Overactivation of immune pathways in obesity is an important cause of insulin resistance and thus new approaches aimed to limit inflammation or its consequences may be effective for treating Type 2 diabetes. The SOCS (suppressors of cytokine signalling) are a family of proteins that play an essential role in mediating inflammatory responses in both immune cells and metabolic organs such as the liver, adipose tissue and skeletal muscle. In the present review we discuss the role of SOCS1 and SOCS3 in controlling immune cells such as macrophages and T-cells and the impact this can have on systemic inflammation and insulin resistance. We also dissect the mechanisms by which SOCS (1–7) regulate insulin signalling in different tissues including their impact on the insulin receptor and insulin receptor substrates. Lastly, we discuss the important findings from SOCS whole-body and tissue-specific null mice, which implicate an important role for these proteins in controlling insulin action and glucose homoeostasis in obesity.

INTRODUCTION

According to the most recent World Health Organization estimates (WHO fact sheet number 311, 2008, updated March 2011) more than 1.4 billion adults and more than 40 million children are overweight. Of these nearly half a billion are clinically obese. These figures are especially worrying in light of the fact that obesity is closely associated with the metabolic syndrome, characterized by insulin resistance, dyslipidaemia and hypertension, and is recognized as a major risk factor for chronic diseases such as cardiovascular disease, Type 2 diabetes and NAFLD (non-alcoholic fatty liver disease) [1,2]. The molecular events mediating the link between obesity and characteristics of the metabolic syndrome are still incompletely understood, but numerous studies conducted in rodents and humans point firmly to chronic low-grade activation of inflammatory pathways as a common underlying factor [36]

The classic paradigm of inflammation consists of a short-term adaptive response to infection or other acute noxious events against chronic inflammation with symptoms and signs including heat, redness, swelling, pain and loss of function. However, what is meant by inflammation in obesity is low-grade expression of inflammatory mediators without clinical features that is maintained in a chronic state and appears to stem from continuous tissue stress and malfunction [4]. These changes are commonly localized around expanding volumes of adipose tissue, in particular visceral adipose tissue, but in previous years it has become well accepted that some level of inflammation is present in nearly all tissues [36]. In light of the obesity epidemic and the importance of inflammation as a pathogenic pathway in the development of many hallmarks of the metabolic syndrome including insulin resistance, the need to develop new and effective strategies in controlling inflammation has become increasingly urgent.

The effective dissipation of cytokine receptor signalling is essential for preventing excessive inflammation and detrimental effects on other signalling pathways. The SOCS (suppressors of cytokine signalling) family [also named JAB (Janus family kinase-binding] proteins or SSI (signal transducer and activator of transcription induced Stat inhibitor)] were initially discovered in 1997 as molecules that are involved in a negative-feedback loop to attenuate cytokine action [79]. Eight members of the SOCS family that share similar structural and functional characteristics have been identified: SOCS1–7 [10] and CIS (cytokine-inducible Src-homology 2-containing protein) [11] (Figure 1). They all contain a unique poorly conserved N-terminal region of variable length and sequence, a central SH2 (Src homology 2) domain and a conserved C-terminal region of approximately 40 amino acids known as the ‘SOCS box’ [10]. The SOCS complex can act as an E3 ubiquitin ligase, facilitating the polyubiquitin-ation and degradation of signalling proteins by the proteasome [12,13]. Within the N-terminal region of SOCS1 and SOCS3 there is also a 12 amino acid KIR (kinase inhibitory region), which functions to inhibit JAKs (Janus kinases) involved in the propagation of cytokine signalling [14]. In SOCS6 and SOCS7, the N-terminal domain appears to be required for their nuclear translocation [15,16], whereas the functional significance for the N-terminus of SOCS4 and SOCS5 has not yet been elucidated [17].

Structural domains of the SOCS family of proteins

Figure 1
Structural domains of the SOCS family of proteins

Cul box, cullin box; KIR, kinase inhibitory region.

Figure 1
Structural domains of the SOCS family of proteins

Cul box, cullin box; KIR, kinase inhibitory region.

The basal expression of SOCS proteins is generally very low, but can be highly and selectively induced in a tissue-specific manner by a diverse range of stimuli. As part of a classical feedback regulatory mechanism, SOCS transcription is induced through cytokine receptor signalling mediated by the JAK/STAT (signal transducer and activator of transcription) pathway and STAT-responsive elements have been identified in the promoters of a number of SOCS proteins, including CIS, SOCS1 and SOCS3 [8,1821]. In addition, cellular abundance of SOCS proteins may also be determined by alterations in protein stability as demonstrated for SOCS1 [22] and SOCS6 [23]. Similarly, SOCS2, SOCS6 and SOCS7 have been suggested to promote the degradation of other SOCS family members [24,25]; however, the physiological role of this regulatory mechanism requires further study. In healthy animals and humans SOCS proteins are widely expressed, with SOCS1, 3 and 5 being highly expressed in lymphoid tissues (thymus, spleen and lymph nodes), suggesting an important role in the regulation of immune cell function [26,27]. CIS and SOCS2 are both induced by cytokines that activate STAT5 signalling [growth hormone, erythropoietin and G-CSF (granulocyte colony-stimulating factor)] and as such have high expression levels in the liver, kidney and lung [11,28]. SOCS7 appears to be abundant in testis, ovaries and spleen, but also in tissues related to glucose and energy homoeostasis, such as skeletal muscle, brain and pancreatic islets [29].

