The human body contains a large amount of WAT, which is primarily found in the subcutaneous regions of the buttocks, deep and shallow abdomen, and visceral area, where it is located beneath the skin. WAT serves as a buffer against external mechanical stress, an insulator against heat loss, and a barrier against skin infections. Vital organs in the peritoneum and ribs of the body are encased in visceral white fat (36).

Triglycerides, which WAT stores as energy, are also a source of energy, which is why they are important for preserving energy homeostasis. Excess fats are stored as triglycerides in WAT when the body uses too much energy. This keeps lipids from building up in other organs, such as the liver, where they could impair normal bodily functions or cause harmful metabolic issues. Moreover, WAT serves as a source of energy in the presence of starvation, malnutrition, and other conditions. The body responds to these stimuli by regulating catecholamines and sympathetic nervous system signals. Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MG) work together to hydrolyze triacylglycerol in adipose tissue, which is then released into the bloodstream. Part of the fatty acids are oxidized by beta oxidation and then the products go into the tricarboxylic acid cycle to produce ATP (5, 37).

Additionally, when WAT browning occurs under certain stimulations, it would become an organ for heat production. It was discovered that inhibition of notch receptor-1 (Notch-1) signaling, deletion of the immediate early response gene X-1 (IEX-1), and activation of adenosine 5’-monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling, all promoted WAT browning (38–40). These signaling pathways have been reported to be linked to immunological responses and macrophage polarization, and offer prospective targets for the treatment of metabolic illnesses, such as obesity.

Beige adipocytes can be formed through progenitor cell differentiation as well as through the transformation of mature white adipocytes through the activation (or reactivation) of thermogenic processes and the proliferation of mature beige adipocytes (7, 41, 42).

Beige adipocytes can be distinguished from white adipocytes due to their expression of uncoupling protein 1 (UCP1) and low mitochondrial count. UCP1, as an inner mitochondrial membrane transporter protein, is able to reduce the pH gradient formed by oxidative phosphorylation so that ATP synthesis is uncoupled from oxidative phosphorylation and energy is released as heat (43). WAT will turn beige and increase energy expenditure in the presence of a cold or increased energy demand, hence delaying the onset of metabolic illness and obesity (6). Without UCP1, beige fat uses glucose more efficiently by increasing the activity of pyruvate dehydrogenase, glycolysis, and tricarboxylic acid metabolism. This leads to ATP-dependent thermogenesis through the Sarco/endoplasmic reticulum (ER) Ca ²⁺ -ATPase 2b (SERCA2b) pathway (44).

The crucial and unique role that brown adipocytes play in energy metabolism is determined by their structural differences from white adipocytes. The inner mitochondrial membrane of brown adipocytes contains the BAT-specific protein UCP1, along with a profusion of mitochondria and a few tiny lipid droplets. BAT uses UCP1 to react to cold stimuli, which also causes it to boost the oxidation of glucose and free fatty acids, maintain high levels of mitochondrial and uncoupled respiration, control non-trembling thermogenesis, and regulate systemic energy balance (38). BAT is mainly found in small mammals and newborns, while it is less distributed in adults (40, 45). Generally, brown adipocytes use the β-adrenergic receptor (β-AR)-dependent signaling pathway and mitochondrial UCP1 to convert energy into heat. If UCP1 is not present, the triglyceride/fatty acid cycle plays a significant role in the heat production of brown adipocytes (46) (47). Considering these two thermogenic pathways, this section will explain how BAT controls energy metabolism, homeostasis, and consumption of energy.

Immune cell function is largely influenced by their metabolic activity, so immune cells need to acquire specific metabolic adaptations to support their diverse immunological functions. Nobel laureate Elie Metchnikoff first hypothesized and highlighted macrophages as a crucial component of innate immunity at the end of the 19th century (69). Admittedly, Hematopoietic stem cells produce monocytes. As the precursor for macrophages, they can mature into circulatory monocytes when entering the peripheral circulation. After that, these monocytes leave the circulation and settle into the tissue, where they mature into tissue-specific macrophages. Different tissues refer to resident macrophages by different names: adipose tissue macrophages, kupffer cells in the liver, and microglial cells in the central nervous system (13).

Macrophage function is strictly regulated by metabolites and metabolic pathways (70). For instance, when macrophages are activated in response to inflammatory signals, glycolytic metabolism is enhanced while Mitochondrial oxidative phosphorylation is attenuated (71, 72). The purpose of this metabolic reprogramming of inflammatory macrophages is to promote the rapid production of ATP, obtaining the energy and biosynthetic precursors necessary to fulfill their roles in the immune response, including phagocytosis and the production of inflammatory mediators (70).

