collagen-expressing macrophages (CEM) and proliferating LAM(P-LAM) [211]. Notably, even though obesity increases the total number of macrophages in the adipose tissue, only LAM and P-LAM increase significantly with a decrease in PVM and NPVM [211]. The heterogeneity of macrophages may be a good explanation for why macrophages have multiple functions. For example, LAMs are found enriching at CLS, which may present a subpopulation that has the function of clearing dead adipocytes [213,217]. These findings further testified the theory that obesity only induces a transition of macrophage from M1 to M2 is too narrow-minded. Moreover, weight loss and weight regain cause the rapid dynamics of LAMs, which may be the reason that anti-obesity therapy easy to regain obesity quickly [218]. In conclusion, single-cell technologies bring the ATM into the single-cell era, exquisite subpopulations help us to understand why macrophages display multiple functions, and finding the key mechanism mediating the shift between different macrophage subpopulations may help explore more specific therapy in the treatment of obesity and diabetes.

5 Strategies for manipulating macrophages

With the deeper investigation of the pathology of metabolic diseases, the mysterious complexity of macrophages has been revealed. The macrophage population represents a group of cells with diverse roles and physiologic characteristics, especially in the induction of obesity and metabolic diseases. Based on the importance of macrophages in obesity, targeting macrophage activation exerts enormous potential for the treatment of metabolic diseases. For example, gut microbiota-derived LPS activates ATMs to exacerbate inflammation and insulin resistance [28], therefore, targeting LPS and TLR4 signaling is a potential strategy. Hematopoietic cell-specific TLR4 deletion mice showed significantly reduced inflammation in adipose tissue and improved insulin sensitivity in liver and adipose tissue after HFD-induced obesity [219]. IKK and MyD88 are both the key downstream of TLR4, and mice with myeloid cell-specific IKKb or MyD88 deletion prevent the development of insulin resistance [220,221], further suggesting targeting TLR4 shows great possibility. As mentioned in our review, macrophage activation is a complex process that involves multiple outer activations and inter-adaption, because obese adipose tissue create much inflammatory stimulation, and macrophage undergoes a series of adaption to activate rapidly. Theoretically, the strategies that can reduce outer inflammatory stimulations or inhibit internal activation to reduce inflammatory activation, or strategies that target the key protein which mediates the dysfunction of obese ATMs, all have the potential to be explored for the development of novel therapeutic targets for metabolic diseases. Some promising targets have been discussed in previous reviews such as ROS controlling and metabolic pathway intervention [222]. Up to now, enormous regulatory functions of macrophages for the development of metabolic diseases have been discovered, and some new regulatory mechanisms and potential targets are being discovered [24]. However, there are many disadvantages to targeting macrophages for the treatment of metabolic diseases. First, macrophages are the immune cell population that spread throughout the body [223], the method of targeting macrophages may impact the macrophages in nontarget organs. Then, the regulatory effect of macrophage on physiologic function shows great heterogeneity. For example, even though inflammation derived from macrophages contributes significantly to the induction of insulin resistance, however, a study found macrophage-derived IL-1β contributed to the postprandial stimulation of insulin secretion [224], suggesting some known targets in macrophages may have unexpected effects. Next, the same target in macrophages and other types of cells may show great heterogeneity. For instance, obesity-induced hypoxia because of increased adipocyte O₂ consumption exacerbates inflammation and insulin resistance, and myeloid cell-specific HIF-1α gene deletion can protect against HFD-induced inflammation, suggesting macrophage HIF-1α is a potential target [41,225]. Nevertheless, it seems that HIF-1α is also important to maintain normal physiologic functions in endothelial cells [226], the off-target effect on endothelial cells from the method that targets macrophage may have the opposite effect. Based on these potential problems, finding strategies that specifically target macrophages with non-off-target effects is of great significance for improving the clinical application of obesity. Here, we list common strategies for targeting macrophages and discuss their characteristics, hoping to further deepen our understanding of strategies for targeting macrophages to improve obesity and metabolism-related disorders.

