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J Mol Cell Biol. 2016 April; 8(2): 120–128.
Published online 2016 March 30. doi:  10.1093/jmcb/mjw012
PMCID: PMC4816149

Adiponectin: a versatile player of innate immunity

Yan Luo1,2 and Meilian Liu1,2,*

Abstract

Adiponectin acts as a key regulator of the innate immune system and plays a major role in the progression of inflammation and metabolic disorders. Macrophages and monocytes are representative components of the innate immune system, and their proliferation, plasticity, and polarization are a key component of metabolic adaption. Innate-like lymphocytes such as group 2 innate lymphoid cells (ILC2s), natural killer T (NKT) cells, and gamma delta T (γδ T) cells are also members of the innate immune system and play important roles in the development of obesity and its related diseases. Adiponectin senses metabolic stress and modulates metabolic adaption by targeting the innate immune system under physiological and pathological conditions. Defining the mechanisms underlying the role of adiponectin in regulating innate immunity is crucial to adiponectin-based therapeutic intervention.

Keywords: adiponectin, innate immunity, macrophage, innate-like lymphocyte

Introduction

Adiponectin is an adipokine whose expression and circulating levels are downregulated during obesity in human subjects and exerts anti-diabetic effects (Fisher et al., 2005; Kadowaki and Yamauchi, 2005; Ahima, 2006). Moreover, it is well established that adiponectin acts as an endogenous insulin sensitizer (Berg et al., 2001; Yamauchi et al., 2001; Tsao et al., 2002). In addition, adiponectin plays an important role in regulating immune responses such as inflammation, being a critical pathogenic mediator of the development of obesity-induced insulin resistance (Esmaili et al., 2014). However, whether adiponectin acts as an anti- or pro-inflammatory factor is still a matter of much debate (Maeda et al., 2002; Xu et al., 2003; Tsatsanis et al., 2005; Park et al., 2007). Some studies report that adiponectin functions as an anti-inflammatory mediator during the progression of metabolic diseases (Maeda et al., 2002; Xu et al., 2003). In contrast, other studies show that adiponectin promotes an inflammatory response by activating NF-κB and inducing inflammatory cytokines IL-1 and IL-6 under certain circumstances (Tsatsanis et al., 2005; Park et al., 2007).

Innate immunity has been defined as the non-specific first line of defense against foreign pathogens. It contains an integral facet of the immune response, which is mediated by dendritic cells (DCs), natural killer (NK) cells, macrophages, neutrophils, basophils, eosinophils, mast cells, and innate-like lymphocytes. Over the past decade, the innate immune response mediators, particularly macrophages and innate-like lymphocytes, have been identified as key modulators in the regulation of energy and glucose homeostasis (Molofsky et al., 2013; Brestoff et al., 2015). Moreover, accumulating evidence suggests that adiponectin regulates energy expenditure and insulin sensitivity via innate immune response-dependent mechanisms (Tsuchida et al., 2005; Luo et al., 2010, 2011; Awazawa et al., 2011; Hui et al., 2015). In this review, we will summarize and discuss the recent findings concerning adiponectin regulation of innate immunity.

Adiponectin regulation of macrophage proliferation, plasticity, and polarization

Macrophages are present in metabolic tissues such as fat, liver, and muscle, and their proliferation, plasticity, and polarization are driven by obesity (Weisberg et al., 2003; Chawla et al., 2011; Odegaard and Chawla, 2011; Bai and Sun, 2015). Obese adipose tissue expression of inflammatory molecules, such as CCR2, can recruit and activate monocytes and macrophages (Weisberg et al., 2003, 2006; Bai and Sun, 2015). Activated macrophages including M1 and M2 macrophages, in turn, modulate thermogenesis, inflammation, and insulin sensitivity (Bourlier and Bouloumie, 2009; Chawla et al., 2011; Nguyen et al., 2011; Odegaard and Chawla, 2011; Qiu et al., 2014; Rao et al., 2014; Hui et al., 2015; Lackey and Olefsky, 2016). M1 or classically activated macrophages trigger the production of pro-inflammatory cytokines and mediate obesity-induced insulin resistance and type 2 diabetes (Chawla et al., 2011; Bai and Sun, 2015). In contrast, M2 or alternatively activated macrophages are polarized by IL-4 and IL-13 and play an important role in the promotion of oxidative metabolism, induction of tissue repair, and blockade of inflammatory responses (Nguyen et al., 2011; Odegaard and Chawla, 2011; Mantovani et al., 2013). Therefore, understanding macrophage activation, which is defined across M1 and M2 polarization states (Mantovani et al., 2004; Gordon and Taylor, 2005), is critical for identification of therapeutic targets toward inflammation-associated metabolic diseases.

