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Edison Biotechnology Institute and Ohio University College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701
Address all correspondence and requests for reprints to: Leonard D. Kohn, Edison Biotechnology Institute, Building 25, The Ridges, Ohio University, Athens, Ohio 45701. E-mail: kohnl{at}ohiou.edu.
The article by C. T. De Souza et al. (1) in this issue supports the conclusion that type II diabetes (DMII) is an autoimmune-inflammatory disease. It raises the possibility that DMII and its complications result from pathological expression of the innate immune system in nonimmune hypothalamic cells, as well as visceral adipocytes, ß-cells of the pancreas, and vascular endothelium.
Innate immunity is the rapid self-defense response of our body (2, 3, 4) to an environmental signature molecule that is perceived as an injuring agent or something foreign, in this case the hyperlipidemia, rather than a bacterial lipopolysaccharide, viral double-stranded RNA (dsRNA), or CpG sequences in the DNA of infectious agents. The response is mediated by Toll-like receptors (TLR), and the result is a cellular gene response that can cause a nonimmune, as well as an immune, cell to produce a cascade of immunologic proteins, e.g. cytokines, such as IL-1ß, TNF-
, and IL-6, which characterize our inflammatory response (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). In atherosclerosis, a disease that is a complication of DMII and, like DMII, is associated with obesity and hyperlipidemia, the pathological innate immune response is associated with overexpression of TLR4 and its signals in vascular endothelial cells and arterial walls (5, 6). A TLR4 knockout improves disease expression by decreasing the pathological inflammatory response (7).
TLRs in nonimmune cells are now implicated in multiple autoimmune-inflammatory diseases including, for example, Hashimoto’s thyroiditis (TLR3 in thyrocytes) (8), colitis (TLR4 in intestinal epithelial cells) (9, 10), and type 1 diabetes (TLR3 in pancreatic ß-cells) (11, 12). In each case, the pathological expression of the TLR in the nonimmune cells is associated with expression of an autoimmune-inflammatory disease.
Acquisition of visceral obesity is now recognized as a significant factor in the development of insulin resistance and DMII. The hyperlipidemia associated with obesity is a recognized factor in the development of visceral obesity, insulin resistance, and DMII. The large visceral fat depots produce excessive amounts of free fatty acids, adipokines, and cytokines including TNF- and IL-6 (reviewed in Ref.13), which can induce insulin resistance (13, 14, 15). TNF- can induce insulin resistance by decreasing serine phosphorylation of the insulin receptor kinase via increases in the suppressor of cytokine signaling (SOCS) (16). Additionally, SOCS-1 and SOCS-3 can bind directly to the insulin receptor (IR), where SOCS-3 inhibits tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and -2 and SOCS-1 inhibits tyrosine phosphorylation of IRS-1 only to induce insulin resistance (17). IL-6 induces insulin resistance by inhibiting GLUT4 synthesis as well as up-regulating SOCS-3 via activation of signal transducer and activator of transcription-(Stat)3 (18, 19).
The study by C. T. De Souza et al. (1) started as an array analysis of genes modulated by a hyperlipidemic (HL) diet to determine which genes might be important in the coordination of food intake and energy expenditure, functions primarily controlled by leptin and insulin. Rats were fed a high-lipid or a normal diet. At 13 and 16 wk, the hypothalamus was collected and 1176 mRNAs were evaluated. Increases in the IR, leptin receptor, and other genes associated with proteins important for modulating consumption and thermogenesis were noted with the HL diet; however, the authors were more intrigued by the clustering of increased mRNAs of immune-related proteins.
The HL mice had increased expression of proinflammatory cytokines IL-6, TNF-, and IL-1ß compared with the control. The HL mice also had increased expression of intermediates involved in the production of proinflammatory cytokines c-Jun N-terminal kinase and nuclear factor-
B (NF-B). Finally, the HL mice also had increased expression of serine phosphorylation of IR and IRS-2 (key elements of the insulin-signaling pathway). Interestingly, the IR protein level in the HL mice was not significantly increased compared with the control mice.
To test the theory that proinflammatory cytokines and their intermediates were involved with insulin resistance, the mice were treated with an inhibitor of c-Jun N-terminal kinase (SP600125). Treatment with this compound led to a lower body mass in the HL mice. SP600125 also reversed the effect of feeding upon insulin-induced tyrosine phosphorylation of IR and IRS-2, as well as increased insulin-induced inhibition of spontaneous food intake.
The paper touches on the mechanisms by which a high-lipid diet leads to leptin resistance. Leptin resistance occurs via a similar mechanism as that of insulin resistance, i.e. being dependent on activated STAT-3 and the immune-related signaling suppressor SOCS-3. The expression of SOCS-3 was increased in the hypothalamic cells of the HL mice. The HL mice also showed an inhibition of leptin-induced tyrosine phosphorylation of STAT-3. In sum, all of the changes seen in visceral adipocytes in DMII, which are implicated in insulin resistance, leptin resistance, and the development of DMII, are also noted in the hypothalamic neuronal cell.