Different metabolic intermediates will drive adipose tissue macrophages, exhibiting polarization bias. In hypoxic environments, a significant amount of lactic acid will be generated during glycolysis, promoting macrophage replacement polarization (73–75). Adipose tissue macrophages that experience disruptions in lipid metabolism generate lipid droplets by encouraging the production of lysosomes, which exacerbates the inflammation inside the adipose tissue (76, 77). Adipokines are disrupted in an obese body, as demonstrated by increased expression of leptin and regulatory proteins, decreased secretion of lipocalin, which controls chemokine expression, and mast cell signaling, which controls glucose metabolism, polarization of macrophages to the M1 type, and pro-inflammatory effects (78, 79). On the other hand, adiponectin reduces inflammation by boosting M2-type macrophage polarization and suppressing TNF-α and IL-6 production (80). In conclusion, energy metabolism and lipid metabolism will control adipose tissue macrophages, influencing their own polarization and ultimately controlling the onset and progression of inflammation.

Additionally, it has been discovered that mitochondria, the hub of cellular metabolism, control the activity of immune cells. Simultaneously, the effects of mitochondrial dynamics on immune cell function have been extensively studied (81). Lipopolysaccharide (LPS)-stimulated macrophages exhibit deficient glucose metabolism, which lowers intracellular ATP levels, activates signaling pathways linked to the energy sensor AMPK, and encourages autophagy (82). While studies have demonstrated that mitochondrial autophagy differs from general autophagy in its regulation of adipose tissue and whole-body energy metabolism, mitochondrial-nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain- containing 3 is a distinct route that results in BAT dysfunction (83). To put it briefly, the inflammatory response is influenced by LPS-stimulated modifications in macrophage metabolism, which are linked to adipose tissue energy metabolism and mitochondrial autophagy.

Apart from mitochondria, there has been a recent focus on the role of macrophage polarization in maintaining metabolic homeostasis, which is governed by calcium homeostasis. Adipose tissue-accumulating M1 macrophages are a primary source of proinflammatory cytokines that obstruct insulin signaling. Conversely, anti-inflammatory cytokines that increase insulin sensitivity are produced by M2 macrophages (84). Inflammation and compromised mitochondrial function result from dysregulation of mitochondrial Ca²⁺ homeostasis. Through its interaction with the MCU, Connexin 43 reduces the amount of succinate dehydrogenase (SDH) oxidation caused by Palmitic acid. Consequently, pro-inflammatory M1 macrophages become more polarized (85).

Nrf2 increases glucose absorption and mTOR signaling in M1 macrophages by suppressing IL-10 gene expression and secretion (86). Intrarenal adipose tissue mass is markedly influenced by macrophage-derived insulin-like growth factor-1 (IGF1) during thermogenic stress, and adipocyte differentiation and lipid storage capacity are tissue-specifically regulated by IGF1 in vitro (87). Furthermore, Glucose transporter type 1 (GLUT1) translocation and glycolytic enzyme gene expression are regulated by IL-10, which suppresses glycolytic flux (88).The principal ligand for the mineralocorticoid receptor (MR) is aldosterone. Improper activation of the MR can cause abnormal adipokine secretion, increased expression of inflammatory factors like TNF-α and IL-6, decreased adiponectin, recruitment of macrophages, and up-regulation of leptin (89, 90). Heme lysine demethylase 6a (Kdm6a)-specific knockout of histone lysine demethylase 2a (Kdm2a) mice leads to a considerable increase in energy expenditure, BAT activity, and macrophage M2 polarization (91, 92). Overall, pro-inflammatory macrophage polarization is controlled by macrophage metabolic reprogramming, which is linked to inflammatory factor expression, mitochondrial calcium homeostasis, and the regulation of adipocyte malfunction and obesity.

Thermogenesis is a mechanism used by all thermostatic organisms to keep their body temperature stable so that physiological functions and regular cell function can persist in cold environments. According to well-known thermogenic models, norepinephrine is released in brown and white adipose tissue when the hypothalamus detects hypothermia. This norepinephrine acts through β3-adrenergic receptors, promoting the expression of thermogenic genes and causing lipolysis in white adipocytes (99, 100).

Inflammatory factors and their mediators are thought to play a major part in the progression of metabolic disorders. For example, IL-25, IL-4, IL-13, IL-17, IL-10, and IL-1β are known to regulate the lipid deposition or breakdown of adipocytes, the browning of WAT, and the heat production of BAT, among other indirect regulatory effects ( Table 2 ).

IL-25 specifically induces M2 macrophage polarization, which enhances mitochondrial respiration and macrophage oxygen consumption rate by lowering fatty acid synthase, encouraging the expression of ATGL and HSL, and facilitating the expression of lipolytic, monoacylglycerol lipase (MAGL), and other adiponectin and β-oxidative enzymes. This results in increased NAD/NADH and ATP production, which in turn decreases weight gain and lipid accumulation (113). Furthermore, by releasing IL-4 and IL-13 and encouraging alternate macrophage activation, IL-25 causes beige adipose tissue accumulation in WAT (111). In perspective, IL-4, IL-13, and IL-25 can simply lower the expression of adipose synthase, increase lipolysis and adipocyte growth, and promote macrophage M2 polarization ( Figure 4 ).