In obesity the expression of SOCS proteins are elevated in a variety of tissues that are vital for regulating metabolism and insulin sensitivity. For example SOCS1 and SOCS3 expression are increased in the liver [30,31], adipose tissue [3235] and muscle [3638] of obese rodents. It should be noted that SOCS proteins are also elevated in the hypothalamus of obese rodents [39,40] and this is vital for controlling energy expenditure and intake as has been reviewed previously [3941], but this topic is not within the scope of the present review. An important question is why are SOCS proteins induced in obesity? In addition to classical activators of the JAK/STAT pathway, such as members of the IL-6 (interleukin-6) family of cytokines [8] and IFNγ (interferon γ) [21], other inducers of SOCS proteins include non-JAK/STAT-activating cytokines such as TNFα (tumour necrosis factor α) [32], growth factors {GM-CSF (granulocyte/macrophage colony-stimulating factor) [8], erythropoietin [11] and LIF (leukaemia inhibitory factor) [8]} and hormones (insulin [42], leptin [43], resistin [44], growth hormone [28], ciliary neurotropic factor [45] and prolactin [46]), many of which are also elevated in obesity. The importance of these cytokines in controlling SOCS expression may depend on the tissue studied. For example, elevated IL-6 production from skeletal muscle myotubes appears to be the dominant factor driving SOCS3 expression in the skeletal muscle of obese humans [47,48]. In contrast, in adipose tissue of rodents TNF may be the most dominant factor as obese TNF-deficient mice have low levels of SOCS3 [34]. Adding to the induction of SOCS3 in obesity by cytokines and hormones, polymorphisms in SOCS3 have been linked with obesity and Type 2 diabetes in some [49,50], but not all [51], studies.

In addition to the classical cytokine activators of SOCS proteins listed above, a recent study has suggested that a key regulator of SOCS1 expression in the liver might be amyloid-β, a molecule that is proposed to be responsible for the link between Alzheimer's disease and the development of liver insulin resistance [52]. Using a transgenic mouse model expressing increased levels of amyloid-β, Zhang et al. [52] showed reduced insulin signalling specifically in the liver, which was associated with increased protein expression of SOCS1. In isolated hepatocytes amyloid-β was able to increase activation of JAK2/STAT3, which resulted in elevated SOCS1 expression. Importantly, siRNA-mediated knockdown of SOCS1 alleviated the effects of amyloid-β on reducing insulin sensitivity suggesting that increases in SOCS1 may help explain the epidemiological evidence linking Alzheimer's disease with Type 2 diabetes.

THE ROLE OF SOCS PROTEINS IN CONTROLLING INFLAMMATION IN IMMUNE CELLS: POTENTIAL IMPLICATIONS FOR OBESITY AND INSULIN RESISTANCE

Chronic low-grade inflammation in obesity primarily involves macrophages, which in obesity home to adipose tissue, but also other metabolic organs critical for the control of insulin sensitivity such as the skeletal muscle and liver [5355]. Regional areas of hypoperfusion and microhypoxia may lead to the activation of cellular stress pathways and secretion of inflammatory cytokines and chemokines from T-cells [5658]. These attract macrophages into adipose tissue where they surround dead adipocytes [53,59] and become activated by local cytokines, chemokines and fatty acids [54,55,60,61]. In lean adipose tissue macrophage inflammation is restricted by anti-inflammatory cytokines produced by TH2 and Treg cells. Increasing obesity is associated with a decline in these anti-inflammatory T-cells and accumulation of CD8+, TH1 and TH17 cells capable of producing factors that induce macrophage activation and recruitment [6264]. Thus the recruitment and activation state of macrophages are greatly influenced by TH1 and TH2 cytokines generated by T-cells and as such the manipulation of T-cell populations and inflammatory status may be important for controlling obesity-induced insulin resistance [65].

SOCS proteins have an important role in the development, maturation and differentiation of T-cells and this is one way SOCS proteins may regulate inflammation in obesity. SOCS1 plays a vital role in controlling T-cell proliferation and activation and SOCS1-knockout mice exhibit severe dysregulation of immune and inflammatory responses [66,67]. These effects can be minimized through the generation of SOCS1/IFNγ or SOCS1/IFNγ receptor double-knockout mice; thus indicating that SOCS1 is a critical regulator of IFNγ, a cytokine primarily secreted from T-cells [68]. Deletion of SOCS1 from CD4+ T-cells causes predominant differentiation into inflammatory TH1 cells [69] and consequently high sensitivity to TH1 diseases, such as dextran sodium-induced colitis [70] or ConA (concanavalin A)-induced hepatitis [71]. SOCS1-deficient Treg cells also show increased production of inflammatory cytokines such as IFNγ and IL-17 due to hyperphosphorylation of STAT1 and STAT3 [72]. Thus SOCS1 may preserve the immunosuppressive phenotype of Treg cells. As IFNγ promotes the development of insulin resistance in obesity [64,7377] future studies examining whether T-cell expression of SOCS1 is important in obesity-induced insulin resistance are warranted.

Among the SOCS family members expressed in naïve T-cells, SOCS3 is most abundant and has been implicated in the regulation of T-cell proliferation. SOCS3 expression is transiently down-regulated upon antigen presentation, suggesting that SOCS3 normally acts to maintain T-cells in a quiescent state [78]. Consistent with this idea, SOCS3 expression is also very low in Treg cells [79]. Importantly, T-cell-specific deletion of SOCS3 results in increased proliferation of CD8+ T-cells, due to hypersensitivity towards IL-6 and IL-27 and prolonged phosphorylation of STAT1, STAT2 and STAT3 [80]. Similarly, silencing of SOCS3 in CD4+ T-cells using siRNA inhibits the TH2 cell response [81]. However, mice with T-cell-specific deletion of SOCS3 showed a reduction of not only TH2, but also TH1 responses [82], which was attributed to a generally immunosuppressive effect of SOCS3 deficiency rather than a direct effect on TH1 differentiation [82]. Whether the expression of SOCS3 is altered in different classes of T-cells as a result of obesity is not currently known.