5.1 Drug development targeting macrophages

The storm of obesity raze the world from 1975 to 2016 with the prevalence ranging from 3.7% in Japan to 38.2% in the United States [227]. There are three kinds of main methods in the management of obesity: lifestyle chang, pharmacotherapy, and surgery [228]. Compared with pharmacotherapy, most obese patients usually cannot hold for a long time by lifestyle changes and a part of obese patients have serious adverse reactions after getting bariatric surgery. Therefore, pharmacotherapy is more appropriate with more convenience than lifestyle change and is more acceptable than bariatric surgery, and pharmacotherapy is recommended to patients with BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with obesity-associated comorbidities [229]. Nowadays, the drugs applied in the clinic such as phentermine, orlistat, contrive, liraglutide and semaglutide control bodyweight mainly through food intake, and some promising pre-clinical compounds such as growth differentiation factor 15 (GDF15) agonist, diacylglycerol acyltransferase 2 (DGAT2) inhibitor and thyroid hormone receptor beta (THR-β) agonist have the effect of weight loss mainly by regulating energy balance including energy intake, energy storage and energy expenditure [230]. There are still no potential compounds specifically targeting macrophages applied in clinical trials because of the difficulties in drug-specific delivery methods. Recently, a newly published article found a new compound (a small-molecule infrared dye), IR-61, that can selectively target macrophages in adipose tissue and inhibit the pro-inflammatory activation of macrophages to improve obesity-related insulin resistance and hepatic steatosis [70]. However, intraperitoneally administered IR-61 has also been found in other organs such as the liver, heart, and lung, suggesting difficulties in targeting ATMs [70]. Actually, the compound targeting ATMs must overcome two barriers: the compound must distribute specifically in adipose tissue and then only exert functions in macrophages. It may be more clinically practical to take macrophages as a secondary target rather than the direct target in the treatment of obesity-related disorders. For example, metformin, a widely used clinical drug, is the first line of oral therapy for the treatment of type 2 diabetes [231]. Even though the concentration of metformin in the liver is higher than in other metabolic organs and the liver is taken as the main effective organ, metformin is also involved in adipose tissue remodeling [157,232]. The characteristics of small molecular weight make metformin have multiple effector cells. Evidence shows that metformin inhibits the inflammation from macrophage, and metformin can decrease the inflammation of adipose tissue in HFD-induced obese mice [233,234]. Several studies found AMPK activation may be the core mechanism of metformin and AMPK is the key regulator of macrophage activation [71,235,236]. It happens that there are other similar cases, other glucose-lowering drugs such as dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors can also decrease the inflammation in macrophage, showing great dual functions of hypoglycemia and anti-inflammation [237–240]. Based on the dual functions, these drugs may be more appliable for those patients with obesity-induced diabetes. In conclusion, it is hard to design a compound that specifically targets macrophages because of the widespread distribution of macrophages throughout the body and the potential off-target effect. The marketed drugs with anti-inflammatory properties for the treatment of inflammation-related diseases may have better efficacy and lower development costs.