Adiponectin, a 30-kDa adipokine exclusively secreted from adipose tissue, exists in cells and plasma in three major forms: trimers, hexamers, and the high-molecular-weight (HMW) form (Scherer et al., 1995; Hu et al., 1996; Maeda et al., 1996; Pajvani et al., 2004). Adiponectin has a similar structure as a complement factor C1q (Scherer et al., 1995). C1q is a well-known component of innate immunity and plays a vital role in regulating macrophage polarization as well as other types of innate immune cells (Bohlson et al., 2014; Kouser et al., 2015). Both C1q and adiponectin promote clearance of apoptotic cells through Mer tyrosine kinase (Mer), a receptor that regulates efficient efferocytosis and prevention of autoimmunity (Galvan et al., 2014). As the most abundant adipokine in the body, adiponectin exerts multiple protective properties against inflammation (Yokota et al., 2000; Ouchi et al., 2001), obesity (Scherer et al., 1995; Hu et al., 1996; Maeda et al., 1996; Pajvani et al., 2004), insulin resistance (Tomas et al., 2002; Gil-Campos et al., 2004; Haluzik et al., 2004; Hoffstedt et al., 2004), and cardiovascular diseases (Goldstein and Scalia, 2004; Ouchi et al., 2004; Shibata et al., 2005). Downregulation of adiponectin has been shown to be associated with high levels of inflammatory markers and various metabolic disease states (Ouchi et al., 2003; Gil-Campos et al., 2004; Pischon et al., 2004). There is extensive evidence showing that adiponectin acts as anti-inflammatory mediator through the regulation of M1 and M2 macrophage proliferation, plasticity, and polarization (Yokota et al., 2000; Wolf et al., 2004; Wulster-Radcliffe et al., 2004; Ajuwon and Spurlock, 2005; Ohashi et al., 2010; Hui et al., 2015). However, adiponectin has also been proposed to exert pro-inflammatory effects under certain circumstances.

Adiponectin suppresses M1 macrophage activation and promotes M2 macrophage proliferation, which accounts for its anti-inflammatory properties. Adiponectin deficiency leads to a classically activated macrophage phenotype in vivo, and recombinant adiponectin acts to promote a switch to an anti-inflammatory phenotype in macrophages (Ohashi et al., 2010). On the one hand, adiponectin suppresses inflammatory activation through downregulation of M1 macrophage markers such as TNF-α, MCP-1, and IL-6 (Wolf et al., 2004; Wulster-Radcliffe et al., 2004; Ajuwon and Spurlock, 2005; Ohashi et al., 2010). On the other hand, adiponectin promotes an anti-inflammatory response as evident by an upregulation of the anti-inflammatory M2 markers arginase-1, Mgl-1, and IL-10 in murine and human macrophages (Wolf et al., 2004; Ajuwon and Spurlock, 2005; Ohashi et al., 2010). The suppressing effect of adiponectin on M1 macrophage markers and promoting effect of adiponectin on M2 macrophage markers have been well studied in various cell types of macrophages (Figure 1). However, the underlying mechanisms remain to be elucidated (Chinetti et al., 2004; Wolf et al., 2004; Wulster-Radcliffe et al., 2004; Ajuwon and Spurlock, 2005; Tsatsanis et al., 2005; Park et al., 2007, 2008a, b; Yamaguchi et al., 2008). Since alternative macrophage polarization is prototypically driven by type 2 helper T cell (Th2) cytokines IL-4 and IL-13 in vivo (Odegaard and Chawla, 2011), it has drawn lots of attention as to whether adiponectin shares a similar mechanistic pathway as Th2 cytokines in regulating macrophage function. Although IL-4 was recently found to be derived from adipocytes and shown to positively regulate M2 macrophage activation and insulin sensitivity (Kang et al., 2008), it remains controversial whether adiponectin is as effective as IL-4 at conferring an anti-inflammatory phenotype to macrophages (Yokota et al., 2000; Ohashi et al., 2010). In addition, different from IL-4, adiponectin behaves as an initial pro-inflammatory factor in response to lipopolysaccharide (LPS), and helps to desensitize cells to further pro-inflammatory stimuli (Tsatsanis et al., 2005, 2006; Park et al., 2007).

Figure 1
Adiponectin regulation of macrophage proliferation and polarization. Adiponectin acts as an anti-inflammatory factor and regulates macrophage proliferation and polarization. On the one hand, adiponectin suppresses differentiation and classical activation ...

Moreover, adiponectin has been shown to inhibit the inflammatory response by suppressing macrophage proliferation. Since monocytes can differentiate into M1 macrophages as well as alternative M2 macrophages, approaches that limit M1 while promoting M2 differentiation represent a unique therapeutic strategy. Yokota et al. (2000) found that adiponectin not only inhibits mature macrophage functions, such as phagocytosis and cytokine production, but also suppresses proliferation of myelomonocytic progenitors by promoting apoptosis. In addition, adiponectin has recently been shown to induce adipose M2 macrophage proliferation (Yokota et al., 2000; Hui et al., 2015). These findings suggest that adiponectin is a critical modulator of both M1 and M2 macrophage proliferation (Figure 1). Given that alternative activation of the M2 macrophage plays a critical role in regulating browning of white adipose tissue by producing and secreting norepinephrine, a hormone driving browning effect and thermogenesis in fat (Nguyen et al., 2011), induction of M2 macrophage proliferation by adiponectin provides a novel mechanism by which adiponectin promotes a cold-induced browning effect in subcutaneous adipose tissue (Hui et al., 2015). This study also demonstrates that the beneficial effect of adiponectin on metabolism is mediated by alternative activation of M2 macrophages and subsequent promotion of browning in adipose tissue. Taken together, these studies suggest that adiponectin is an important regulator of macrophage proliferation, plasticity, and function in inflammation and its related metabolic disorders (Figure 1).