Macrophages normally co-localize within tissues, functioning as scavengers and participating in remodelling [59] and neovascularization [83]. In obesity, both the content and activation state of macrophages are increased [5355]; thus, limiting the activation state of macrophages may be important for preventing low-grade chronic inflammation in obesity. One mechanism by which macrophages may become activated involves the TLR (Toll-like receptor) family of pattern recognition receptors that detect structural motifs associated with pathogens or tissue injury. Of these, TLR2 and TLR4 have been most intensely studied in the context of nutritional overload due to their increased expression in immune cells and metabolic tissues in obesity and diabetes [8486]. In obesity TLR4 may become activated by circulating LPS (lipopolysaccharide) due to increased Gram-negative bacteria [87,88]. Although previous studies also suggested a role for saturated fatty acids, such as palmitic acid, in TLR4 activation [60,89] this has been challenged and attributed to LPS contamination [90]. Irrespective of the key ligand driving activation of TLR signalling it is clear that inhibition of this pathway may be important for protecting against obesity-induced insulin resistance.

SOCS1 directly inhibits the TLR signalling pathway by promoting the ubiquitination and proteasomal degradation of Mal (MyD88-adaptor-like) and NF-κB (nuclear factor κB) [9194]. Sachithanandan et al. [95] investigated the effects of macrophage/lymphocyte-specific SOCS1 deletion (SOCS1 LysM-Cre) and found that macrophages from SOCS1 LysM-Cre mice displayed hypersensitivity to both LPS and palmitic acid, resulting in elevated expression and secretion of inflammatory cytokines and systemic inflammation. Furthermore, SOCS1 LysM-Cre mice showed increased macrophage accumulation and inflammation in the liver. Increased inflammation in SOCS1 LysM-Cre mice led to the development of hepatic insulin resistance, accompanied by hyperinsulinaemia, glucose intolerance and reduced insulin signalling in the liver, consistent with findings that liver Kupffer cells are a major cause of insulin resistance in obesity [96]. Similar findings have also been observed by Whyte et al. [97] who showed that SOCS1 is essential for the maintenance of IL-4-induced expression and activity of the anti-inflammatory enzyme arginase I and concomitant attenuation of LPS/IFNγ-induced inflammatory cytokine expression. Thus SOCS1 in macrophages protects mice against systemic inflammation and hepatic insulin resistance by restraining TLR-induced macrophage inflammation (Figure 2). These findings may explain why paradoxically (given the role of SOCS1 in inhibiting liver insulin sensitivity discussed in detail below) a SOCS1 genetic polymorphism that enhances transcriptional activity is associated with enhanced insulin sensitivity [98].

SOCS1 in macrophages inhibits TLR4 activation limiting inflammation, hepatic insulin resistance and hyperglycaemia

Figure 2
SOCS1 in macrophages inhibits TLR4 activation limiting inflammation, hepatic insulin resistance and hyperglycaemia

Mal, MyD88-adaptor-like; MCP-1, monocyte chemoattractant protein.

Figure 2
SOCS1 in macrophages inhibits TLR4 activation limiting inflammation, hepatic insulin resistance and hyperglycaemia

Mal, MyD88-adaptor-like; MCP-1, monocyte chemoattractant protein.

Although SOCS1 plays a vital role in blunting TLR-mediated inflammatory responses, the role of SOCS3 in macrophages appears to be more complicated as mice deficient in SOCS3 display hyper-responsiveness to IL-6, but do not develop overt inflammation [99,100]. Instead, macrophage-specific SOCS3 knockout mice display a reduced immune response with lowered sensitivity to LPS-induced endotoxaemia and reduced serum TNFα levels [100]. This phenotype has been attributed to prolonged IL-6-induced STAT3 activation, which in macrophages seems to promote the production of the anti-inflammatory cytokine IL-10 and thus supporting the idea that IL-6 is primarily an anti-inflammatory cytokine [101]. However, these findings are not without controversy as a recent study investigating the pattern of macrophage polarization in myeloid-specific SOCS3-knockout mice reported the opposite phenotype with the conclusion that SOCS3 is involved in suppressing M1 activation [102]. The reasons for this stark discrepancy in the findings from studies using similar cell systems and mouse-knockout models are so far unclear, but clearly warrant further study to establish the importance of macrophage SOCS3 in modulating inflammation.

The above studies suggest a vital role for SOCS1 and SOCS3 in limiting inflammatory responses in T-cells and macrophages. As obesity is associated with hyperactivation of these immune cells, efforts to increase the expression of SOCS proteins in immune cells may confer protection from inflammation-induced insulin resistance. Although data from macrophage SOCS1-deficient mice support this conclusion, future studies examining the importance of other SOCS proteins in T-cells and in macrophages in the context of obesity and insulin resistance are warranted.

HOW DO SOCS PROTEINS REGULATE INSULIN ACTION?

The inflammatory cascade and pro-inflammatory cytokines generated by the immune cells discussed above directly influence insulin action in metabolic organs vital for the control of insulin sensitivity such as skeletal muscle, liver and adipose tissue [3,5,65,103]. One of the most widely studied mechanism by which pro-inflammatory cytokines inhibit insulin signalling is through increased S/T (serine/threonine) phosphorylation of IRS (insulin receptor substrate) proteins. S/T phosphorylation impedes the association of IRS proteins with the insulin receptor and reduces their ability to interact with downstream effectors [104106]. Furthermore, it turns IRS proteins into inhibitors of the insulin receptor kinase [107109], promotes their interactions with 14-3-3 proteins, which displace the IRS–PI3K (phosphoinositide 3-kinase) complex from the plasma membrane [110,111] and targets IRS proteins for degradation [112,113]. Among the S/T kinases responsible for IRS inhibition, many are activated by insulin, such as atypical PKC (protein kinase C) isoforms, mTORC1 (mammalian target of rapamycin complex 1), JNK, S6K1 (S6 kinase 1), ERK1/2 (extracellular-signal-regulated kinase 1/2) and GSK-3 (glycogen synthase kinase-3), indicating that inhibitory S/T phosphorylation may be part of a negative-feedback mechanism that is necessary for the fine tuning of insulin signalling under healthy conditions. Although the large amount of correlative data over the last 10 years support the association between inflammation, IRS S/T phosphorylation and the development of insulin resistance, genetic evidence does not support this conclusion as IRS1 S307A-knockin mice have normal or even enhanced insulin sensitivity [114,115]. These data suggest that potentially multiple S/T residues on IRS1 need to be simultaneously phosphorylated or that alternatively, other mechanisms primarily contribute to inflammation-induced insulin resistance.