5.2 Nanoparticle

Nanoparticle is a general term for multiple engineered materials with a diameter between 1 and 1000 nm and a large surface-to-volume ratio, which has excellent properties of drug loading with higher efficiency and lower off-target effect, and nanoparticle-related delivery methods are popular in clinical and pre-clinical research [241–244]. Up to now, multiple nanomaterial-related drugs have been applied in clinical trials, especially in cancer imaging because nanomaterial delivery systems can provide visualization in a rapid, longitudinal, and non-invasive way [245,246]. Macrophages are the cell population of part of the innate immune system and can phagocytize or engulf foreign material in a receptor-dependent way, and that is the base for nanoparticles that can target macrophages with minimal toxicity and off-target effects [247]. The greatest advantage of nanoparticles is that any protein can be targeted once the nanoparticles can be delivered precisely into the target cell. For example, nanoparticles can coat siRNA and knockdown target protein to intervene in the activatory state of macrophage. p5RHH (VLTTGLPALISWIRRRHRRHC), a cationic amphipathic peptide was designed to transfect siRNA to create 55-nm nanoparticles that are phagocytosed by macrophages without significant cytotoxicity at all tested doses [248]. The p5RHH-based NF-κB p65 siRNA delivery system has a potent therapeutic effect for inflammation and osteoarthritis, verifying the clinical application potential of nanoparticles [249,250]. To testify the potential therapeutic effect on obesity-related disorders by manipulating macrophage polarization, Wei Zou and colleagues coated Asxl2 siRNA with p5RHH and subjected to HFD-induced mice by intravenous injection [132]. Nanoparticles-mediated Asxl2 knockdown in macrophages significantly combats weight gain in HFD-induced obesity compared with GFP-siRNA-associated nanoparticles, further confirming the therapeutic potential through the nanoparticles-delivered system in macrophages [132]. Meanwhile, this work also found it is hard to only target adipose tissue for the siRNA-associated nanoparticles can be detected in many organs such as the kidney, spleen, bone, lung, muscle, and white adipose tissue, which can be attributed to the fact that obesity is a kind of disease with system inflammation across many organs [132,251]. Mechanically, nanoparticles-mediated Asxl2 knockdown inhibits the inflammatory activation of macrophages to ameliorate HFD-induce obesity [132], and targeting macrophage polarization is a promising field for the treatment of metabolic disorders [222]. It is only necessary to change the type of siRNA to easily achieve the role of targeting different key proteins for the inflammatory activation of macrophages. Another advantage of nanoparticle-mediated delivery is that nanoparticles are not limited to only one single form, and nanoparticles can be designed and modified flexibly according to various requirements. For example, based on the expression of dextran binding C-type lectins and scavenger receptors in macrophages [252–254], a new type of polysaccharide nanocarriers was designed to carry drugs specific into macrophages, and 40%–63% of injected dose nanocarriers was accumulated in adipose tissue after injection for 24 h, which is a predominant high level for targeting [255]. Next, the authors conjugated the polysaccharide nanocarriers with a classical drug with the effect of anti-inflammation, steroid dexamethasone, and found that polysaccharide nanocarriers conjugated dexamethasone can decrease the inflammation in adipose tissue after intraperitoneal injection for 24 h, confirming the potential therapeutic effect of this nanocarrier for obesity [255]. Another example reflecting the flexibility in the design of nanoparticles is that nanoparticles are coated with the extra macrophage cell membrane to decrease some practical challenges such as immune barriers, limited blood circulation time, biodistribution, and toxicity, and this strategy shows great therapeutic potential in inflammation and cancer [247]. With the development of deeper investigation, the field of nanoparticles has made great achievements in finding new types of nanoparticles in raw material composition or delivery methods, providing more choices for clinical applications. In brief, nanoparticle-based drug delivery systems provide a more precise method for targeting macrophages, and more and more novel nanomaterial and nano-related delivery improvements promote diversity in the treatment of inflammatory diseases.

