Immune Cells Gate White Adipose Tissue Expansion

M I N I - R E V I E W

Immune Cells Gate White Adipose Tissue Expansion

Aaron R. Cox,1 Natasha Chernis,1 Peter M. Masschelin,1,2 and Sean M. Hartig1,2

1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College ofMedicine, Houston, Texas 77030; and 2Department of Molecular and Cellular Biology, Baylor College ofMedicine, Houston, Texas 77030

ORCiD numbers: 0000-0002-3330-5746 (A. R. Cox); 0000-0002-2695-2072 (S. M. Hartig).

The immune system plays a critical role in white adipose tissue (WAT) energy homeostasis and, byextension, whole-body metabolism. Substantial evidence from mouse and human studies firmlyestablishes that insulin sensitivity deteriorates as a result of subclinical inflammation in the adiposetissue of individuals with diabetes. However, the relationship between adipose tissue expandabilityand immune cell infiltration remains a complex problem important for understanding thepathogenesis of obesity. Notably, a large body of work challenges the idea that all immune re-sponses are deleterious to WAT function. This review highlights recent advances that describe howimmune cells and adipocytes coordinately enable WAT expansion and regulation of energy ho-meostasis. (Endocrinology 160: 1645–1658, 2019)

The prevalence of obesity doubled in the last 25 years(1), increasing the burden of care on medical centers

and government (2). The epidemiologic associations ofobesity with type 2 diabetes mellitus (T2DM) and car-diovascular disease are unequivocal, but detailed mech-anisms accounting for these links are not well understood.Nonetheless, it is clear that obesity promotes chronic al-terations in energy storage and utilization resulting in lipiddeposition in nonadipose tissues, insulin resistance, andT2DM.

White adipose tissue (WAT) is an endocrine organ thatdynamically expands and contracts to meet the metabolicdemands of the organism. WAT also secretes peptides,hormones, and metabolites that contribute to insulinsensitivity in other peripheral tissues. WAT mass char-acterizes obesity and correlates with a strong predispo-sition for insulin resistance, T2DM, and cardiovasculardisease. Adipocytes remain the singular cell type capableof sequestering lipids and protecting the periphery fromlipotoxicity.

Subcutaneous (peripheral) and visceral (central) WATdepots broadly constitute the bulk of adipose tissues inadults. In humans, the visceral (omental) fat resembles

mouse epididymal fat based on gene expression profiling,inflammation, and expandability, despite anatomicaldifferences; subcutaneous fat depots are anatomicallyand functionally similar in mice and humans (3–7).Excess calorie intake evokes WAT expansion throughboth increased adipocyte size (hypertrophy) and number(hyperplasia). Hyperplasia has been linked to increasedgene expression of transcriptional regulators essen-tial for adipose tissue formation, such as peroxisomeproliferator–activated receptor g (PPARg) (8). In chronicstates of positive energy balance, such as consuming aWestern diet, subcutaneous WAT differentiation becomesimpaired (9) and visceral WAT expands (10–13), drivingmetabolic maladaptation.

Increased hypertrophy is a hallmark of WAT en-largement in obesity and is typically associated withmetabolic alterations, proinflammatory response, andincreased risk of developing T2DM independent of totalfat mass (14–16). Experimental observations indicatethat larger, hypertrophic fat cells behave differently thando smaller, hyperplastic adipocytes, namely in responsesto lipolytic stimuli, secretory functions, and the anaboliceffects of insulin. Consequently, the failure of integral

ISSN Online 1945-7170Copyright © 2019 Endocrine SocietyReceived 1 April 2019. Accepted 14 May 2019.First Published Online 20 May 2019

Abbreviations: eWAT, epididymal WAT; FFA, free fatty acid; Foxp3, forkhead box proteinp3; HFD, high-fat diet; HIF1, hypoxia-inducible factor 1; ILC2, group 2 innate lymphoidcell; IFNg, interferon g; KO, knockout; PAHSA, palmitic acid–hydroxystearic acid; PPARg,peroxisome proliferator–activated receptor g; T2DM, type 2 diabetes mellitus; Treg,regulatory T cell; UCP1, uncoupling protein 1; WAT, white adipose tissue.

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lipid metabolism and insulin sensitivity effectors reflectslow subcutaneous adipocyte differentiation and thuslimits WAT expandability. Subcutaneous WAT safelysequesters excess energy and promotes insulin sensitivityin the face of diet-induced obesity, though the molecularmechanisms underpinning these observations remainincompletely understood.