Adiponectin action in monocytes/macrophages

Adiponectin exerts multiple beneficial effects by binding to its receptors, adiponectin receptor 1 and receptor 2 (AdipoR1 and AdipoR2) (Yamauchi et al., 2003, 2007; Kadowaki et al., 2006). As the predominant receptors for adiponectin, AdipoR1 and AdipoR2 play important roles in the regulation of inflammation, glucose and lipid metabolism, and oxidative stress shown both in vivo and in vitro (Yamauchi et al., 2003, 2007, 2014; Chinetti et al., 2004; Yamaguchi et al., 2005). In addition, T-cadherin, a cell surface-anchored glycoprotein, is effective in binding to adiponectin and mediates adiponectin signaling, while it falls short of being a receptor that both binds and transduces intracellular signaling pathways (Denzel et al., 2010). There is accumulating evidence showing that adiponectin exhibits insulin-sensitizing effects through multiple signaling pathways downstream of adiponectin receptors, such as AMPK, Ca2+, PPARα, ceramide, and S1P (Yamauchi et al., 2007; Zhou et al., 2009; Iwabu et al., 2010; Holland et al., 2011). However, the signaling events underlying adiponectin modulation of immune cell function remain to be established.

AdipoR1, AdipoR2, and T-cadherin are present in monocytes/macrophages with high abundance of AdipoR1 (Chinetti et al., 2004; Yamaguchi et al., 2005; Hui et al., 2015); however, whether these receptors play important roles in mediating anti-inflammatory action of adiponectin in macrophages remains controversial. AdipoR1 predominantly binds to globular adiponectin (gAd) and mediates adiponectin suppression of NF-κB activation and pro-inflammatory cytokine expression in macrophages (Yamaguchi et al., 2005; Mandal et al., 2010a, b). On the other hand, AdipoR2 is required for full-length adiponectin-mediated M2 polarization (Mandal et al., 2011). In addition, T-cadherin, rather than AdipoR1 or AdipoR2, is stimulated by cold exposure and is essential for the stimulatory effects of adiponectin on M2 macrophage proliferation (Hui et al., 2015). However, suppression of AdipoR1, AdipoR2, or T-cadherin has little effect on adiponectin-stimulated uptake of apoptotic THP-1 cells (Takemura et al., 2007). These findings suggest that adiponectin may regulate macrophage proliferation and function through currently unknown receptor-mediated mechanisms.

Several intracellular signaling pathways appear to mediate adiponectin action in regulating macrophage proliferation and function (Figure 2). Firstly, Toll-like receptor (TLR)-mediated NF-κB signaling plays a critical role in adiponectin suppression of M1 macrophage proliferation and function (Ajuwon and Spurlock, 2005; Tsatsanis et al., 2005; Yamaguchi et al., 2008). Furthermore, adiponectin promotes endotoxin tolerance via activation of the Erk pathway in primary macrophages (Zacharioudaki et al., 2009). Against its anti-inflammatory action, adiponectin has been shown to initially promote a pro-inflammatory response by upregulation of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8 by activating NF-κB and Erk pathways (Lappas et al., 2005; Tsatsanis et al., 2005, 2006; Park et al., 2007). However, the pro-inflammatory action of adiponectin is a transient effect, which contributes to LPS tolerance and eventually dampens LPS-mediated cytokine production in macrophages with continuous exposure to adiponectin, suggesting that chronic adiponectin induces LPS resistance (Tsatsanis et al., 2005, 2006; Park et al., 2007). Consistent with this, gAd treatment profoundly suppressed the ability of LPS to increase TNF-α transcription and reduced LPS-induced stabilization of TNF-α mRNA (Park et al., 2007, 2008b). Moreover, adiponectin promotes the expression of anti-inflammatory factor IL-10 via cAMP-dependent mechanisms in macrophages (Park et al., 2008a). In addition to NF-κB, Erk, and cAMP pathways, the Akt pathway was recently reported to mediate adiponectin-induced M2 macrophage proliferation (Hui et al., 2015). Whether adiponectin activates these signaling pathways in an adiponectin receptor-dependent manner in macrophages remains to be clarified in the future.

Figure 2
Adiponectin action is mainly mediated by adiponectin receptors and downstream signaling pathways in monocytes/macrophages. AdipoR1 mediates the suppressing effect of adiponectin on NF-κB activation and subsequent transcriptions of TNF-α, ...

Adiponectin regulation of innate-like lymphocytes

Innate-like lymphocytes, including group 2 innate lymphoid cells (ILC2), gamma delta T (γδ T) cells, natural killer T (NKT) cells, B1 cells, and marginal zone B cells, have emerged as an important cellular component of the immune system and have been suggested to regulate both innate and adaptive immunity. Interestingly, several types of innate-like lymphocytes such as ILC2, γδ T, and NKT cells are present in metabolic organs including adipose tissue and play important roles in regulating energy and glucose metabolism (Lynch et al., 2009, 2012; Brestoff et al., 2015; Lee et al., 2015). Consistently, ILC2s and NKT cell fractions are decreased, while γδ T cell density is increased in adipose tissue of obese mice or human subjects, indicating the correlation between these types of innate-like lymphocytes and obesity (Brestoff et al., 2015; Costanzo et al., 2015; Lee et al., 2015; Mehta et al., 2015). Therefore, ILC2s, NKT, and γδ T cells have offered novel therapeutic approaches for the treatment of metabolic diseases such as obesity, insulin resistance, and type 2 diabetes. Adiponectin has been proposed to regulate energy and glucose metabolism by targeting innate-like lymphocytes (Figure 3).

Figure 3
Adiponectin plays a critical role in the regulation of non-macrophage innate immune cells. Accumulating data suggest that adiponectin suppresses the activation of eosinophils, neutrophils, γδ T cells, NK cells, and DCs through common or ...

