Adipose tissue has attracted a great deal of attention as a pathogenic site of obesity-induced insulin resistance, partly because changes in adiposity are easy to see but also because fat produces bioactive proteins that are readily detected and reflect the inflammatory state of the organ. However, it has also been firmly established that all fat is not equal; adipose tissue in the subcutaneous versus abdominal or visceral depots differs by cell size (69, 70), metabolic activity, and potential role in insulin resistance (71, 72). Visceral fat is more pathogenic. The adipocyte itself is integral to the development of obesity-induced inflammation. As discussed above, proteins produced by adipocytes that might collaboratively initiate the process include TNF-α, IL-6, resistin, leptin, adiponectin, MCP-1, PAI-1, and angiotensinogen, but since the recruited immune cells produce many of the same substances, with the exception of leptin and adiponectin, it is difficult to pinpoint precise sites of production. Myeloid-selective deletion of IKKβ improves obesity-induced insulin resistance, underscoring potential roles for both NF-κB and inflammatory cells including macrophages (73), but this has not helped to distinguish where the process is initiated. Both cell types, lipid-laden adipocytes and recruited macrophages, seem to participate in the pathogenesis of inflammation-induced insulin resistance (Figure 2). Since the bulk of accumulated lipid is stored in adipocytes, it is generally assumed that the adipocyte initiates the process and the macrophage serves to amplify the signal. Since many of the bioactive proteins involved are NF-κB targets, and NF-κB activation can be self-sustaining, antiinflammatory therapies including salicylates may coordinately decrease their expression and improve insulin resistance.

Figure 2 Potential mechanisms for activation of inflammation in adipose tissue. Dietary excess and obesity cause lipid accumulation in adipocytes, initiating a state of cellular stress and activation of JNK and NF-κB. These inflammatory signaling pathways regulate protein phosphorylation and cellular transcriptional events, thereby leading to increased adipocyte production of proinflammatory cytokines, including TNF-α, IL-6, leptin, and resistin, chemokines such as MCP-1, and other proatherogenic mediators, for example PAI-1. Endothelial adhesion molecules (e.g., ICAM-1 and VCAM-1) and chemoattractant molecules (designated CCX) bind integrins and chemokine receptors (CCR), respectively, on the monocyte surface to recruit them to the adipose tissues. The monocytes that differentiate into macrophages produce many of the same inflammatory cytokines and chemokines as those listed above, and additional ones, to further promote local inflammation and propagate the inflammatory diathesis systemically. pS, phosphoserine.

It is important to understand how increasing adiposity leads to the recruitment of immune cells to adipose tissue. MCP-1 (CCL2), a chemoattractant for monocytes, DCs, and memory T cells, is produced by adipocytes in parallel with increasing adiposity (74, 75), suggesting that MCP-1 might play a role in recruitment of monocytes. Consistent with this, mice lacking CCR2, an important receptor for MCP-1, are partly protected from developing high-fat diet–induced insulin resistance and exhibit reductions in adipose tissue macrophage recruitment and inflammatory gene expression (76). The fact that protection is incomplete implies that additional chemoattractant ligand-receptor pairs might be involved. It is also interesting that some macrophages found in the adipose tissue of obese rodents are large and multinucleated (74, 75, 77). Such multinucleate giant cells are often found at sites of chronic inflammation and result from the fusion or engulfment of macrophages by each other. Macrophages including multinucleate giant cells may aggregate at sites of adipocyte necrosis (77).

Other cell types in adipose tissue may also participate in the inflammatory process. Vascular cells are an obvious place to look. Adipose tissue is highly vascularized, with multiple capillaries in contact with each adipocyte (78). Moreover, adipose tissue rapidly proliferates and expands as nutrient stores increase, possibly using processes similar to the angiogenesis that supports tumor growth (77). In addition to being important for fat expansion, the microvasculature undoubtedly plays important roles in adipose tissue inflammation. For example, circulating leukocytes do not adhere to normal endothelium, but after initiation of a high-fat Western diet the endothelium expresses cell adhesion molecules that bind leukocytes (79). Adipose tissue endothelial cells may increase the expression of one or more of the adhesion proteins ICAM-1, VCAM-1, E-selectin, or P-selectin in response to increased adiposity. As mentioned earlier, MCP-1 induces the migration of blood monocytes into the subendothelial space and augments differentiation into macrophages. Thus changes are predicted in adipose tissue endothelial cells in response to altered adiposity. As macrophages rarely function alone, other types of immune cells are likely to participate in adipose tissue inflammation, although this has not yet been reported. In addition to cytokine and protease release, the actions of macrophages in inflammation include antigen presentation and T cell activation. Classical inflammation involves the added presence of neutrophils, DCs, NK cells, mast cells, and various subtypes of T lymphocytes. Potential roles for these other immune cells in adipose tissue inflammation will doubtless be topics for future investigation.