5.3 Liposomes

Liposomes are the general term for a kind of phospholipid vesicles, another well-investigated delivery platform for drug targeting, which has a size of 15–1000 nm and can carry various drugs in their bilayer membrane or core space [256]. The development of liposome-mediated delivery systems optimizes various ways such as medicine stability, technological obstacles in tissue and cell target, and biodistribution to improve the therapy that is hard to realize previously [257–260]. Different from the diversity of nanoparticles, liposomes are usually composed of lipid bilayers, and these lipid bilayers can form a core aqueous space [261]. Except for the delivery of drugs in the lipid bilayers or aqueous space, the outer membrane can be modified including conjugating antibodies or ligands to increase cell targeting [261]. Some modifications in the outer membrane can increase the specific targeting of macrophages. For example, CD163, a constitutive endocytotic receptor, is highly expressed in cells of the monocytic-macrophage lineage [262,263], mediating the clearance of the Hp-Hb complex from circulation in macrophages [264]. The liposomes conjugated with CD163 antibodies on the surface can be accumulated in macrophage-rich tissue [265]. There are other similar designs such as liposomes conjugated with IL-6 receptors to increase the affinity with activated macrophages [256]. Many studies are using modified liposomes targeting monocytes or macrophages, trying to design novel therapeutic methods for the treatment of inflammatory diseases such as atherosclerosis and inflammatory lung disease [266,267]. Another example of liposomes targeting macrophages is that clodronate-contained liposomes are used to delete macrophages of target organs in pre-clinical research. Clodronate is a kind of bisphosphonate previously used to cure osteolytic bone disease and post-menopausal osteoporosis for its function of inhibiting osteoclast, and clodronate can result in the death of macrophage through irreversible metabolic damage [268,269]. Through changing the way of administration, clodronate liposomes can deplete tissue-resident macrophages in different organs. For instance, intravenous injection of clodronate liposomes can deplete macrophages in the liver, spleen and bone marrow, and intraperitoneal injection of clodronate liposomes can deplete peritoneal macrophages [268,270]. Rooijen and colleagues developed clodronate-contained liposomes to delete macrophages primarily based on the principle that liposomes have the property for targeting mononuclear phagocytic cells and the clodronate liposomes with enough size can be rapidly taken up by macrophages [271]. Based on this technology, multiple regulatory functions of macrophages in physiologic or pathological have been revealed. A study in 2013 reported that intraperitoneal injection of clodronate liposomes to delete macrophages in visceral adipose tissue presents an improved metabolic phenotype in weight gain, fat accumulation, insulin resistance, and hepatic steatosis after HFD, suggesting the key regulatory functions of macrophage in the induction of metabolic disorders [272]. However, another study reported in 2017 found that macrophage in adipose tissue is crucial in the induction of adaptive thermogenesis after cold exposure because macrophage deletion in subcutaneous adipose tissue by clodronate-liposomes decreases the expression of macrophages and UCP-1 [88]. The contrasting metabolic phenotype resulting from macrophage deletion may be ascribed to the state of macrophage. The inflammatory activation of macrophages in the state of obesity exacerbates the progression of obesity and insulin resistance, thereby potentially explaining why deleting macrophages can alleviate disorders associated with obesity [31,35,188]. On the contrary, in the context of cold exposure, alternatively activated macrophages play a crucial role in adipose tissue thermogenesis, potentially accounting for the compromised thermogenic activity observed after macrophage deletion during cold exposure [133,139]. Although it is still controversial for the functions of macrophages, however, liposome-mediated delivery systems have been a common tool for macrophage studies. In conclusion, liposome mediated-deliver system is another attractive therapeutics like nanoparticles, which can solve many current problems such as off-target effects and undesired distribution of drugs in clinical drug application. After all, the basic structure of liposomes has been investigated fully, and many drugs can be delivered more precisely once mature liposomes have been approved for clinical usage only through optimized carriers instead of developing new compounds.

5.4 Manipulating macrophages in vitro

As functional assisting cells, macrophages have the potential to be modified without influencing the normal functions of target organs. Based on this property, macrophages can be modified in vitro and then imported into the body for therapeutic effect. There are two primary sources of ATMs, tissue-resident and monocyte-derived macrophages [222]. Obese adipose tissue increases the infiltration of macrophages from monocytes that derive bone marrow through MCP-1 [31,273–279], and the infiltrated macrophages in the adipose tissue can form CLS around necrotic adipocytes to secrete inflammatory cytokines [182,185]. Therefore, the modification of bone marrow may ultimately affect the macrophage infiltrated into the obese adipose tissue. Sandra Galic and colleagues transplanted the bone marrow of AMPKβ knockout into lethally irradiated wild-type mice and found that wild-type mice receiving AMPKβ knockout bone marrow incur more inflammation and result in exacerbated insulin resistance in metabolic organs after HFD, suggesting the manipulation of bone marrow can influence the activation of macrophages in metabolic organs [39]. Similar data were observed in a study that Pellegrinelli and colleagues observed a significantly reduced adipose tissue fibro-inflammation and improved insulin sensitivity in obese mice after transplanting Pepd knockout bone marrow into wild-type mice, suggesting the manipulation of potential protein in bone marrow may be another therapeutic method for metabolic disease [165]. However, the research on BMT is limited in pre-clinical trials because of the unexpected cost loading and adverse effects, and a patient with obesity will not choose to treat metabolism-related disorders by BMT. Nevertheless, this method can provide some advice for reference in the clinic, for example, the bone marrow from the lean donor or the bone marrow from the donor with a mutation that inhibits macrophage activation may have a better therapeutic effect for the obese patient with leukemia who will receive the treatment of BMT. Except for the violent operation on bone marrow, the direct manipulation of macrophage in vitro may have a potential therapeutic effect on metabolic. Yi-Na Wang and colleagues overexpressed Slit3 in macrophages and injected these gene-manipulated macrophages into adipose tissue and found the function of adipose tissue is improved remarkably, suggesting the therapeutic effect of macrophage manipulation in vitro. Similarly, this method is primarily applicable in pre-clinic trials because many practical obstacles remain to be overcome. Even mature cell therapy like CAR-T that manipulates T cells in vitro still has many restrictions on clinical use. Nowadays, the technology that manipulates macrophages in vitro is more applicable to pre-clinical trials, and the clinical application of macrophage therapy for obesity-related disorders needs more technological improvement.