ILC2s were first discovered in the lung (Price et al., 2010), which are activated by epithelial cell-derived cytokines IL-33, IL-25, and thymid stromal lymphopoietin (TSLP) in response to allergens. Activated ILC2s orchestrate type 2 innate and adaptive immune responses (Koyasu and Moro, 2013; Licona-Limon et al., 2013; Cayrol and Girard, 2014). Very recently, ILC2s were identified in murine and human adipose tissue as a conserved characteristic of obesity, and have been shown to drive browning of fat and prevent the development of obesity (Brestoff et al., 2015; Lee et al., 2015). On the one hand, ILC2s produce IL-5 and IL-13, type 2 cytokines that stimulate the maturation and infiltration of eosinophils and activate M2 macrophages, respectively. Both eosinophils and M2 macrophages subsequently promote adipose tissue browning (Nguyen et al., 2011; Molofsky et al., 2013; Lee et al., 2015). On the other hand, IL-33-elicited ILC2s themselves produce methionine-enkephalin peptides that directly target adipocytes to promote browning and thermogenesis (Brestoff et al., 2015). In addition, cold stress enhances the ILC2 population through IL-33 in white adipose tissue (Brestoff et al., 2015). However, whether ILC2s are recruited into or produced in adipose tissue remains unclear. Mechanistically, the regulation of ILC2 function in adipose tissue also has yet to be defined. Hui et al. (2015) found that adiponectin promotes M2 macrophage proliferation and subsequent browning effect and energy expenditure. However, adiponectin deficiency has little effect on ILC2 population and downstream cytokines including IL-4 and IL-13 in white adipose tissue in response to chronic cold, a well-defined stimuli promoting browning of fat (Hui et al., 2015). However, two groups have reported that adiponectin knockout (KO) mice display increased thermogenesis and energy expenditure (Kajimura et al., 2013; Qiao et al., 2014). Moreover, acute cold stress has been shown to induce the activation of ILC2s in adipose tissue (Brestoff et al., 2015). During chronic stress, ILC2 population and activity are both significantly decreased, suggesting that secondary effects of chronic stress may account for suppression of ILC2s in adipose tissue (Hui et al., 2015). These inconsistent observations highlight the need to further study what is the true physiological function of adiponectin in the regulation of innate immunity and energy expenditure.

In addition, NKT cells are present in human adipose tissue and play an important role in regulating metabolic pathways (Akbari et al., 2003; Lynch et al., 2009, 2012). Invariant NKT cells are decreased in human obesity, and confer protection against the development of metabolic syndrome and inflammation in an IL-4 and IL-10-dependent manner (Lynch et al., 2009, 2012). However, the density of total T lymphocytes is increased in adipose tissue during the development of obesity (Kintscher et al., 2008; Duffaut et al., 2009). Although there is no direct evidence showing that adiponectin regulates NKT cell function, it was reported that adiponectin activates plasma B cells and induces secretion of the B cell-derived peptide PEPITEM, which inhibits memory T cell migration (Chimen et al., 2015). Moreover, AdipoR1 and AdipoR2 are expressed in B cells and may mediate the suppressing effect of adiponectin on B cell-specific PEPITEM production and secretion.

Notably, γδ T cells, another type of adipose resident innate-like lymphocytes, are positively correlated with obesity and promote diet-induced inflammation and insulin resistance (Costanzo et al., 2015; Mehta et al., 2015). γδ T cells, which contain γδ+ T cell receptor (TCR), only compose a minority of total T cells and are predominantly CD4 and CD8. Some subsets of γδ T cells show anti-tumor and immunoregulatory activities (Girardi, 2006). A very recent study shows that adiponectin deficiency results in marked upregulation of dermal γδ T cells and severe psoriasiform skin inflammation through induction of IL-17 (Shibata et al., 2015). This study also demonstrates that adiponectin negatively regulates the recruitment of inflammatory cells and IL-17 production via AdipoR1- but not AdipoR2-dependent cell autonomous mechanisms in the skin (Shibata et al., 2015). However, whether adiponectin modulates the function of adipose resident γδ T cells remains to be clarified.

Adiponectin regulation of other innate immune cells

Adiponectin and eosinophils

Eosinophil granulocytes, usually called eosinophils, appear brick-red after staining with eosin and act as one of the immune system components responsible for allergen-induced inflammation responses and parasitic infection. Recent studies demonstrate that eosinophils are recruited to adipose tissue and are responsible for the alternative activation of macrophages as well as browning of adipose tissue through IL-4 in response to cold (Qiu et al., 2014; Rao et al., 2014). Adiponectin negatively regulates the recruitment of eosinophils in the airways, suppressing allergic airway inflammation (Medoff et al., 2009). Furthermore, adiponectin suppresses eosinophil recruitment through the regulation of the macrophage-derived chemokine CCL11/eotaxin (Medoff et al., 2009). Although both AdipoR1 and AdipoR2 have been detected in human eosinophils (Yamamoto et al., 2013), whether adiponectin regulates the function of eosinophils through an adiponectin receptor-mediated signaling pathway remains to be clarified. Moreover, whether adiponectin plays a role in regulating the function of adipose resident eosinophils remains to be investigated.

Adiponectin and neutrophils

Neutrophils, the most abundant immune cell population in the blood, work as the first defense against microbial pathogens, migrating to eliminate pathogens through phagocytosis, degranulation, neutrophil extracellular traps (NETs), and reactive oxygen species (ROS) production (Wright et al., 2010). Full-length adiponectin inhibits the phagocytic ability of neutrophils by suppressing NADPH oxidase and ROS production in an AMPK-dependent manner (Chedid et al., 2012). Consistently, adiponectin suppresses ceramide accumulation in the neutrophil membrane and subsequently inhibits neutrophil apoptosis through AMPK (Rossi and Lord, 2013b). In addition, adiponectin treatment inhibits neutrophil phagocytosis of Escherichia coli through inhibiting PI3K/PKB pathways and Mac-1 activation (Rossi and Lord, 2013a). These data demonstrate that adiponectin negatively regulates the function of neutrophils.