Moreover, by blocking the lipogenic gene PPARγ, the IL-17 subfamily of IL-25 inhibits adipogenesis and controls adipose differentiation. Conversely, elevated ILC2 or IL-33 translocation stimulates browning in vivo, while ILC2 upregulates UCP1 expression in vitro (114). It is unclear, therefore, if IL-17 has any effect on the control of adipogenesis and differentiation, which has an additional impact on thermogenesis and fat browning. Vascular endothelial growth factor indirectly affects M2 macrophage polarization, and the browning of WAT controls thermogenic activity, which raises energy expenditure, improves insulin sensitivity, and ultimately enhances systemic metabolism (115–117). To sum up, cold stimulation increases the expression of adipose-vascular endothelial growth factor, which controls M2 macrophage polarization and hence enhances browning of the adipose tissue.

Unexpectedly, more research has revealed that total macrophages (MΦs) stimulated by IL10/TGFβ express low amounts of CD40 and high levels of CD163, and they also release chemicals that stop white adipocytes’ ATP-related respiration. Adipocytes with low CD163 expression and high CD40 expression had increased mitochondrial activity due to chemicals generated by LPS/IFNγ-activated MΦs (118). This suggests that whereas M2 macrophages block mitochondrial respiration, M1 macrophages behave in a counteractive manner. In conclusion, it appears that resident macrophages control energy metabolism in human adipocytes through an activation-dependent paracrine mechanism. Nevertheless, the precise variations in resident macrophage regulation of energy metabolism in various tissues require additional research.

NLRP3 activation in macrophages decreases mitochondrial respiration and UCP1 induction in primary adipocyte cultures (119). Other research indicates that fat-sensing macrophages send this signal to obese hepatocytes, which then release FGF21 to promote BAT thermogenesis. On the other hand, in the absence of p38 activation, there is an increase in IL-12 release in macrophages, which suppresses FGF21 and lowers BAT thermogenesis (120). This suggests that proinflammatory factors and components associated with macrophages will be expressed more frequently, and then adipocyte browning and thermogenesis will be suppressed.

In response to external stimuli, macrophages polarize into distinct metabolic forms that alter, generating various intermediate products, impacting mitochondrial biogenesis, mitochondrial transfer, browning of white fat, and ultimately thermogenesis and energy homeostasis.

Mitochondrial failure has been reported to be associated with a decrease in the insulin receptor substrate 1 (IRS1) gene due to a decrease in the number of M2 macrophages and an increase in adipogenic genes such as acetyl coenzyme A carboxylase α (ACACA), fatty acid synthase (FASN), and thyroid hormone responsiveness (THRSP) (121). Adipocytes’ mitochondrial bioenergetics were markedly changed following exposure to TNF-α, exhibiting increased proton leakage, increased basal respiration, and decreased ATP conversion. Furthermore, a decline in cytochrome c oxidase IV (COX IV) and cytochrome complex (CytC) expression coincided with the reduction in peroxisome prolilerators-activated receptor γ coactivator lalpha (PGC-1α) mRNA expression. Reduced mitochondrial activity and adipocyte reprogramming were the outcomes of TNF-α (122). Additionally, it was discovered that deleting TLR4 specifically in hematopoietic cells improved homeostasis in perivascular adipose tissue, which decreased TNF-α release triggered by macrophages and increased mitochondrial biogenesis in brown adipocytes (123). To sum up, elevated production of TNF-α by macrophages suppresses thermogenesis via impeding mitochondrial biogenesis ( Figure 5 ).

It was shown that mitochondrial absorption requires the heparan sulfate (HS) biosynthesis pathway, which is crucial in preserving lipid and glucose homeostasis in humans and animals. Ext1 (the gene responsible for HS biosynthesis) deletion causes an increase in WAT mass, a decrease in energy expenditure, a reduction in the transfer of mitochondria from adipocytes to macrophages within cells, and an aggravation of in vivo obesity brought on by a high-fat diet (124). In addition, macrophage polarization has a major impact on macrophage migration in adipose tissue. M1-type macrophage polarization in obese patients limits mitochondrial uptake, whereas M2-type macrophage polarization promotes mitochondrial transfer to macrophages in adipose tissue (33, 125). The information above also implies that high expression of HS and macrophage alternative activation enhance macrophage mitochondrial uptake and increase energy expenditure. In addition to directly phagocytosing extracellular matrix (EVs) containing mitochondrial pieces, macrophages also phagocytose EVs to prevent the thermogenic effects of BAT. Brown adipocyte macrophages extract EVs that contain pieces of mitochondria. By preventing the drop in mitochondrial protein UCP1 and peroxisome proliferator-activated receptor γ signaling caused by brown adipocytes reabsorbing EVs, this prevents the thermogenesis process from failing (126) ( Figure 6 ).