5.5 Other methods targeting macrophages

Except for the classical nanoparticle and liposomes, many novel carriers have been used to deliver drugs targeting macrophages. For example, macrophages have a high expression of Dectin-1 which is a macrophage receptor of β-glucans, and β-glucans are the sugars of bacteria cell walls [280,281]. Based on this relationship, yeast-derived β-glucans have been used to coat siRNA and small molecules to target macrophages independent of the activatory state of macrophages in the form of hollow particles with the size of 2–4 μm [282–284]. Another interesting molecular target of macrophages is the dendrimer which is a three-dimensional macromolecule with many branches [285]. Kumar and colleagues developed a mannosylated dendritic architecture loading rifampicin to selectively deliver rifampicin to alveolar macrophages and found this mannosylated dendrimer can promote the uptake of alveolar macrophages [286]. Moreover, some specifically modified oligopeptide complexes have been found to have the potential for targeting macrophages. The designed oligopeptide complexes that target specific cell populations can silence genes through peptide-bound oligonucleotide sequences such as siRNA or shRNA [256]. Yong and colleagues designed an adipocyte-targeting sequence (ATS-9R) conjugated TACE shRNA that can be taken up by ATMs specifically after intraperitoneal injection and found that this complex can decrease inflammation in adipose tissue, providing a new strategy for macrophage targeting [287]. In a word, the drug delivery system targeting macrophages is not unique, more and more new drug delivery systems are being developed.

The current focus of combating obesity through macrophage targeting primarily lies in pre-clinical research. The development of obesity is typically attributed to an energy imbalance, where energy intake surpasses energy expenditure even though obesity can also be influenced by inherited, physiologic, and/or environmental factors [288,289]. Therefore, therapeutic methods targeting the correction of this energy imbalance can yield significant positive outcomes without necessitating a comprehensive understanding of the intricate pathological mechanisms underlying obesity. The primary clinical approach for treating obesity is currently focused on reducing food intake to limit energy consumption. For example, short-term drugs such as phentermine, phendimetrazine, diethylpropion, and benzphetamine can effectively combat obesity by suppressing appetite. Additionally, newly approved GLP-1R agonists like semaglutide can be used for long-term weight management by inhibiting food intake through the suppression of appetite and gastric emptying [230,290,291]. Compared with other methods of combating obesity, targeting energy metabolism can directly exert an anti-obesity effect, disregarding the intricate pathogenesis, which is why certain potential approaches, such as macrophage targeting, are still in the pre-clinical stage. Even though there is still time for the implementation of the macrophage-targeting approach in clinical settings, comprehending the pathology of obesity and facilitating drug development for its management can be facilitated by understanding the intricate mechanisms of activation and diverse functions exhibited by macrophages within obese adipose tissue.