Adiponectin and NK cells

NK cells are defined as large granular lymphocytes (LGL) that play a critical role in the innate immune response. Activated NK cells trigger a pro-inflammatory response by promoting M1 macrophage activation and causing insulin resistance (Wensveen et al., 2015). Meanwhile, NK cell-activating receptor NCR1 ligands, which are expressed and localized on the surface of adipocytes, are upregulated by obesity and promote the proliferation and activation of NK cells (Wensveen et al., 2015). It has been shown that adiponectin plays an important role in regulating the function of NK cells. However, whether adiponectin suppresses or stimulates NK cells remains controversial. One in vivo study suggests that adiponectin downregulates the frequencies while enhancing the efficiency of NK cells in the spleen (Wilk et al., 2013). In contrast, adiponectin treatment suppresses IL-2-induced cytotoxicity and IFN-γ production in both human and murine NK cells (Kim et al., 2006). The differential effects of adiponectin in vivo and in vitro may be a result of the secondary effects of adiponectin deficiency rather than direct targeting to NK cells. Although it has been reported that adiponectin receptors are expressed in human and murine NK cells (Kim et al., 2006), there is no direct evidence showing that adiponectin receptors mediate the role of adiponectin in regulating NK cells.

Adiponectin and dendritic cells

Dendritic cells (DCs) are particularly specialized antigen-presenting cells (APCs) and are essential for the onset of immunity and its tolerance. Both density and activity of DCs are induced by obesity in mice (Stefanovic-Racic et al., 2012; Chen et al., 2014). Adiponectin appears to regulate the function of DCs, whereas it remains controversial as to whether adiponectin positively or negatively regulates DC function. Tsang et al. (2011) showed that adiponectin treatment downregulates the expression of co-stimulatory molecules and impairs activation of allogenic T cells in murine bone marrow-derived DCs, suggesting that adiponectin inactivates DCs. On the contrary, a different study found that adiponectin induces maturation and activation of DCs in both bone marrow-derived murine and monocyte-derived human DCs (Jung et al., 2012). Along this line, adiponectin stimulates DC activation via phospholipase C γ/JNK/NF-κB pathways, leading to Th1 and Th17 polarization, a mechanism that is adiponectin receptor dependent (Jung et al., 2012). The opposite conclusion may result from the differential doses and times of adiponectin treatment. Therefore, further studies are needed to understand the mechanism underlying the regulatory role of adiponectin in DCs.

Conclusion

The innate immune system senses metabolic stress, and in turn orchestrates various intermediary metabolic pathways linked with the progression of obesity and its related disorders. Adiponectin is a well-defined obesity marker and exerts multiple beneficial properties against inflammation, insulin resistance, and cardiovascular diseases. The beneficial effects of adiponectin, on the one hand, are mediated by its insulin-sensitizing action. On the other hand, adiponectin modulates metabolic adaption by targeting the innate immune system, including macrophage plasticity and polarization, innate-like lymphocyte activity, and other innate immune cell functions (Figures 113). However, the insulin-sensitizing effects of adiponectin do not appear under physiological conditions. The average level of plasma adiponectin in humans is 5–10 μg/ml, nearly 1000-fold higher than most other adipokines and metabolic related hormones. Therefore, the key question that remains is to decipher what the physiological role of adiponectin is. The regulatory effect of adiponectin on innate immunity under physiological conditions may emerge as an important determinant of metabolic adaption. In addition, it has been shown that adiponectin regulates bone metabolism and food intake (Kubota et al., 2007; Kajimura et al., 2013; Wu et al., 2014). A better understanding of the physiological role of adiponectin in the regulation of innate immunity may provide a basis for the development of adiponectin-based therapeutic strategies.

Funding

This work was supported by the Junior Faculty Research Award (1-13-JF-37 to M.L.) from the American Diabetes Association, Grant in Aid Award (#15GRNT24940018 to M.L.) from the American Heart Association, Centers of Biomedical Research Excellence Pilot Award (to M.L.) associated with P30 [P30GM103400 (PI: J. Liu)] from the National Institutes of Health, and Research Allocation Committee Pilot Award (to M.L.) at the University of New Mexico Health Sciences Center (UNMHSC).

Conflict of interest: none declared.