Distinct Precursor Cells andMicroenvironments Contributeto WAT Mass

WAT depots develop in a spatiotemporal manner,which likely engenders functional identity. Adipocyteprogenitor cells express overlapping progenitor andmesenchymal cell surface markers, including platelet-derived growth factor receptor-a (PDGFR-a), CD29,CD34, stem cell antigen-1 (SCA1), and CD24 (17–20).Mural and smooth muscle–related cells that expressActa2, Myh11, or Pdgfrb also contribute to adipocyteformation under certain conditions (21–25). Lineagetracing studies performed in mice argue that sub-cutaneous and intra-abdominal depots emanate fromdistinct lineages (26). Visceral adipocytes descend fromcells expressing the mesothelial cell marker Wilms tu-mor 1 (26, 27), whereas subcutaneous adipocytes can bemarked with paired related homeobox 1 (PRRX1)–Cre(28, 29) and myxovirus 1 (Mx1)–Cre transgenes (6).Adding to the complexity, anatomically distinct depotsmay contain a network of adipocytes and other stromalprecursor cells that express molecular and secretoryprograms to restrict or enable responses to dietarychallenges (7, 30–35). Such functional cell–cell in-teractions likely exert stop-and-go signals for WATdevelopment and metabolic plasticity.

Of note, murine and human adipose tissue depotsperform physiological and endocrine behaviors basedon distinct anatomical locations.Modern molecular andsingle-cell approaches have partly revealed the specificorigins of subcutaneous and visceral adipocytes in miceand humans (30, 34, 36, 37). A few studies indicate thatspecific anatomical niches provide adipose precursors invarious human tissues (38–40). Recent work discoveredthat DPP41 interstitial progenitors give rise to com-mitted populations of preadipocytes poised to undergoadipocyte differentiation (36). These cells reside in thefluid-filled collagen network of collagen and elastinfibers that surround adipose tissues and many otherorgans. Other efforts identified distinct populationsof adipocyte progenitor cells in human WAT thatvary in endocrine function and anatomical distributionby differential CD34 expression (37). These typesof studies ultimately elaborate the specification of

anatomical fat depots and how fat cells interpret mi-croenvironment cues.

Obesity as an Inflammatory Disease

Obesity-induced chronic inflammation in adipose tissuescontributes to the manifestation of insulin resistanceand T2DM. However, the precise triggers of obesity-associated inflammation remain poorly characterized.Numerous mechanisms have been investigated in rodentmodels of dietary and genetic obesity. It is likely thatthe trigger of inflammation in adipose tissue originatesfrom the anabolic pressure of positive energy balance.The catabolic inflammatory response alleviates anabolicpressure and supports the expansion of adipose tissues tomeet the need for increased lipid storage. However, overtime, the persistent stress of obesity permanently skewsthe reparative immune response and new thresholds foradipose tissue expansion cannot be met. This conceptsuggests that the insults that ultimately constrain fat cellexpandability must be buffered appropriately to counterthe energetic demands of dietary stress.

Many early observations in humans corroborate linksbetween inflammation and T2DM. The initial observa-tions noted that patients with meningitis also exhibitedtransient hyperglycemia (41). A large volume of studies inhumans continue to underscore the importance of im-mune cells in T2DM [reviewed in (42)]. Althoughmost ofthe direct evidence linking chronic inflammation to thecomorbidities of obesity stems from rodent studies,primary human cells ex vivo support the notion thatinflammation disrupts the metabolic flexibility in adi-pocytes (43–50).

The causal role for inflammation in the etiology ofobesity and T2DM remains unclear in humans. Genome-wide association studies mostly identify loci that predictT2DM risk near genes critical for insulin secretion andprocessing (51, 52). The lack of T2DM risk loci thatenrich in immune pathways may weaken the genetic linksbetween obesity and inflammation. However, humangenetic variability likely only partly contributes to theheritability of complex traits. Many questions remainunanswered, including how to restore the endocrine andanti-lipotoxic functions of WAT during excess nutrientintake.

WAT expandability and nutrient storage are closelylinked to hypoxia. As reviewed elsewhere, abundantevidence suggests that adipocytes experience hypoxicstress that triggers local inflammatory signatures (53).Hypoxia develops as adipose tissue grows in size due tolack of tissue perfusion, mechanical stress, or increasedoxygen consumption (54). The ensuing hypoxia activateshypoxia-inducible factor 1 (HIF1), which stimulates

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transcription of numerous inflammatory genes and che-mokine release. HIF1 knockout (KO) prevents obesity-induced inflammation and insulin resistance (55), whichfirmly demonstrates that HIF1 mediates maladaptiveresponses to hypoxia in adipose tissues. Likewise, im-munostaining of WAT from obese rodents and humanswith obesity reveals that regions of hypoxia correlatewith macrophage infiltration and fat cell necrosis (56,57). Despite the evidence that links hypoxia and in-flammation in WAT, it remains uncertain whether hyp-oxia is a consequence of adipose tissue expansion or adirect causative contributor to obesity-associated meta-bolic disease.