An important mechanism by which inflammation may induce insulin resistance in metabolic organs involves the induction of SOCS proteins. The most widely studied isoforms involved with the regulation of insulin sensitivity are SOCS1 and SOCS3; however, SOCS6 and SOCS7 have also been implicated in the control of insulin action. Three mechanisms have been proposed to explain how SOCS proteins may inhibit insulin action and they include: (i) the inhibition of the catalytic activity of the insulin receptor, (ii) competition with IRS proteins for crucial phosphotyrosine-binding residues in the activated receptor, and/or (iii) the targeting of IRS proteins for proteasomal degradation (Figure 3). In the following sections we will discuss the evidence linking SOCS proteins with insulin signal transduction and review the current evidence of their importance in tissue-specific mouse models. The findings of these studies are summarized in Table 1.

Regulation of insulin signalling by SOCS proteins

Figure 3
Regulation of insulin signalling by SOCS proteins

SOCS1 and SOCS3 prevent insulin-induced activation of IRS proteins by competing for phosphotyrosine-binding sites on the insulin receptor. Another important mechanism for the inhibition of insulin signalling by SOCS1, SOCS3 and SOCS7 is targeting of IRS1/2 for proteasomal degradation by coupling to the elongin ubiquitin-ligase complex. SOCS1 and SOCS6 have been reported to inhibit the tyrosine kinase activity of the insulin receptor. However, SOCS6 seems to have an overall positive effect on insulin signalling by reducing excess free p85 regulatory PI3K subunit, which in its monomeric form is known to inhibit insulin-induced Akt activation. SOCS1 and SOCS3, when co-expressed with JAK1 and JAK2, can reduce insulin-induced IRS1 phosphorylation by JAKs. However, it is unclear whether this mechanism is relevant under physiological conditions. IR, insulin receptor; KD, kinase domain; Ub, ubiquitin.

Figure 3
Regulation of insulin signalling by SOCS proteins

SOCS1 and SOCS3 prevent insulin-induced activation of IRS proteins by competing for phosphotyrosine-binding sites on the insulin receptor. Another important mechanism for the inhibition of insulin signalling by SOCS1, SOCS3 and SOCS7 is targeting of IRS1/2 for proteasomal degradation by coupling to the elongin ubiquitin-ligase complex. SOCS1 and SOCS6 have been reported to inhibit the tyrosine kinase activity of the insulin receptor. However, SOCS6 seems to have an overall positive effect on insulin signalling by reducing excess free p85 regulatory PI3K subunit, which in its monomeric form is known to inhibit insulin-induced Akt activation. SOCS1 and SOCS3, when co-expressed with JAK1 and JAK2, can reduce insulin-induced IRS1 phosphorylation by JAKs. However, it is unclear whether this mechanism is relevant under physiological conditions. IR, insulin receptor; KD, kinase domain; Ub, ubiquitin.