References

  • Ahima R.S. (2006). Adipose tissue as an endocrine organ. Obesity (Silver Spring) 14(Suppl 5), 242S–249S. [PubMed]
  • Ajuwon K.M., Spurlock M.E. (2005). Adiponectin inhibits LPS-induced NF-κB activation and IL-6 production and increases PPARγ2 expression in adipocytes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R1220–R1225. [PubMed]
  • Akbari O., Stock P., Meyer E. et al. (2003). Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9, 582–588. [PubMed]
  • Awazawa M., Ueki K., Inabe K. et al. (2011). Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway. Cell Metab. 13, 401–412. [PubMed]
  • Bai Y., Sun Q. (2015). Macrophage recruitment in obese adipose tissue. Obes. Rev. 16, 127–136. [PMC free article] [PubMed]
  • Berg A.H., Combs T.P., Du X. et al. (2001). The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7, 947–953. [PubMed]
  • Bohlson S.S., O'Conner S.D., Hulsebus H.J. et al. (2014). Complement, c1q, and c1q-related molecules regulate macrophage polarization. Front. Immunol. 5, 402. [PMC free article] [PubMed]
  • Bourlier V., Bouloumie A. (2009). Role of macrophage tissue infiltration in obesity and insulin resistance. Diabetes Metab. 35, 251–260. [PubMed]
  • Brestoff J.R., Kim B.S., Saenz S.A. et al. (2015). Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246. [PMC free article] [PubMed]
  • Cayrol C., Girard J.P. (2014). IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr. Opin. Immunol. 31, 31–37. [PubMed]
  • Chawla A., Nguyen K.D., Goh Y.P. (2011). Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738–749. [PMC free article] [PubMed]
  • Chedid P., Hurtado-Nedelec M., Marion-Gaber B. et al. (2012). Adiponectin and its globular fragment differentially modulate the oxidative burst of primary human phagocytes. Am. J. Pathol. 180, 682–692. [PubMed]
  • Chen Y., Tian J., Tian X. et al. (2014). Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS One 9, e92450. [PMC free article] [PubMed]
  • Chimen M., McGettrick H.M., Apta B. et al. (2015). Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease. Nat. Med. 21, 467–475. [PMC free article] [PubMed]
  • Chinetti G., Zawadski C., Fruchart J.C. et al. (2004). Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARα, PPARγ, and LXR. Biochem. Biophys. Res. Commun. 314, 151–158. [PubMed]
  • Costanzo A.E., Taylor K.R., Dutt S. et al. (2015). Obesity impairs γδ T cell homeostasis and antiviral function in humans. PLoS One 10, e0120918. [PMC free article] [PubMed]
  • Denzel M.S., Scimia M.C., Zumstein P.M. et al. (2010). T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J. Clin. Invest. 120, 4342–4352. [PMC free article] [PubMed]
  • Duffaut C., Galitzky J., Lafontan M. et al. (2009). Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem. Biophys. Res. Commun. 384, 482–485. [PubMed]
  • Esmaili S., Xu A., George J. (2014). The multifaceted and controversial immunometabolic actions of adiponectin. Trends Endocrinol. Metab. 25, 444–451. [PubMed]
  • Fisher F.M., Trujillo M.E., Hanif W. et al. (2005). Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia 48, 1084–1087. [PubMed]
  • Galvan M.D., Hulsebus H., Heitker T. et al. (2014). Complement protein C1q and adiponectin stimulate Mer tyrosine kinase-dependent engulfment of apoptotic cells through a shared pathway. J. Innate Immun. 6, 780–792. [PMC free article] [PubMed]
  • Gil-Campos M., Canete R.R., Gil A. (2004). Adiponectin, the missing link in insulin resistance and obesity. Clin. Nutr. 23, 963–974. [PubMed]
  • Girardi M. (2006). Immunosurveillance and immunoregulation by γδ T cells. J. Invest. Dermatol. 126, 25–31. [PubMed]
  • Goldstein B.J., Scalia R. (2004). Adiponectin: A novel adipokine linking adipocytes and vascular function. J. Clin. Endocrinol. Metab. 89, 2563–2568. [PubMed]
  • Gordon S., Taylor P.R. (2005). Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964. [PubMed]
  • Haluzik M., Parizkova J., Haluzik M.M. (2004). Adiponectin and its role in the obesity-induced insulin resistance and related complications. Physiol. Res. 53, 123–129. [PubMed]
  • Hoffstedt J., Arvidsson E., Sjolin E. et al. (2004). Adipose tissue adiponectin production and adiponectin serum concentration in human obesity and insulin resistance. J. Clin. Endocrinol. Metab. 89, 1391–1396. [PubMed]
  • Holland W.L., Miller R.A., Wang Z.V. et al. (2011). Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17, 55–63. [PMC free article] [PubMed]
  • Hu E., Liang P., Spiegelman B.M. (1996). AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 271, 10697–10703. [PubMed]
  • Hui X., Gu P., Zhang J. et al. (2015). Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab. 22, 279–290. [PubMed]
  • Iwabu M., Yamauchi T., Okada-Iwabu M. et al. (2010). Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313–1319. [PubMed]
  • Jung M.Y., Kim H.S., Hong H.J. et al. (2012). Adiponectin induces dendritic cell activation via PLCγ/JNK/NF-κB pathways, leading to Th1 and Th17 polarization. J. Immunol. 188, 2592–2601. [PubMed]
  • Kadowaki T., Yamauchi T. (2005). Adiponectin and adiponectin receptors. Endocr. Rev. 26, 439–451. [PubMed]
  • Kadowaki T., Yamauchi T., Kubota N. et al. (2006). Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792. [PMC free article] [PubMed]
  • Kajimura D., Lee H.W., Riley K.J. et al. (2013). Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 17, 901–915. [PMC free article] [PubMed]
  • Kang K., Reilly S.M., Karabacak V. et al. (2008). Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 7, 485–495. [PMC free article] [PubMed]
  • Kim K.Y., Kim J.K., Han S.H. et al. (2006). Adiponectin is a negative regulator of NK cell cytotoxicity. J. Immunol. 176, 5958–5964. [PubMed]