Hypoxia and inflammation likely foster fibrosis torestrict WAT expandability. During early WAT expan-sion, hypoxia induces HIF1-regulated profibrotic genesassociated with increased inflammation, insulin re-sistance, and adipocyte cell hypertrophy (58). Notably,subcutaneous WAT fibrosis is negatively correlated withthe effectiveness of weight loss following gastric bypasssurgery (53). Clinical studies show a strong correlationbetween increased subcutaneous WAT fibrosis with in-sulin resistance and obesity (59–61). Conversely, in-hibition of fibrosis through collagen VI or HIF1 KOreduces inflammation, glucose intolerance, and adipo-cyte cell size (62, 63). Hasegawa et al. (64) similarlydemonstrated that repression of WAT fibrosis improvesglucose homeostasis and insulin sensitivity. Fibrosis isoften viewed as a mere consequence of obesity, but thesestudies suggest that fibrosis may be a pathogenic factorthat restricts WAT expansion in obesity and degradesinsulin sensitivity.

Nutrient excess and activation of the immune re-sponse coincides with the pathogenesis of obesity and itscomorbidities, including fatty liver, insulin resistance,T2DM, and cardiovascular disease. Moreover, obesity-induced inflammation involves multiple metabolic andendocrine organs, including WAT, pancreas, skeletalmuscle, heart, and brain. Although obesity-inducedinflammation occurs in many tissues, WAT remains aprimary site for complex skewing of the immune system.The low level of persistent WAT inflammation inobesity should not be confused with acute infectionresponses. Successful immune responses require short-lived reactions necessary for survival of the organism. Incontrast, the nature of obesity-induced inflammationinvolves sustained low-level activation of the immuneresponse. Macronutrient overload ultimately leads tocompromised WAT function accompanied by in-filtration of proinflammatory cells, including fibrogeniccells (30), neutrophils (65), M1 macrophages (66),CD81 lymphocytes (67, 68), helper T cells (69), andadipogenesis regulatory cells (34). Supporting these

observations, proinflammatory mediators secreted byimmune cells and other fibroinflammatory progenitors,such as interferon g (IFNg) and TNFa, correlate withinsulin resistance and central WAT accumulation (45,46, 70, 71).

Macrophages comprise up to 40% of all stromalvascular cells (72) and supply inflammatory cytokinesthat disrupt homeostatic WAT function. Recruitmentof polarized M1 macrophages defines the adipose tis-sue inflammation that accompanies obesity. Althoughthe spectrum of polarization varies across adipose tis-sue volume (73–75), the term M1 depicts the proin-flammatory state of recruited adipose tissue macrophagesthat express CD11c. In obesity, free fatty acids (FFAs)promote polarization of adipose tissue M1 macrophages,which secrete factors and perform functions that can blockinsulin action. Indeed, numerous studies demonstrate thatgenetic alterations that deplete the function of M1 mac-rophages protect against obesity-induced insulin re-sistance and glucose intolerance (76).Many other immunecell types, including dendritic cells, mast cells, eosinophils,and lymphocytes, also contribute to the impact of in-flammation in WAT. Despite the numerous discoverieslinking these cells to the metabolic profile of obesity, thetissue-dependent and pleiotropic functions of the immunesystem foster inherent challenges that slow development oftherapies to minimize the dysfunction caused by diet-induced inflammation.

Immune Signals Mediate AdiposeTissue Expansion

WAT expansion in response to excess nutrients dependsgreatly on a microenvironment composed of immunecells, blood vessels, and stromal cells. In particular,crosstalk between adipocytes and immune cells involvesan intricate signaling network to modulate inflamma-tion and consequently whole-body energy homeostasis.Broadly, insulin sensitivity is preserved when WAT ex-pansion maintains an anti-inflammatory state, primarilythrough the actions of M2 macrophages (77), innatelymphoid type 2 cells, and regulatory T cells (Tregs) (78).Tregs play a prominent role in WAT to promote an anti-inflammatory environment (79). In contrast, several mousemodels of obesity [ob/ob, high-fat diet (HFD), Ay/a,New Zealand obese mice] exhibit dramatically reducednumbers of Tregs in epididymal WAT (eWAT) (79–81).Treg depletion in obesity correlates with infiltration ofWAT by Th1 CD41 T cells, cytotoxic CD81 T cells, andclassically activated macrophages (M1), leading to aproinflammatory milieu that is highly associated withobesity and insulin resistance (79, 81, 82). These ob-servations highlight the complex relationship between

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Treg suppressive functions, cytokines, and insulin sen-sitivity in adipocytes.