In addition to adipose tissue, the liver is affected by obesity (Figure 3). Nonalcoholic fatty liver disease (NAFLD) often accompanies abdominal adiposity, and its prevalence is increasing and closely parallels the prevalence of the comorbid conditions T2D and hyperlipidemia. The pathological spectrum of NAFLD ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Inflammation clearly plays a pivotal role in the progression of this disease process. While inadequate suppression of hepatic glucose production, due at least in part to hepatic insulin resistance, is an established contributor to hyperglycemia in T2D, the role of inflammation in the pathogenesis of these processes has only recently been explored. Inflammatory gene expression increases in liver with increasing adiposity (43). This suggests that hepatocyte lipid accumulation (steatosis) might induce a subacute inflammatory response in liver that is similar to the adipose tissue inflammation that follows adipocyte lipid accumulation. Alternatively, proinflammatory substances in the portal circulation, potentially produced in abdominal fat, might initiate hepatic inflammation. Regardless, NF-κB is activated in the hepatocyte, and cytokines including IL-6, TNF-α, and IL-1β are overproduced in fatty liver. The proinflammatory cytokines participate in the development of insulin resistance and activate Kupffer cells, the resident hepatic macrophages. Unlike adipose tissue, where macrophages are relatively sparse basally but increase numerically with adiposity, the liver is densely populated with Kupffer cells, which account for over 5% of total cells. The number of Kupffer cells does not increase with adiposity, but their activation state does (43). A wide variety of other immune cells are present in normal liver and may also play roles in inflammation-induced insulin resistance, including T and B lymphocytes, NK cells, and DCs as well as hepatic stellate cells and liver sinusoidal endothelial cells (80). NKT cells are enriched in normal mouse liver, and their numbers decrease in ob/ob or high-fat diet models of obesity (81, 82). NKT cells are regulatory lymphocytes, with features of both classical T (CD3+) and NK (NK1.1+) cells and characteristic expression of CD1d, an MHC class I homologue that presents glycolipid antigens to TCRs. Adoptive transfer of NKT cells reportedly improves nonalcoholic steatohepatitis and glucose intolerance in ob/ob mice (83), consistent with a role for decreased NKT numbers in the pathogenesis of these disorders.

Figure 3 Potential mechanisms for adiposity-induced inflammation in the liver. Healthy liver contains a broad repertoire of cells that participate in inflammatory and immune responses, including resident hepatic macrophages (Kupffer cells), B and T cells, NK and NKT cells, DCs, liver sinusoidal endothelial cells, hepatic stellate cells, and hepatocytes. Hepatic steatosis and obesity are accompanied by the activation of inflammatory signaling pathways in liver. Proinflammatory cytokines and FFAs, produced either by hepatocytes in response to steatosis or by abdominal fat tissue, may activate Kupffer cells. Numbers of regulatory NKT cells decrease in parallel with the Kupffer cell activation.

Skeletal muscle is another major site of insulin resistance in obesity and T2D. However, increasing adiposity does not appear to activate inflammatory cascades in skeletal muscle, as it does in fat and liver. Inflammation is activated in muscle by intralipid infusion, but this is distinct from the effects of increasing adiposity. The lipid infusion model is a research tool used to acutely raise circulating and intratissue fatty acid levels and induce insulin resistance. Intralipid infusion activates PKC-θ and IKKβ in mouse muscle, and the associated insulin resistance is inhibited by salicylate or IKKβ depletion (54, 56). This is in contrast with high-fat diet–induced and obesity-induced insulin resistance, neither of which activates IKKβ/NF-κB in skeletal muscle (84, 85) or leads to an increase in skeletal muscle macrophages (75). Concordantly, neither muscle-specific ablation of IKKβ nor muscle-specific inhibition of NF-κB improves insulin resistance in obese mice (84, 85). It is perhaps more appropriate to think of skeletal muscle as a target of inflammation-induced insulin resistance as opposed to a site of initiation (Figure 4).