This has potential, but far-reaching implications, by possibly relating DMII to autoimmune-inflammatory diseases associated with overexpression of TLRs and TLR signaling. The overexpression is seen in nonimmune cells and results in the production of cytokines and chemokines that can be activated through the TNF receptor-associated factor-6/NF-B and interferon (IFN) regulatory factor-3/type 1 IFN signal pathway, which together increase IL-6 and phosphorylate STAT-3. In short, pathological expression of TLR/TLR signaling when evident in nonimmune cells can result in IL-6 and Stat-3 activation of Socs genes and cause insulin/leptin resistance as well as produce TNF- and IL-1, which are also implicated in insulin resistance.
TLRs are a family of 10 known cell-surface receptors related to IL-1 receptors (2, 3, 4). They protect mammals from pathogenic organisms, such as viruses, by generating an innate immune response to products of the pathogenic organism (2, 3, 4). The innate immune response increases genes for several inflammatory cytokines and costimulatory molecules; it is critical for the development of antigen-specific adaptive immunity, both humoral and cell mediated (2, 3, 4). TLRs are present in most monocytes, macrophages, or immune cells; TLR3, which mediates a potent antiviral response (2, 3, 4), is present primarily on dendritic cells in humans, e.g. antigen presenting cells, which process and then present antigenic peptides to lymphoid cells in lymphoid organs (2, 3, 4).
The TLRs signal through adaptor molecules that bind to the cytoplasmic portion of the TLR. TLR3 and TLR4, for example, which recognize dsRNA or lipopolysaccharide, respectively, have either two adaptor molecules (TLR4), MyD88 and TIR domain-containing molecule adapter inducing IFN-ß/TIR-containing adapter molecule (TRIF/TICAM)-1 (2, 3, 4), or one (TLR3), TRIF/TICAM-1, which links to two separate signal pathways. In the case of dsRNA binding to TLR3, the TRIF/TICAM bypasses MyD88 and activates TNF receptor-associated factor, which then activates NF-B, MAPK, and various cytokines that direct an inflammatory response. In a separate interaction, TRIF/TICAM-1 activates IRF-3 and causes the synthesis and release of the type I IFNs and chemokines such as IFN-inducible protein 10. The type I IFN can induce a positive feedback loop, further up-regulating TLR3, or can interact with other cells, a phenomenon closely linked to the antiviral gene defense program. The type 1 IFN can induce a secondary, or delayed, activation of NF-B signaling to reinforce its actions. In recent work, the TLR and signal system have been recognized in nonimmune cells by different groups (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 20, 21, 22). TLR pathological expression on nonimmune cells is now recognized as a potential cause of humoral and cell-based autoimmune/inflammatory diseases (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 20, 21, 22) wherein the noxious environmental event or infectious agent attacks a nonimmune rather than the immune cell. The immune cell becomes a bystander response (20, 21, 22).
The question is: how do proinflammatory cytokines released from nonimmune cells in innate immunity (possibly via TLRs) tie in with the receptors for leptin and insulin? The receptors for leptin and insulin share a common pathway. After the receptors bind their respective ligand, Stat-3 is activated by phosphorylation. The activated Stat-3 will then up-regulate socs-3 gene expression. Subsequently, by means of feedback inhibition, SOCS-3 works to block the binding of insulin and leptin to their receptor, causing resistance. As previously shown, activation of TLRs (particularly TLR3 and TLR4) leads to a cascade of interactions that initiates the activation of NF-B and IRF-3. Activated NF-B then induces the transcription of proinflammatory cytokines IL-6 and TNF- as well as others. The important link between the two pathways is that IL-6 then acts to phosphorylate STAT-3, leading to the insulin and leptin resistance.
The link between obesity and disease is not completely clear. The paper by De Souza et al. (1) helps to strengthen the role of proinflammatory cytokines and their intermediates as being important in the disease process, particularly in diseases such as DMII. By pointing out the association between a high-fat diet and the increased inflammation in the hypothalamus, many new areas of treatment and research could be explored. This paper also raises questions for further study, such as: what is the link between a high-lipid diet and a proinflammatory status in the hypothalamus? and if nonimmune cells such as the hypothalamus and adipose tissue can become proinflammatory, what other cells in the body act in the same way? A very glaring aspect of the paper is to emphasize that nonimmune cells can cause the release of proinflammatory cytokines that can lead to insulin and leptin resistance. This begs further research in this exciting but fledgling area and could open the door to exciting ideas in research and treatment.
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B, nuclear factor-B; SOCS, suppressor of cytokine signaling; Stat, signal transducer and activator of transcription; TLR, Toll-like receptor; TRIF/TICAM, TIR domain-containing molecule adapter inducing IFN-ß/TIR-containing adapter molecule. Received July 21, 2005.
Accepted for publication July 22, 2005.
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—a potential link in the pathogenesis of viral-induced type 1 diabetes and autoimmunity. Clin Immunol. 111:225–233
-agonist-mediated improvements in hepatic insulin sensitivity? Int J Obes Relat Metab Disord. 29(Suppl 1):S17–S23
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