The type 1 immune phenotype in obesity derives fromM1 macrophages, cytotoxic CD8 T cells, CD4 type 1helper T cells, natural killer cells, and B cells (Fig. 1). Type2 immunity in WAT reflects the behavior of M2-likemacrophages, eosinophils, group 2 innate lymphoid cells(ILC2s), CD4 type 1 helper T cells, and Tregs. Type 1inflammation in WAT can be counteracted by the im-munosuppressive cytokine IL-10, secreted from Tregsand other type 2 immune cells. eWAT Tregs producehigher levels of IL-10 compared with Tregs from lym-phoid tissues and exhibit enhanced IL-10 signaling (79).IL-10 suppresses M1 macrophage polarization andprevents macrophage recruitment by decreasing theadipocyte-derived chemokine MCP-1 (83, 84). Notably,systemic overexpression of IL-10 in mice reduces weightgain and improves insulin sensitivity with fewer eWATmacrophages (85). IL-10 also protects against TNFa-induced expression of inflammatory genes (MCP-1, IL-6,MMP-3, SAA-3, RANTES) in cultured mouse and hu-man adipocytes (72, 79).

IL-10 and forkhead box protein p3 (Foxp3) showreduced expression in both rodent and human eWATduring obesity (79, 80, 86, 87). Decreased Foxp3 ex-pression and Treg function can be attributed, at least inpart, to proinflammatory cytokine secretion by adipo-cytes and infiltrating CD41 Th1 T cells, causing an al-tered Treg phenotype marked by upregulation of IFNg

(79, 80, 86, 87). This shift in Treg phenotype mightpromote Treg fragility (88) andmay underlie some loss ofeWAT Tregs in obesity. IL-2 treatment of HFD-fed mice

increased eWAT Tregs and IL-10 expression, althoughadoptive transfers of eWAT Tregs into obese mice havebeen limited by isolation of sufficient Tregs, among othertechnical challenges (79). Induction of Tregs by anti-CD3and b-glucosylceramide administration reduced WATinflammation and restored insulin sensitivity in ob/obmice (89). Although these studies suggest that expansionof IL-10–producing Foxp31 Tregs in eWAT might be aneffective therapeutic strategy, further studies are neededto understand how Tregs and adipocytes communicateand mediate metabolic effects.

Eosinophils and ILC2s support Treg suppression oftype 1 immunity. ILC2 secretion of IL-5 stimulates thematuration and infiltration of eosinophils, and both celltypes promote M2 macrophage polarization throughtype 2 cytokines IL-4 and IL-13 (90–92). However, HFD-induced obesity reduces ILC2s and eosinophils in mice,whereas ILC2s are decreased in WAT of humans withobesity (90, 92–94). Activation of the ILC2–eosinophilaxis induces metabolic effects related with subcutaneousWAT expandability and “browning,”whichmay involveimmune cell secretion of peptides and other hormones(93–96).

IL-33 secretion from adipocytes and stromal cellsactivates ILC2s (90, 94, 95, 97, 98). Interestingly, IL-33also acts directly on eWAT Tregs through the ST2 re-ceptor (Il1rl1) (81). IL-33–deficient mice show reducednumbers of Tregs specifically in eWAT, indicating thesignificance of IL-33 to maintain eWAT Tregs. IL-33administration in HFD and New Zealand obese micerestored eWAT Tregs with increased Foxp3 and PPARgexpression, resulting in improved glucose tolerance. One

Figure 1. White adipose immune cell composition in obesity. (A) WAT from lean individuals is primarily composed of Tregs, alternativelyactivated M2 macrophages, ILC2s, and eosinophils that suppress proinflammatory responses and support insulin-sensitive adipocytes. In contrast,adipocytes from individuals with obesity are hypertrophic and insulin resistant due, in part, to infiltrating B cells and various T cells (CD41 Th1,CD81, and natural killer), as well as differentiation and polarization of M1 macrophages with reductions in Tregs and ILC2s. (B) The inset tablesummarizes skewing of immune cells in obesity. This proinflammatory environment impinges on adipocyte insulin signaling, adipocytehyperplasia, and function.