  • Kintscher U., Hartge M., Hess K. et al. (2008). T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler. Thromb. Vasc. Biol. 28, 1304–1310. [PubMed]
  • Kouser L., Madhukaran S.P., Shastri A. et al. (2015). Emerging and novel functions of complement protein C1q. Front. Immunol. 6, 317. [PMC free article] [PubMed]
  • Koyasu S., Moro K. (2013). Th2-type innate immune responses mediated by natural helper cells. Ann. NY Acad. Sci. 1283, 43–49. [PubMed]
  • Kubota N., Yano W., Kubota T. et al. (2007). Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 6, 55–68. [PubMed]
  • Lackey D.E., Olefsky J.M. (2016). Regulation of metabolism by the innate immune system. Nat. Rev. Endocrinol. 12, 15–28. [PubMed]
  • Lappas M., Permezel M., Rice G.E. (2005). Leptin and adiponectin stimulate the release of proinflammatory cytokines and prostaglandins from human placenta and maternal adipose tissue via nuclear factor-κB, peroxisomal proliferator-activated receptor-γ and extracellularly regulated kinase 1/2. Endocrinology 146, 3334–3342. [PubMed]
  • Lee M.W., Odegaard J.I., Mukundan L. et al. (2015). Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87. [PMC free article] [PubMed]
  • Licona-Limon P., Kim L.K., Palm N.W. et al. (2013). TH2, allergy and group 2 innate lymphoid cells. Nat. Immunol. 14, 536–542. [PubMed]
  • Luo N., Liu J., Chung B.H. et al. (2010). Macrophage adiponectin expression improves insulin sensitivity and protects against inflammation and atherosclerosis. Diabetes 59, 791–799. [PMC free article] [PubMed]
  • Luo N., Wang X., Chung B.H. et al. (2011). Effects of macrophage-specific adiponectin expression on lipid metabolism in vivo. Am. J. Physiol. Endocrinol. Metab. 301, E180–E186. [PubMed]
  • Lynch L., O'Shea D., Winter D.C. et al. (2009). Invariant NKT cells and CD1d+ cells amass in human omentum and are depleted in patients with cancer and obesity. Eur. J. Immunol. 39, 1893–1901. [PubMed]
  • Lynch L., Nowak M., Varghese B. et al. (2012). Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37, 574–587. [PMC free article] [PubMed]
  • Maeda K., Okubo K., Shimomura I. et al. (1996). cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). Biochem. Biophys. Res. Commun. 221, 286–289. [PubMed]
  • Maeda N., Shimomura I., Kishida K. et al. (2002). Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat. Med. 8, 731–737. [PubMed]
  • Mandal P., Park P.H., McMullen M.R. et al. (2010a). The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells. Hepatology 51, 1420–1429. [PMC free article] [PubMed]
  • Mandal P., Roychowdhury S., Park P.H. et al. (2010b). Adiponectin and heme oxygenase-1 suppress TLR4/MyD88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure. J. Immunol. 185, 4928–4937. [PMC free article] [PubMed]
  • Mandal P., Pratt B.T., Barnes M. et al. (2011). Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin. J. Biol. Chem. 286, 13460–13469. [PMC free article] [PubMed]
  • Mantovani A., Sica A., Sozzani S. et al. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686. [PubMed]
  • Mantovani A., Biswas S.K., Galdiero M.R. et al. (2013). Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176–185. [PubMed]
  • Medoff B.D., Okamoto Y., Leyton P. et al. (2009). Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling. Am. J. Respir. Cell Mol. Biol. 41, 397–406. [PMC free article] [PubMed]
  • Mehta P., Nuotio-Antar A.M., Smith C.W. (2015). γδ T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. J. Leukoc. Biol. 97, 121–134. [PubMed]
  • Molofsky A.B., Nussbaum J.C., Liang H.E. et al. (2013). Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549. [PMC free article] [PubMed]
  • Nguyen K.D., Qiu Y., Cui X. et al. (2011). Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108. [PMC free article] [PubMed]
  • Odegaard J.I., Chawla A. (2011). Alternative macrophage activation and metabolism. Annu. Rev. Pathol. 6, 275–297. [PMC free article] [PubMed]
  • Ohashi K., Parker J.L., Ouchi N. et al. (2010). Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J. Biol. Chem. 285, 6153–6160. [PMC free article] [PubMed]
  • Ouchi N., Kihara S., Arita Y. et al. (2001). Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103, 1057–1063. [PubMed]
  • Ouchi N., Kihara S., Funahashi T. et al. (2003). Obesity, adiponectin and vascular inflammatory disease. Curr. Opin. Lipidol. 14, 561–566. [PubMed]
  • Ouchi N., Kobayashi H., Kihara S. et al. (2004). Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J. Biol. Chem. 279, 1304–1309. [PMC free article] [PubMed]
  • Pajvani U.B., Hawkins M., Combs T.P. et al. (2004). Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J. Biol. Chem. 279, 12152–12162. [PubMed]
  • Park P.H., McMullen M.R., Huang H. et al. (2007). Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-α (TNF-α) expression via ERK1/2 activation and Egr-1 expression: role of TNF-α in adiponectin-stimulated interleukin-10 production. J. Biol. Chem. 282, 21695–21703. [PMC free article] [PubMed]
  • Park P.H., Huang H., McMullen M.R. et al. (2008a). Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in RAW 264.7 macrophages. J. Leukoc. Biol. 83, 1258–1266. [PubMed]
  • Park P.H., Huang H., McMullen M.R. et al. (2008b). Suppression of lipopolysaccharide-stimulated tumor necrosis factor-α production by adiponectin is mediated by transcriptional and post-transcriptional mechanisms. J. Biol. Chem. 283, 26850–26858. [PMC free article] [PubMed]
  • Pischon T., Girman C.J., Hotamisligil G.S. et al. (2004). Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291, 1730–1737. [PubMed]