Table 1
Changes in insulin sensitivity resulting from genetic manipulation of SOCS1 and SOCS3 in different tissues
SOCS protein Cell type/tissue Treatment Insulin sensitivity Reference(s) 
SOCS1     
In vitro 3T3L1 adipocytes Inhibition with antisense oligonucleotides Increased: TNF-induced down-regulation of IRS2 is partially restored [30
 3T3L1 adipocytes Overexpression Decreased: inhibition of glucose uptake [30
 L6 myotubes Overexpression Decreased: inhibition of glycogen synthesis [30
In vivo Liver Overexpression by adenoviral injection Decreased: exacerbated insulin resistance [30,31,120,121
 db/db mouse Inhibition with antisense oligonucleotides Increased: improved insulin signalling in liver [31
 Whole-body Knockout Increased: reduced blood glucose (assumed to involve improvement in insulin sensitivity) [126
 Whole-body Double knockout with IFNγ Increased: increased insulin sensitivity specifically in liver [128
 Whole-body Double knockout with RAG2 No change in insulin sensitivity not protected from effects of high-fat diet [129
 Macrophages and lymphocytes Tissue-specific knockout Decreased: increased systemic inflammation hepatic insulin resistance [95
SOCS3     
In vitro COS7 cells Overexpression Decreased: inhibition of IRS phosphorylation and association with p85 [32,42
 3T3L1 adipocytes Inhibition with antisense oligonucleotides Increased: TNF-induced down-regulation of IRS1 and IRS2 phosphorylation is restored [30
 3T3L1 adipocytes Overexpression Decreased: inhibition of glucose uptake [30
 L6 myotubes Overexpression Decreased: inhibition of glycogen synthesis [30
In vivo Adipose tissue Transgenic overexpression Decreased: reduced insulin signalling in acipocytes [122
   Increased: improved systemic insulin sensitivity on a high-fat diet  
 Adipose tissue Tissue-specific knockout No change in insulin sensitivity or glucose tolerance on chow diet [132
   Increased: improved systemic insulin sensitivity on a high-fat diet in female mice  
 Liver Overexpression by adenoviral injection Decreased: exacerbated insulin resistance [30,31
 Liver Tissue-specific knockout Increased: improved hepatic insulin sensitivity in young mice [134
   Decreased: increased obesity and systemic insulin resistance from 4 months of age  
 Liver Tissue-specific knockout Increased: improved hepatic insulin sensitivity on chow diet [135
   Decreased: increased inflammation and systemic insulin resistance on high-fat diet  
 Skeletal muscle Transgenic overexpression No change in insulin signalling in skeletal muscle [124
   Decreased: reduced insulin sensitivity due to increased obesity  
 Skeletal muscle Transgenic overexpression Decreased: reduced insulin signalling in muscle; reduced systemic insulin sensitivity [123
 Skeletal muscle Tissue-specific knockout No change in insulin sensitivity on chow diet [138
   Increased: increased glucose disposal and improved systemic insulin sensitivity on high-fat diet  
SOCS protein Cell type/tissue Treatment Insulin sensitivity Reference(s) 
SOCS1     
In vitro 3T3L1 adipocytes Inhibition with antisense oligonucleotides Increased: TNF-induced down-regulation of IRS2 is partially restored [30
 3T3L1 adipocytes Overexpression Decreased: inhibition of glucose uptake [30
 L6 myotubes Overexpression Decreased: inhibition of glycogen synthesis [30
In vivo Liver Overexpression by adenoviral injection Decreased: exacerbated insulin resistance [30,31,120,121
 db/db mouse Inhibition with antisense oligonucleotides Increased: improved insulin signalling in liver [31
 Whole-body Knockout Increased: reduced blood glucose (assumed to involve improvement in insulin sensitivity) [126
 Whole-body Double knockout with IFNγ Increased: increased insulin sensitivity specifically in liver [128
 Whole-body Double knockout with RAG2 No change in insulin sensitivity not protected from effects of high-fat diet [129
 Macrophages and lymphocytes Tissue-specific knockout Decreased: increased systemic inflammation hepatic insulin resistance [95
SOCS3     
In vitro COS7 cells Overexpression Decreased: inhibition of IRS phosphorylation and association with p85 [32,42
 3T3L1 adipocytes Inhibition with antisense oligonucleotides Increased: TNF-induced down-regulation of IRS1 and IRS2 phosphorylation is restored [30
 3T3L1 adipocytes Overexpression Decreased: inhibition of glucose uptake [30
 L6 myotubes Overexpression Decreased: inhibition of glycogen synthesis [30
In vivo Adipose tissue Transgenic overexpression Decreased: reduced insulin signalling in acipocytes [122
   Increased: improved systemic insulin sensitivity on a high-fat diet  
 Adipose tissue Tissue-specific knockout No change in insulin sensitivity or glucose tolerance on chow diet [132
   Increased: improved systemic insulin sensitivity on a high-fat diet in female mice  
 Liver Overexpression by adenoviral injection Decreased: exacerbated insulin resistance [30,31
 Liver Tissue-specific knockout Increased: improved hepatic insulin sensitivity in young mice [134
   Decreased: increased obesity and systemic insulin resistance from 4 months of age  
 Liver Tissue-specific knockout Increased: improved hepatic insulin sensitivity on chow diet [135
   Decreased: increased inflammation and systemic insulin resistance on high-fat diet  
 Skeletal muscle Transgenic overexpression No change in insulin signalling in skeletal muscle [124
   Decreased: reduced insulin sensitivity due to increased obesity  
 Skeletal muscle Transgenic overexpression Decreased: reduced insulin signalling in muscle; reduced systemic insulin sensitivity [123
 Skeletal muscle Tissue-specific knockout No change in insulin sensitivity on chow diet [138
   Increased: increased glucose disposal and improved systemic insulin sensitivity on high-fat diet  

SOCS1 and SOCS3 interact with the insulin receptor in vitro, in vivo or in the yeast-2-hybrid system [30,116118]. Specifically SOCS3 interacts with phosphorylated Tyr960, a binding site for IRS1 and IRS2 proteins [32], and therefore competition with SOCS3 for this site has been proposed as one potential mechanism for the attenuation of insulin signalling. Accordingly, overexpression of SOCS3 significantly reduces insulin-induced IRS1 and IRS2 phosphorylation and inhibits binding bet-ween IRS1 and downstream PI3K [32]. Interestingly, SOCS1's binding site on the insulin receptor is distinct from that of SOCS3 and involves the three major tyrosine phosphorylation sites 1146, 1150 and 1151 of the kinase domain [30] that bind IRS2. Thus overexpression of SOCS1 in cultured cells seemed to inhibit IRS2 more potently than IRS1, whereas SOCS3 overexpression affected the phosphorylation of both IRS proteins equally [30]. Similarly, antisense oligonucleotide treatment against SOCS1 preferentially restored IRS2 phosphorylation, whereas suppression of SOCS3 restored the phosphorylation of both IRS1 and IRS2 [30].

SOCS6 has also been implicated in the regulation of insulin signalling through direct binding to the insulin receptor as indicated in co-immunoprecipitation studies in human and rat hepatoma cells [118]. This interaction was only observed upon insulin stimulation and resulted in a suppression of insulin-induced ERK1/2 and Akt phosphorylation [118]. Although neither SOCS1 nor SOCS6 affected insulin-induced autophosphorylation of the insulin receptor, they seemed to be able to inhibit the insulin receptor kinase activity resulting in a subsequent decrease in IRS phosphorylation [118]. However, the exact site of SOCS6 binding to the insulin receptor has not been reported. In vitro, SOCS6 and SOCS7 also bind to other components of the insulin signalling pathway via their SH2 domain, including IRS4, IRS2 and the p85 regulatory subunit of PI3K [119], indicating that SOCS6 and SOCS7 could inhibit propagation of the insulin signal by blocking access of downstream SH2-containing proteins to phosphotyrosine-binding sites on IRS proteins.