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study suggested that ILC2s are not required for IL-33–induced Treg effects (99); in contrast, Brestoff et al.(93) demonstrate IL-33–elicited ILC2 induction ofuncoupling protein 1 (UCP1)1 beige adipocytes in sub-cutaneous WAT from mice lacking adaptive immunecells. Although Tregs have not been shown to promoterecruitment of UCP11 adipocytes in subcutaneousWAT,Tregs and ILC2s interact through ICOS and ICOSLcostimulatory molecules, which are inhibited by IFNg

(100). Perhaps the ILC2–eosinophil axis and Tregs act asintegrated or partly redundant systems to suppress type 1inflammation and enableWAT expandability and insulinsensitivity.

Treg-Derived Signals Promote AdipocyteInsulin Sensitivity and Metabolism

In addition to Treg-mediated suppression of proin-flammatory immune cells, Tregs might also directly affectadipocyte function and metabolism. Depletion of Tregsin Foxp3–diphtheria toxin receptor mice worsens theinflammatory profile and degrades insulin action ineWAT (79). Most studies suggest that Tregs likely pro-mote insulin signaling in adipocytes via IL-10–directedrepression of inflammatory cytokine synthesis (72, 79).Seminal work by Hotamisligil and many others dem-onstrated that inflammatory cytokines (TNFa, IL1b, andIFNg) interfere with insulin receptor signaling in adi-pocytes (43, 44, 72, 101, 102). Accordingly, TNFa andIFNg lowerGlut4 expression in adipocytes, contributingto reduced insulin-stimulated glucose uptake (72, 79).However, treatment of adipocytes with IL-10 enhancesinsulin-stimulated glucose uptake and antagonizes TNFablockade of insulin receptor signaling and glucose uptake(72). These studies suggest an important role of Tregs tomodulate adipocyte function through IL-10 signaling.

Several studies, however, established divergent effectsof IL-10 on metabolism and insulin resistance in IL-10KO mice (103–106). A recent study demonstrated thatinjection of IL-10 receptor (IL-10Ra)–targeted antisenseoligonucleotides decreased body weight and fat mass inchow-fed mice and increased UCP1 expression in sub-cutaneous WAT (107). Accordingly, IL-10 treatment ofsubcutaneous WAT ex vivo suppressed UCP1 and otherthermogenic genes and oxygen consumption. As a directtarget of PPARg, IL-10Ra expression likely coincideswith adipogenesis and other critical insulin sensitivitygenes in adipocytes (107). It is also unclear whether othertype 2 cytokines (such as IL-4, IL-13) and associatedsignaling pathways might be altered in the absence of IL-10. Treg depletion studies in vivo and IL-10–stimulatedadipocytes in vitro present (72, 79, 108) a strong argu-ment for their role in adipocyte metabolism and insulin

sensitivity; however, the adipose microenvironment is adiverse network of cells and signals that requires furtherstudy given recent findings.

Inter-Cell Crosstalk Performs MetabolicFunctions in WAT

While cytokines comprise a substantial portion of in-tercellular communication within the WAT microenvi-ronment, adipokines and extracellular vesicles also play arole. In particular, Tregs express receptors for leptin,adiponectin, and FFAs (109–113). The suppressive ac-tions of leptin on Treg function and proliferation havebeen well described (110, 111, 114). De Rosa et al. (110)demonstrated that in vitro stimulation of activated hu-man Tregs reduced proliferation and the ability to sup-press CD41 T effector cells, which was partially restoredwith addition of a leptin monoclonal antibody. In vivo,Treg proliferation and Foxp3 expression increased withleptin monoclonal antibody administration in wild-typemice, although transfer of wild-type Tregs into ob/obleptin-deficient mice also exhibited a higher degree ofproliferation. The nutrient-sensing mTOR signalingcascade mediates leptin effects in Tregs while leptin re-ceptor (db/db)–deficient Tregs exhibited reduced mTORsignaling and higher proliferative capacity (111). Incontrast, leptin stimulates proliferation of CD41 Th1T cells coupled with increased IFNg expression (110,114, 115). Thus, elevated leptin production duringobesity might contribute to Treg depletion and expansionof CD41 Th1 T cells, thereby altering the inflammatoryenvironment in WAT.

Adiponectin production by adipocytes exerts anti-inflammatory, antidiabetic, and cardioprotective effects(116–118). Adiponectin KO mice have fewer Tregs ineWAT (119) and, although not directly tested to date,might induce IL-10 production by Tregs, as observed inmacrophages (79, 120). Ramos-Ramırez et al. (112)showed that eWAT-resident Tregs expressed higherlevels of adiponectin receptor 1 than did Tregs in thespleen, and its expression on adipose tissue Helios1Tregscorrelated negatively with eWAT mass. Thus, it is pos-sible that the inverse relationship between adiponectinand leptin reflects the dynamic regulation of Tregs byadipocytes during changes in the nutritional status of leanindividuals and those with obesity.