This suggests that adipocytes and macrophages depend on intercellular mitochondrial transfer as a mechanism of immune metabolic crosstalk to regulate metabolic disorders in obesity, but the mechanism of mitochondrial transfer is unclear and needs to be further studied. In addition, macrophages participate in the mitochondrial quality control (MQC) system by removing extracellular mitochondrial debris to maintain the thermogenic function of BAT (127).

Moreover, in order to preserve BAT’s thermogenic activity, macrophages remove extracellular mitochondrial debris as part of the MQC system (127). The mechanism of intercellular mitochondrial transfer is unclear and requires more research; however, these data indicate that there is an immune metabolic crosstalk between adipocytes and macrophages to regulate metabolic abnormalities in obesity.

Ablation of adipocyte fatty acid-binding protein (FABP4/aP2) in macrophages leads to increased expression of uncoupling proteins 2 and Sirt3, increased oxygen production, lipopolysaccharide-induced mitochondrial dysfunction, and fatty acid oxidation, leading to an anti-inflammatory state in situ and in vivo (128). FABP4/aP2 regulates macrophage redox signaling and inflammosome activation by controlling UCP2 expression (129). Peanut sprouts (PS) inhibit triglyceride accumulation in adipocytes through fatty acid oxidation, whereas PSE extracts (PSEs) in macrophages and adipocytes impede LPS-mediated inflammation induction. PSE also prevents LPS-induced inhibition of adipocyte browning and activates mitochondria in Bt-cAMP-treated adipocytes (130).

Co-culture of adipocytes and macrophages stimulates endogenous fatty acid released from adipocytes via β3 adrenergic stimulation, leading to activation of NF-κB, a major regulator of the inflammatory response in both cell types. Pharmacological inhibition of NF-κB significantly inhibits co-culture-induced production of pro-inflammatory factors and adipocyte lipolysis (131). Short-chain fatty acids (SCFA) activate free fatty acid receptor 2 (Ffar2), also called G protein-coupled receptor (GPR43), which is found in the gut, adipocytes, and immune cells. It is involved in the regulation of lipids and the immune system. Knockout of Ffar2 in the HFD-treated mice can enhance thermogenesis and energy expenditure and reduce macrophage concentration in the WAT (132). In summary, elevated fatty acid oxidation in macrophages prevents adipocyte thermogenesis and causes mitochondrial dysfunction.

Since M1 macrophages rely heavily on fatty acid oxidation, glycolysis is the main source of energy for them (133, 134). PPARγ and STAT6 have been demonstrated to be regulated by pyruvate kinase isoform M2 (PKM2), which also stimulates M2-type differentiation and macrophage activation. These events ultimately trigger a metabolic transition from glycolysis to fatty acid oxidation (135–137). When the macrophages are metabolically activated, they will exhibit higher oxidative phosphorylation (OXPHOS) and glycolysis. Co-culturing macrophages with adipocytes also induces increased cytokine production in macrophages and overexpression of glycolysis-related proteins (138). Adipocyte-produced soluble factor adiponectin inhibits naïve T cells from developing into Th1 and Th17 cells and reduces CD4 T cells positive for IL-17 and IFN-γ in HFD-treated mice. Adiponectin suppresses glycolysis and reduces Th17 cell development in an adenosine 5’-monophosphate-activated protein kinase-dependent manner (139). Triggering receptor expressed on myeloid cells 2 (Trem2) expression in macrophages prevents the progression of metabolic disorders by promoting the formation of coronary structures around lipid-rich and cell-dead adipocytes, restricting fat cell hypertrophy, and decreasing cholesterol levels in mice fed a high-fat diet (140).

Following lipolysis in obese mice, macrophages profoundly infiltrate adipocytes (97). In palmitate-treated macrophages, hypoxia stimulates JNK and p38 MAPK expression (141). Palmitate not only facilitates macrophages to express more HIF-1α but also promotes the polarization of macrophages to M1-type macrophages, as well as the increased level of IL-1β and genes involved in the palmitate-induced glycolysis pathway. This enhancement of glycolysis causes an increase in lactic acid secretion and succinate, a TCA product (142, 143). The buildup of succinate results in an inflammatory signal through HIF-1α that increases the production of IL-1β (144). The upregulated mRNA level of IL-1β in WAT and macrophages from obese mice can inhibit the activation of extracellular signal-regulated kinase (ERK) in adipocytes and block the UCP1 production stimulated by the β-adrenergic receptor (145). In summary, palmitate promotes macrophage M1 polarization, expresses more HIF-1α as well as IL-1β, and promotes glycolysis ( Figure 7 ).