  • Price A.E., Liang H.E., Sullivan B.M. et al. (2010). Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl Acad. Sci. USA 107, 11489–11494. [PubMed]
  • Qiao L., Yoo H., Bosco C. et al. (2014). Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia 57, 1027–1036. [PMC free article] [PubMed]
  • Qiu Y., Nguyen K.D., Odegaard J.I. et al. (2014). Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308. [PMC free article] [PubMed]
  • Rao R.R., Long J.Z., White J.P. et al. (2014). Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291. [PMC free article] [PubMed]
  • Rossi A., Lord J. (2013a). Adiponectin inhibits neutrophil phagocytosis of Escherichia coli by inhibition of PKB and ERK 1/2 MAPK signalling and Mac-1 activation. PLoS One 8, e69108. [PMC free article] [PubMed]
  • Rossi A., Lord J.M. (2013b). Adiponectin inhibits neutrophil apoptosis via activation of AMP kinase, PKB and ERK 1/2 MAP kinase. Apoptosis 18, 1469–1480. [PMC free article] [PubMed]
  • Scherer P.E., Williams S., Fogliano M. et al. (1995). A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749. [PubMed]
  • Shibata R., Sato K., Pimentel D.R. et al. (2005). Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat. Med. 11, 1096–1103. [PMC free article] [PubMed]
  • Shibata S., Tada Y., Hau C.S. et al. (2015). Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells. Nat. Commun. 6, 7687. [PubMed]
  • Stefanovic-Racic M., Yang X., Turner M.S. et al. (2012). Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 61, 2330–2339. [PMC free article] [PubMed]
  • Takemura Y., Ouchi N., Shibata R. et al. (2007). Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies. J. Clin. Invest. 117, 375–386. [PubMed]
  • Tomas E., Tsao T.S., Saha A.K. et al. (2002). Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc. Natl Acad. Sci. USA 99, 16309–16313. [PubMed]
  • Tsang J.Y., Li D., Ho D. et al. (2011). Novel immunomodulatory effects of adiponectin on dendritic cell functions. Int. Immunopharmacol. 11, 604–609. [PubMed]
  • Tsao T.S., Murrey H.E., Hug C. et al. (2002). Oligomerization state-dependent activation of NF-κB signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J. Biol. Chem. 277, 29359–29362. [PubMed]
  • Tsatsanis C., Zacharioudaki V., Androulidaki A. et al. (2005). Adiponectin induces TNF-α and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem. Biophys. Res. Commun. 335, 1254–1263. [PubMed]
  • Tsatsanis C., Zacharioudaki V., Androulidaki A. et al. (2006). Peripheral factors in the metabolic syndrome: the pivotal role of adiponectin. Ann. NY Acad. Sci. 1083, 185–195. [PubMed]
  • Tsuchida A., Yamauchi T., Takekawa S. et al. (2005). Peroxisome proliferator-activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARα, PPARγ, and their combination. Diabetes 54, 3358–3370. [PubMed]
  • Weisberg S.P., McCann D., Desai M. et al. (2003). Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808. [PMC free article] [PubMed]
  • Weisberg S.P., Hunter D., Huber R. et al. (2006). CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115–124. [PubMed]
  • Wensveen F.M., Jelencic V., Valentic S. et al. (2015). NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376–385. [PubMed]
  • Wilk S., Jenke A., Stehr J. et al. (2013). Adiponectin modulates NK-cell function. Eur. J. Immunol. 43, 1024–1033. [PubMed]
  • Wolf A.M., Wolf D., Rumpold H. et al. (2004). Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem. Biophys. Res. Commun. 323, 630–635. [PubMed]
  • Wright H.L., Moots R.J., Bucknall R.C. et al. (2010). Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 49, 1618–1631. [PubMed]
  • Wu Y., Tu Q., Valverde P. et al. (2014). Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice. Am. J. Physiol. Endocrinol. Metab. 306, E1418–E1430. [PubMed]
  • Wulster-Radcliffe M.C., Ajuwon K.M., Wang J. et al. (2004). Adiponectin differentially regulates cytokines in porcine macrophages. Biochem. Biophys. Res. Commun. 316, 924–929. [PubMed]
  • Xu A., Wang Y., Keshaw H. et al. (2003). The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Invest. 112, 91–100. [PMC free article] [PubMed]
  • Yamaguchi N., Argueta J.G., Masuhiro Y. et al. (2005). Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS Lett. 579, 6821–6826. [PubMed]
  • Yamaguchi N., Kukita T., Li Y.J. et al. (2008). Adiponectin inhibits induction of TNF-α/RANKL-stimulated NFATc1 via the AMPK signaling. FEBS Lett. 582, 451–456. [PubMed]
  • Yamamoto R., Ueki S., Moritoki Y. et al. (2013). Adiponectin attenuates human eosinophil adhesion and chemotaxis: implications in allergic inflammation. J. Asthma 50, 828–835. [PubMed]
  • Yamauchi T., Kamon J., Waki H. et al. (2001). The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7, 941–946. [PubMed]
  • Yamauchi T., Kamon J., Ito Y. et al. (2003). Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769. [PubMed]
  • Yamauchi T., Nio Y., Maki T. et al. (2007). Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332–339. [PubMed]
  • Yamauchi T., Iwabu M., Okada-Iwabu M. et al. (2014). Adiponectin receptors: a review of their structure, function and how they work. Best Pract. Res. Clin. Endocrinol. Metab. 28, 15–23. [PubMed]
  • Yokota T., Oritani K., Takahashi I. et al. (2000). Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96, 1723–1732. [PubMed]
  • Zacharioudaki V., Androulidaki A., Arranz A. et al. (2009). Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expression. J. Immunol. 182, 6444–6451. [PubMed]
  • Zhou L., Deepa S.S., Etzler J.C. et al. (2009). Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways. J. Biol. Chem. 284, 22426–22435. [PMC free article] [PubMed]

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