FFAs derived from WAT may also contribute to pe-ripheral insulin sensitivity (121). For example, palmito-leate treatment of eWAT-derived adipocytes reducesproinflammatory cytokine expression (MCP-1, TNFa).Interestingly, anti-inflammatory IL-4 may also inducelipolysis, in addition to dampening of WAT inflam-mation and mitigating effects of diet-induced obesity


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(122, 123). FFAs are the preferred substrate for func-tional Tregs (114, 124, 125) and therefore might secretelipolytic cytokines to increase the local concentration ofFFAs for use as fuel (122). Kahn and colleagues (126)identified a new class of lipids called fatty acid estersof hydroxy fatty acids, which include palmitic acid–hydroxystearic acids (PAHSAs) abundantly found inmouse serum, WAT, brown adipose tissue, and, to a lesserextent, liver. PAHSAs correlate with insulin sensitivityin serum and subcutaneous WAT in humans. PAHSAsalso regulate insulin-stimulated glucose uptake throughGLUT4 translocation in adipocytes in vitro and decreaseinflammatory cytokine production by macrophages inHFD-fed mice. Future studies should help illustrate howspecific classes of lipids act on Treg metabolism andfunction, and how theymight impact Tregs during obesity.

Aside from adipokines, local insulin levels are abundantin WAT. Whereas insulin acts on adipocytes to suppresslipolysis and promote energy storage, insulin stimulation ofTregs decreases IL-10 production and reduces the ability tosuppress CD41 Th1 T cells in vitro (86). In obese,hyperinsulinemic mice, elevated serum insulin was associ-ated with decreased Foxp31Tregs in the eWAT, expressinglower levels of IL-10 with a switch toward increased ex-pression of the type 1 cytokine, IFNg (86). A recent re-port showed a moderate reduction in insulin production(Ins12/2;Ins2fl/1;Pdx1-CreER mice) induced weight loss onan HFD, mainly affecting eWAT mass, without alteringglucose tolerance (127). It will be interesting to considerhow eWATTregs and other immune cell populationsmightvary in the setting of reduced insulin. However, anecdotalevidence suggests that Treg-specific insulin receptor de-letion might not impact glucose tolerance (128). Thus,although reducing insulin appears important for adipocytemetabolism, it might not be a key signal during the obesity-related shift to a proinflammatory environment and thesuppression of Treg function.

Another potential signaling mechanism between im-mune cells and adipocytes may occur through extracel-lular vesicles, such as exosomes. Local and circulatingexosomes carry cargo-containing proteins, RNA, andparticularly miRNAs that can affect function of acceptorcells [reviewed in detail in (129)]. Multiple studies haveshown that adipocyte-derived circulating exosomesregulate gene expression and insulin sensitivity of pe-ripheral tissues (130–133). Mainly, miRNAs withincirculating exosomes from obese mice confer glucoseintolerance and insulin resistance when transferred tolean mice (130, 134). Obese adipose tissue secretes twiceas many exosomes as do lean mice, which induce dif-ferentiation of bone marrow–derived cells into macro-phages (135). Similar findings were observed with humanadipocyte exosomes, which induced differentiation of

monocytes into macrophages that, in turn, could reduceadipocyte insulin signaling (136). Adipose-derived exo-somes from ob/ob mice also activate circulating macro-phages marked by increased serum IL-6 and TNFa levels(131). In contrast, adipose-derived stem cell exosomesfrom lean mice induced M2 macrophage polarization inobese mice associated with improved insulin resistance andhepatic steatosis (137). Additionally, macrophages withinadipose tissue also secrete exosomes that influence glucosetolerance and insulin sensitivity. Exosomes derived frommacrophages in lean mice improve insulin sensitivity,whereas macrophages collected from obese mice secreteexosomes that promote insulin resistance (134). Of note,miR-155withinmacrophages targets PPARg, whichmightlead to restricted WAT expansion (134).