SOCS proteins also target IRS proteins for proteasomal degradation [30,120]. As discussed above SOCS1 and SOCS3 preferentially associate with IRS2 and IRS1 respectively [30]. Expression of SOCS1 proteins with mutations within the SOCS box that rendered them incapable of interacting with the elongin BC ubiquitin-ligase complex failed to promote ubiquitination and proteasomal degradation of IRS proteins [120]. The acute overexpression of SOCS1 [30,31,120,121] or SOCS3 [30,31] in the liver by adenoviral injection exacerbates insulin resistance, hyperglycaemia and hyperinsulinaemia and is associated with a dramatic reduction in IRS proteins. Importantly, treatment of obese, diabetic, leptin-receptor-deficient mice (db/db) with antisense oligonucleotides against SOCS1 and SOCS3 also improved insulin signalling in the liver due to increased expression of IRS2 and IRS1 respectively [31]. Similarly, in adipose tissue the transgenic overexpression of SOCS3 (by greater than 100-fold) also reduces IRS1 protein levels leading to reduced insulin-stimulated glucose uptake and lipogenesis [122]. The transgenic overexpression of SOCS3 in skeletal muscle has also been reported to inhibit IRS1 expression in some [123], but not all, [124] studies. Collectively, these studies indicate that a primary mechanism by which SOCS1 and SOCS3 inhibit insulin action is through their ubiquitination of IRS protein expression.

Finally, SOCS proteins may also attenuate IRS phosphorylation via inhibition of JAKs. Co-expression of the insulin receptor and JAK1 or JAK2 in cellular systems has shown that insulin stimulation can lead to phosphorylation and activation of JAKs, which in turn phosphorylate IRS1 on sites different to those phosphorylated by the insulin receptor [125]. This mechanism is used by several cytokines, hormones and growth factors, such as IGF-1 (insulin-like growth factor-1), growth hormone, leptin, IL-2, IL-4, IL-13 and LIF, to induce tyrosine phosphorylation of IRS proteins with subsequent PI3K activation and downstream effects on cell growth and proliferation. Similarly, in response to insulin, JAK1 and JAK2, but not TYK2 (tyrosine kinase 2), have been shown to co-immunoprecipitate with the insulin receptor and IRS1 and lead to IRS1 phosphorylation [126]. The degree of IRS1 phosphorylation was greatly reduced by co-expression of SOCS1 or SOCS3, but not SOCS5. However, the physiological significance of this mechanism of SOCS-mediated inhibition of insulin signal transduction, when compared with the direct effects of SOCS proteins on the insulin receptor or IRS phosphorylation and stability, might be minor, as JAK activation in response to insulin appears to be very modest [127].

The above-described studies highlight three biochemical mechanisms by which SOCS proteins may acutely regulate insulin action. The exact quantitative importance of these three pathways in controlling insulin action may be cell-type-specific which may explain the different actions in different cell types; however, the majority of studies suggest that SOCS proteins control insulin action by reducing the expression of IRS proteins. However, a caveat of many studies that have described the importance of this pathway is that transgenic overexpression of SOCS proteins (in many cases to an extent much greater than observed during low-grade chronic inflammation in obesity) may have non-specific effects due to the inhibition of multiple SOCS proteins simultaneously. Therefore the physiological importance of these pathways in the control of tissue-specific insulin action and ultimately their importance in controlling glucose homoeostasis in obesity can only be tested in genetic mouse models in which SOCS expression is genetically reduced. The results of these studies are discussed in the following section.

GENETIC KNOCKOUT MOUSE MODELS OF SOCS PROTEINS AND THEIR ROLE IN CONTROLLING INSULIN ACTION AND GLUCOSE HOMOEOSTASIS

SOCS1-null mice

Mice with whole-body deficiency of SOCS1 die before weaning from multi-organ inflammation; however, biochemical analyses from 7–10-day-old animals showed reduced blood glucose levels in knockout mice when compared with wild-type controls [126]. The lower blood glucose levels in SOCS1−/− mice were initially attributed to enhanced insulin sensitivity, a finding also supported by accelerated differentiation of SOCS1−/− mouse embryonic fibroblasts into adipocytes. However, the hypoglycaemia observed in SOCS1-knockout mice in vivo might have also been a consequence of the severe inflammation and subsequent liver damage present in these animals. Therefore to investigate the metabolic effects of SOCS1 Jamieson et al. [128] generated SOCS1−/− mice that were also deficient for IFNγ, the cytokine responsible for the severe inflammatory syndrome with SOCS1 deletion. Neutralization of IFNγ and SOCS1/IFNγ-double-null mice showed mildly reduced glucose and insulin levels. Subsequent findings using hyperinsulinaemic–euglycaemic clamps established that improved whole-body insulin sensitivity was due to enhanced insulin action in the liver and subsequently greater suppression of hepatic glucose production [128]. Consistent with the in vitro findings linking SOCS1 with IRS2 discussed above, enhanced insulin action in the liver of SOCS1/IFNγ-double-null mice was associated with increased IRS2 (but not IRS1) expression and was linked to enhanced IRS2 and Akt phosphorylation [128]. In contrast, SOCS1 deficiency did not seem to affect the expression and phosphorylation of IRS1 in muscle and adipose tissue. Consistent with the more dominant role of IRS1 over IRS2 in these tissues, peripheral glucose disposal was unchanged in SOCS1-deficient mice as indicated by hyperinsulinaemic–euglycaemic clamp experiments. Similar results were also observed in SOCS1−/−/RAG2−/− (where RAG2 is recombination activating gene 2) mice; however, the differences were only observed during a chow diet and did not translate into improvements in insulin sensitivity when mice were made obese through feeding of a high-fat diet [129]. Collectively, these studies suggest that whole-body deletion of SOCS1 might have modest effects on improving insulin action on a background of T-cell or IFNγ deficiency, effects which may be due to enhanced insulin action in the liver. Future studies examining SOCS1 floxed mice with tissue-specific deletions in the liver, adipose tissue and muscle are required to fully evaluate the importance of this molecule in controlling insulin action in obesity.