6 Discussion

The population of macrophages, which are a diverse group of immune cells, play pivotal roles in the pathogenesis of various metabolic disorders such as obesity, non-alcoholic fatty liver disease (NAFLD), and atherosclerosis [292]. Investigating the role of macrophages in the pathogenesis of metabolic diseases facilitates the development of potential therapeutic strategies for enhancing metabolism-related disorders. Over the past two decades, it has been challenging to elucidate the underlying reasons for the divergent roles of macrophages in obesity development. This is because while inflammation from obese macrophages can exacerbate tissue disorders and induce insulin resistance, these cells also play a crucial role in maintaining adipose tissue homeostasis through angiogenesis and clearance of dead adipocytes. Recently, the heterogeneity mechanisms of macrophages in obese adipose tissue have been elucidated through the integration of single-cell technologies. First, the remarkable plasticity of macrophages in response to external signals forms the foundation for heterogeneity within adipose tissue because the phenotype of macrophages varies in response to different stimulations. There exist classically activated M1 macrophages, which are stimulated with LPS and express pro-inflammatory cytokines, as well as alternatively activated M2 macrophages, which are stimulated with IL-4 and express anti-inflammatory cytokines [293,294]. The presence of metabolically activated macrophages, which are stimulated by elevated levels of glucose, insulin, and palmitate, highlights the remarkable versatility of macrophages as they possess the ability to secrete pro-inflammatory cytokines and eliminate deceased adipocytes [295,296]. Then the heterogeneity of adipose tissue creates a microenvironment with diverse stimulation, which serves as the foundation for the heterogeneous functions of macrophages. For instance, a novel model has been proposed suggesting that the expression of M-CSF and IL-13 from adipocyte precursor cells and innate lymphoid cells, respectively, may induce monocyte differentiation into perivascular macrophages to facilitate tissue homeostasis in a lean state. Whereas, the activation of innate lymphoid cells and natural killer cells can stimulate the differentiation of pro-inflammatory macrophages in individuals with obesity [13,211,297]. The high plasticity of macrophages and the heterogeneity of the microenvironment in adipose tissue, therefore, constitute the foundation for functional heterogeneity of macrophages in obese adipose tissue. The macrophages in this state undergo pro-inflammatory stimulation, such as exposure to LPS and fatty acids, leading to their differentiation into an inflammatory phenotype, mediating the development of inflammation, fibrosis, and impairment of thermogenesis. The macrophages close to apoptotic adipocytes are capable of phagocytosing the debris and mitochondria released by the adipocytes, thereby facilitating tissue homeostasis. In fact, the individual macrophages in obese adipose tissue may receive multiple signals and exhibit simultaneous inverse functions, which could potentially explain why certain studies have observed unique characteristics of ATMs compared to those tested in vitro [298]. The investigation of macrophage activation and functions in the microenvironment should be expanded to include different signals that mimic the complex environment of obese adipose tissue, rather than relying solely on classical stimulations such as LPS or IL-4 in vitro tests. Moreover, the various subgroups of macrophages should now be regarded as distinct cellular populations for further investigations.

In recent decades of exploration, research has primarily focused on three aspects of the involvement of macrophages in obesity development. The first aspect pertains to the intricate mechanisms underlying the pro-inflammatory activation of macrophages in obese adipose tissue. The pro-inflammatory activation of macrophages is widely acknowledged as a primary driving force in the development of insulin resistance during obesity, and identifying key mechanisms underlying this activation can help identify potential targets for treating obesity. Up to now, multiple external pro-inflammatory stimulations have been identified, and intricate intracellular metabolic pathways and pivotal proteins involved in the adaptive activation process have been found, which are potential targets for the inhibition of inflammation and the treatment of obesity. The second aspect of the studies on macrophages in adipose tissue involves investigating novel functions of macrophages beyond inflammation, as well as exploring potential mechanisms underlying their formation. Maybe it is challenging to comprehend the multifaceted functions of macrophages in obese adipose tissue a decade ago, however, with the advancements in single-cell technologies, the integration of transcriptome and spatial analysis has facilitated our understanding of the underlying mechanisms. The third aspect of the studies on macrophages in adipose tissue is the endeavors aimed at targeting macrophages for obesity treatment. The development of drug discovery or novel delivery systems enhances the potential for clinical translation in targeting macrophages for pharmaceutical applications.

The application of research on macrophages in clinical treatment still poses challenges because the attempt to suppress inflammation to improve obesity did not yield satisfactory outcomes. It does not mean that targeting macrophages is not a promising method, on the contrary, it underscores the intricate pathogenesis of obesity, which is the reason why the limited number of anti-obesity drugs are available, despite centuries of research, and all of these anti-obesity drugs exert effect primarily relies on suppressing food intake. The issue of obesity has been a formidable challenge that humanity has grappled with for centuries, however, the investigation into macrophages in obese adipose tissue has only spanned two decades, and further time is required to translate the findings from mouse research into clinical applications. Currently, the research priorities regarding ATMs may have shifted from the previous emphasis on target verification to clinical application. More precise identification of cell clusters and their respective functions of every cluster is necessary, potentially requiring the use of single-cell technologies. Additionally, based on the mechanisms and key functions of ATMs activation, potential therapeutic targets of macrophages should be expedited to clinical trials as soon as possible, which necessitates the acceleration of drug delivery systems targeting macrophages.

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