We know less about how exosomes affect Tregfunction in obesity and metabolic diseases. In a mousemodel of type 1 diabetes, treatment with exosomes de-rived from adipose tissue mesenchymal stem cells in-creased the percentage of splenic Tregs, along withincreased type 2 cytokines IL-4, IL-10, and TGF-b (138).In support of these observations, human mesenchymalstem cell exosomes induced differentiation of Tregs withenhanced suppressive capacity (139, 140). Studies havealso shown in various contexts that Tregs generateexosomes (141–144). Okoye et al. (142) demonstratedthat Tregs produce miRNA-containing exosomes de-pendent on Dicer (required for biogenesis of mostmiRNAs) expression and canonical exosomal extrusionpathways. The authors subsequently showed that Tregexosomes suppress Th1 T cell proliferation and IFNg

production through let-7d. Treg-derived exosomes alsoskew dendritic cells toward a type 2 phenotype, markedby increased IL-10 and decreased IL-6 production, whichinvolved transfer of miR-150-5p and miR-142-3p (144).Whether resident adipose Tregs exhibit similar exosomalsuppressive activity upon type 1 immune cells duringobesity will be an important question in the emergingarea of the adipose tissue exosomes. Additionally, Tregexosomes might also influence adipocyte-specific in-flammatory pathways, such as IFNg and TNFa, tomodulate insulin sensitivity. Meanwhile, adipocyte-derived exosomes carry lipids (135) that could influ-ence Treg metabolism and function.

In summary, the adipose microenvironment involvescomplex and delicate signaling between adipocytes andimmune cells. In insulin-sensitive WAT, Tregs pro-duce IL-10 to suppress CD41 Th1 T cell function, po-larize M2 macrophages, and repress adipocyte-derivedinflammatory cytokines (Fig. 2). IL-33 derived fromadipocytes and stromal cells activates Tregs and ILC2s.ILC2s recruit and activate esosinophils, and in combi-nation, they produce type 2 cytokines that polarize M2


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macrophages. Adipocytes secrete adiponectin and FFAs,which also suppress macrophage cytokine production andmight influence Treg function, whereas the relative ab-sence of leptin allows Tregs to proliferate and maintainsuppressive activity. Both adipocytes and Tregs produceexosomes, with adipocyte-derived exosomes influencingmacrophage differentiation and function, although Tregexosomes suppress T cells in some contexts. Lastly, adi-pocytes secrete fatty acid esters of hydroxy fatty acids, suchas PAHSAs, that regulate macrophages and peripheral in-sulin sensitivity. In contrast, obese insulin-resistant adipo-cytes secrete inflammatory cytokines (IFNg, IL-6, RANTES,SAA) and recruit M1 macrophages (via MCP-1). Tregs,ILC2s, and eosinophils are reduced, with Tregs shiftingtoward IFNg production. High levels of leptin and insulinalso reduce Treg proliferation, function, and fatty acidmetabolism. Accumulation of CD41 Th1 T cells and M1macrophages contributes to the increasing inflammatory

milieu that restricts adipocyte insulin signaling, function,and expansion. Obesity-derived adipocyte or macrophageexosomes also reduce insulin sensitivity. Notably, theseobservations largely focused on immune cell–adipocytesignaling in eWAT given its propensity for greater immunecell infiltration in obese mice; however, some studies arebeginning to uncover roles of immune cells in subcutaneousWAT and the signals that might preserve insulin sensitivityand WAT expansion (43, 145). Finally, the complexity ofthe adipose tissue microenvironment suggests that thera-peutic intervention will likely require targeting of multiplesignals and cell types to restore adipocyte expansion andinsulin sensitivity in individuals with obesity.

Future Perspectives

More than 20 years of detailed mechanistic and physio-logical studies firmly establish that chronic inflammation

Figure 2. Inter-cell crosstalk regulates metabolic and inflammatory functions in WAT. In lean WAT, insulin-sensitive adipocytes expandappropriately to anabolic pressure and secrete adipokines (adiponectin), FFAs and PAHSAs, and exosomes. Tregs produce IL-10 to suppress CD41

Th1 T cell function, polarize M2 macrophages, and repress adipocyte-derived inflammatory cytokines. IL-33 derived from adipocytes and stromalcells activates Tregs and ILC2s. ILC2s recruit and activate esosinophils and, in combination, they produce type 2 cytokines that polarize M2macrophages. Adipocytes secrete adiponectin and FFAs, which also suppress macrophage cytokine production and might influence Tregfunction, whereas the relative absence of leptin allows Tregs to proliferate and maintain suppressive activity. Both adipocytes and Tregs produceexosomes, with adipocyte-derived exosomes influencing macrophage differentiation and function, whereas Treg exosomes suppress T cells insome contexts. Lastly, lean adipocytes secrete fatty acid esters of hydroxy fatty acids, such as PAHSAs, that regulate macrophages and peripheralinsulin sensitivity. In summary, type 2 immune cells promote adipocyte insulin sensitivity, differentiation, and function through cytokines IL-4, IL-10, and M2 macrophage-derived exosomes. In obese adipose tissue, insulin resistance develops, and adipocyte differentiation is restricted, whichcontributes to ectopic lipid deposition. Adipocytes secrete inflammatory cytokines (IFNg, TNFa, IL-6, RANTES, SAA) and recruit M1 macrophages(via MCP-1). Tregs, ILC2s, and eosinophils are reduced, with Tregs shifting toward IFNg production. High levels of leptin and insulin also reduceTreg proliferation, function, and fatty acid metabolism. Obese adipocyte- or macrophage-derived exosomes also reduce insulin sensitivity.Collectively, accumulation of CD41 Th1 T cells and M1 macrophages contributes to the increasing inflammatory milieu (IFNg, TNFa, IL-6, andexosomes) that restricts adipocyte insulin sensitivity, expansion, and function.