SOCS2-null mice

The phenotype of SOCS2-knockout mice suggests that SOCS2 plays an important role in the suppression of growth hormone signalling. These mice are characterized by gigantism and hypersensitivity to exogenous growth hormone with increased bone size and enlarged organs most likely due to prolonged JAK2/STAT5b activation [28]. Consistent with growth hormone being a regulator of hepatic triglyceride (triacylglycerol) mobilization, SOCS2-knockout mice show increased triglyceride secretion from the liver and protection from high-fat diet-induced hepatic steatosis, but have increased lipid deposition in skeletal muscle and adipose tissue [130]. Although this is not associated with changes in systemic insulin sensitivity when mice are fed on a normal chow diet, under high-fat-diet conditions SOCS2-null mice are glucose intolerant and insulin resistant and show increased expression of inflammatory cytokines. The latter has been suggested to be a consequence of increased sensitivity of SOCS2-knockout macrophages to LPS, leading to increased NF-κB activation and inflammatory signalling in the liver despite reduced steatosis [130]. These data indicating a vital role for SOCS2 in controlling insulin sensitivity in mice support findings showing that SNPs (single nucleotide polymorphisms) in SOCS2 are linked with susceptibility to Type 2 diabetes in the Japanese population [131]. Future studies investigating the role of SOCS2 in controlling insulin action and lipid metabolism are certainly warranted.

SOCS3-null mice

White adipose tissue

A recent study investigated the effects of white adipose tissue-specific deletion of SOCS3 (SOCS3 AKO mice) in mice fed on a chow or obesity-promoting high-fat diet [132]. In this context there was no difference in adipocyte cell size, total adiposity, food intake or energy expenditure between wild-type and SOCS3 AKO mice on chow or a high-fat diet [132]. SOCS3 deficiency also did not affect adiponectin expression from adipose tissue and muscle insulin sensitivity was unaltered. Accordingly, there was no difference in whole-body glucose tolerance or insulin sensitivity between SOCS3 AKO and wild-type mice under chow-fed conditions, presumably due to the low SOCS3 expression levels in lean animals. However, when fed a high-fat diet, which increased SOCS3 production in wild-type mice (by approximately 3-fold), female, but not male, SOCS3 AKO mice showed mild protection from obesity-induced insulin resistance. Improved whole-body insulin sensitivity was due to increased rates of glucose uptake into adipose tissue as a result of enhanced IRS1 expression and phosphorylation [132]. The reason for the sexual dimorphism is unclear, but may be due to the enhanced insulin-sensitizing effects of oestrogen which has been shown to increase SOCS3 expression [133]. These data indicate that in adipose tissue from female obese mice SOCS3 is an important component contributing to the development of insulin resistance, effects which are mediated through degradation of IRS1.

Liver

In mice with hepatocyte-specific deletion of SOCS3 driven by the Alb-Cre promoter, insulin-induced IRS1 protein levels are increased, an effect which protects mice from IL-6-induced insulin resistance [134]. Similarly, Sachithanandan et al. [135] also showed improved hepatic insulin sensitivity in a distinct line of young liver-specific SOCS3-knockout mice fed a control chow diet. However, rather unexpectedly, when mice are aged [134] or fed on an obesity-inducing high-fat diet [135], SOCS3 liver-specific knockout mice develop increased obesity and systemic insulin resistance. In the case of aging this effect appeared to be a consequence of increased STAT3 activation in the liver, which, in turn, resulted in increased inflammation due to secretion of the acute-phase proteins SAA1 (serum amyloid A1), SAA2 (serum amyloid A2) and CRP (C-reactive protein), and subsequent impairment of insulin signalling in other organs such as skeletal muscle. SOCS3 deficiency in the context of high-fat feeding led to increased liver lipogenesis driven by elevated levels of lipogenic enzymes [SREBP1c (sterol-regulatory-element-binding protein 1c), SCD1 (stearoyl-CoA desaturase 1), FAS (fatty acid synthase) and GPAT (glycerol-3-phosphate acyltransferase)], which resulted in increased steatosis and systemic inflammation. This liver lipid deposition seemed independent of any potential effects of insulin or STAT3 activation on lipogenic gene expression, which is in contrast with a previous study showing reduced hepatic steatosis in db/db mice upon SOCS3 knockdown [31]. As systemic inflammation causes hypothalamic leptin resistance and increased appetite [136], these studies suggest that a chronic deficiency of liver SOCS3 unexpectedly contributes to the development of obesity. Thus, under conditions of high-calorie intake, hepatic SOCS3 protects the liver from excessive lipid accumulation and inflammation. These studies suggest that therapeutic targeting of SOCS3 in the liver may have the unintended consequence of promoting liver steatosis and obesity during prolonged nutrient excess or aging.

Skeletal muscle

With obesity, endogenous levels of SOCS3 have been shown to co-immunoprecipitate with the insulin receptor and IRS1 in skeletal muscle [137]. To clarify the importance of skeletal muscle SOCS3 Jorgensen et al. [138] generated mice with muscle-specific deletion of SOCS3 (SOCS3 MKO). These mice did not show any abnormalities in muscle function or energy expenditure and had body weights and adiposities similar to wild-type mice, irrespective of diet. Consistent with this, muscle STAT3 and AMPK (AMP-activated protein kinase) phosphorylation and lipid content were comparable between genotypes, indicating that SOCS3 in skeletal muscle is not required for the regulation of energy expenditure or AMPK activity (potentially due to the inhibition of leptin signalling) as suggested by studies involving the overexpression of SOCS3 [38,48,123]. In contrast with SOCS3 liver-KO mice [134,135], there were no detectable differences in insulin sensitivity when mice were fed on a chow diet. However, when exposed to a diet high in fat, which increased SOCS3 expression in wild-type, but not in knockout, muscle, SOCS3 MKO mice showed increased peripheral glucose disposal and were partially protected from the development of insulin resistance. Enhanced insulin action was not due to changes in IRS1 protein expression, but instead was associated with increased phosphorylation of IRS1. These findings suggest that the inhibition of skeletal muscle SOCS3 could potentially serve as a favourable strategy to enhance insulin action and improve glucose homoeostasis in obesity.