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in WAT depots leads to systemic glucose and lipid dys-regulation. Although WAT inflammation is one con-served pathway that links obesity to insulin resistanceand T2DM, numerous questions remain unanswered,including how to sustain healthy noninflamed sub-cutaneous WAT expansion during excess nutrient in-take. For people with T2DM, we are hopeful that theimmune system will be leveraged as a tool to maintaininsulin sensitivity. However, targeting the immunecomponent of obesity has proved elusive. For example,antibodies that neutralize TNF improve insulin sensi-tivity in obese mice, but humans showed no metabolicimprovements (146). In clinical trials, anti-inflammatorysalicylates improved glycemia and adipose inflamma-tion profiles in individuals with obesity and T2D, butinsulin sensitivity was unaffected (147–149). New strat-egies that target higher baseline inflammation in adiposetissues appear promising (150) in small clinical trials.Note that several well-established antidiabetic drugsinfluence anti-inflammatory endpoints. Metformin in-hibits reactive oxygen species production and the pro-duction of numerous inflammatory cytokines (151, 152).Thiazolidinediones also exert anti-inflammatory effectsinmacrophages and adipocytes (153). In both cases, thesedrugs block nuclear factor kB (151, 154) and restore theM2 phenotype of macrophages (134, 155). Further ex-ploration into how biologics targeting inflammation inrheumatoid arthritis and Crohn disease (156) may revealtherapeutic vulnerabilities for obesity. A thoughtful sur-vey of how manipulating the immune response impactsphysiology is warranted. Importantly, note that generaldisruption of inflammatory pathways may compromiseimmune responses, but also result in tissue damage,dysbiosis, and amplification of other autoimmune con-ditions (157).

The anatomical and functional differences of WATdepots portend distinct immune cell niches that con-tribute to adipocyte function and expansion duringobesity. The subcutaneous WAT has a tremendous ca-pacity to expand and store excess nutrients, as demon-strated by MitoNEET transgenic mice (158, 159). Inaddition to varied WAT depots, a recent study suggestedthat beige fat may also exist in multiple distinct forms,conventional and glycolytic beige fat (160). The immunecell composition also greatly varies, with the eWATcontaining a greater abundance of immune cells, evenduring metabolic homeostasis, in contrast to the lessinfiltrated brown adipose tissue. The tissue- and depot-specific roles for immune cells is unknown, but there isclearly an extensive communication network betweenadipocytes and immunity through multiple signalingmechanisms (e.g., hormones, cytokines, exosomes, poly-unsaturated fatty acids) within anatomical niches. The

characterization of immune cells within WAT marchesforward, as highlighted by the identification of multiplemacrophage subtypes in WAT beyond the traditionalM1/M2 subtypes (161). Ultimately, treatment of obesityand T2DM will require a multipronged approach to ad-dress adipocyte insulin sensitivity and nutrient storagewhile maintaining an anti-inflammatory environment. Ad-vances in immunotherapy and gene editing tools mightprovide unique opportunities to skew macrophage andT cell populations toward an anti-inflammatory state.Collaborative efforts to couple cell biology with immu-nology and genetics will be pivotal to address the currentknowledge gaps and identify new therapeutic strategies toimprove insulin sensitivity and nutrient storage for patientswith obesity and T2DM.

Acknowledgments

We apologize to our colleagues in the field for not being able todiscuss all of the outstanding studies that detail how immunecells regulate WAT function. We thank RobbMoses for criticalreading of the manuscript and useful discussions.

Financial Support: This work was supported by AmericanDiabetes Association Grant 1-18-IBS-105 and National In-stitutes of Health/National Institute of Diabetes and Digestiveand Kidney Diseases Grant R01 DK114356.

Correspondence: Sean M. Hartig, PhD, Baylor College ofMedicine, One Baylor Plaza, BCM185, Houston, Texas 77030.E-mail: [email protected].

Disclosure Summary: The authors have nothing todisclose.

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