SOCS6- and SOCS7-null mice

Studies involving the overexpression of SOCS6 and SOCS7 have shown an important role for these proteins in controlling multiple aspects of insulin signalling. This possibility was tested initially in SOCS6-null mice, but, surprisingly, these mice showed no signs of hyper-responsiveness to insulin and performed similarly in insulin and glucose tolerance tests, suggesting that other SOCS proteins implicated in the inhibition of the insulin signal, such as the highly homologous SOCS7, could potentially compensate for the loss of SOCS6 [119]. Accordingly, SOCS7-knockout mice showed increased levels of IRS proteins and enhanced insulin signalling in skeletal muscle, which was associated with lower systemic glucose levels and increased rates of glucose clearance during glucose tolerance tests [29]. In agreement with these findings in mice, a previous report indicated that common variants and haplotypes of SOCS7 are strongly associated with the development of obesity and lipid disorders in non-diabetic men [139]. These studies suggest that targeting both SOCS3 and SOCS7 in skeletal muscle may have dramatic effects for improving glucose homoeostasis in obesity.

CONCLUDING REMARKS

SOCS proteins are induced by and regulate signalling of a plethora of cytokines, growth factors and hormones in a diverse range of cell types. Although there is currently a breadth of studies supporting an important role for SOCS proteins in the negative regulation of insulin action, many issues regarding the role of SOCS proteins in whole-body insulin resistance remain unresolved. The first major problem when interpreting studies targeting SOCS proteins for the treatment of obesity and Type 2 diabetes involves the duration and degree of overexpression or inhibition. For example, transient and partial reductions in SOCS3 expression induced by siRNA results in enhanced insulin sensitivity in isolated hepatocytes treated with inflammatory cytokines or in the liver of leptin receptor-deficient mice [30,31]. The observations that SOCS3 is important for inducing insulin resistance in the liver are also supported by studies in young lean mice lacking SOCS3 due to Alb-Cre deletion [134,135]. However, in the context of aging [134] or a high-fat diet [135] SOCS3 deficiency promotes NAFLD, systemic inflammation and the exacerbation of obesity. So whereas SOCS3 in the liver blunts insulin-induced suppression of hepatic glucose production it also limits insulin-induced liver lipid accumulation, which over time has a much more dramatic impact on influencing whole-body glucose homoeostasis. Thus the inhibition of SOCS3 in the liver of obese patients may have detrimental side effects of promoting NAFLD and hyperphagia. Therefore an important consideration and challenge when designing therapies for chronic diseases such as obesity is to carefully consider the potential impact of short-term improvements against long-term health implications. Specifically, it becomes important to consider that insulin resistance induced by increases in liver SOCS3 may be a protective mechanism to prevent further deterioration in glucose homoeostasis under conditions of hyperinsulinaemia and high nutrient availability.

Another important challenge when developing therapies aimed towards SOCS proteins for the treatment of obesity and insulin resistance involves identifying tissue-specific exposure profiles. For example, whereas inhibiting SOCS1 in the liver may improve liver insulin sensitivity [30,31,120,121,128], if the same compound also inhibits SOCS1 expression in macrophages (or for that matter Kupffer cells) any beneficial effect may be offset by greater inflammation as a result of enhanced sensitivity to TLR4 ligands such as LPS [96,97]. Similarly, whereas the inhibition of SOCS3 in skeletal muscle improves insulin-stimulated glucose disposal [138], chronic SOCS3 deletion in the liver will likely have a detrimental impact on overall glucose homoeostasis in the context of obesity [134,135]. Lastly, and perhaps most importantly, reduced SOCS expression is associated with inflammatory disorders and malignancies. For example, reduced levels of SOCS1 are linked with the severity of disease in patients with pulmonary fibrosis [140] and arthritis [141], whereas SOCS1 and SOCS3 are silenced in a variety of cancers [142145]. Thus the challenge is to determine which elements of the SOCS-regulated pathways could be targeted with favourable outcomes without causing or exacerbating other detrimental aspects of SOCS function. This will require a detailed understanding of the role of SOCS proteins in disease pathophysiology in order to prevent the unintentional negative side effects that systemic and chronic reductions in SOCS proteins are likely to have.

Abbreviations

     
  • AMPK

    AMP-activated protein kinase

  •  
  • CIS

    cytokine-inducible Src-homology 2-containing protein

  •  
  • ERK1/2

    extracellular-signal-regulated kinase 1/2

  •  
  • IFNγ

    interferon γ

  •  
  • IL-6

    interleukin-6

  •  
  • IRS

    insulin receptor substrate

  •  
  • JAK

    Janus kinase

  •  
  • LIF

    leukaemia inhibitory factor

  •  
  • LPS

    lipopolysaccharide

  •  
  • NAFLD

    non-alcoholic fatty liver disease

  •  
  • NF-κB

    nuclear factor κB

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • SH2

    Src homology-2

  •  
  • SOCS

    suppressors of cytokine signalling

  •  
  • S/T

    serine/threonine

  •  
  • STAT

    signal transducer and activator of transcription

  •  
  • TLR

    Toll-like receptor

  •  
  • TNFα

    tumour necrosis factor α

FUNDING

Research grants from the National Health and Medical Research Council of Australia and the Canadian Institutes of Health Research support research on SOCS proteins in the laboratories of T.W.K. and G.R.S respectively. G.R.S. is a Canada Research Chair in Metabolism and Obesity.

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