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Organizer Name: Meredith Hawkins

Institution: Albert Einstein College of Medicine

Since the late 1800s, clinical observations have indicated that high-dose aspirin lowers blood glucose in type 2 diabetes, but the mechanism was not understood. More recently, epidemiologists have reported that patients with obesity and type 2 diabetes mellitus (T2DM) have elevated plasma levels of inflammatory markers. This suggests that inflammation is associated with obesity and may contribute to the development of diabetes. Additionally, various experimental models have demonstrated that these inflammatory markers, including such cytokines as tumor necrosis factor α (TNF-α) and interleukin-6, can actually cause insulin resistance. In 2003, Anthony Ferrante's group made the seminal observation that obesity is associated with increased macrophage infiltration into adipose tissue. The C-C motif chemokine receptor 2 (CCR2) regulates macrophage recruitment and is necessary for macrophage-dependent inflammatory responses. In obese mice, both genetic Ccr2 deficiency and pharmacologic inhibition of CCR2 reduced macrophage content and the inflammatory profile of adipose tissue, as well as improving systemic glucose homeostasis and insulin sensitivity. Recruitment of adipose tissue macrophages (ATMs) may therefore be an important component of the chronic systemic inflammation observed in obesity and may play a crucial role in the development of insulin resistance and diabetes.

Ironically, until recently adipose tissue was considered to be merely a storage compartment for triglyceride. It is now becoming clear that adipocytes are highly responsive to extracellular stimuli and are also essential for certain aspects of the immune system. In particular, Philipp Scherer's laboratory has been studying the significance of the adipocyte as a source of systemic inflammatory markers in T2DM. Adipocytes are highly responsive to bacterial endotoxin and can themselves secrete a number of inflammatory cytokines. Importantly, Dr. Scherer's group has demonstrated that adipocytes exert a strong inflammatory stimulus on macrophages, suggesting a ‘crosstalk’ between adipocytes and interstitial macrophages in adipose tissue in vivo. These effects appear to be mediated by an adipocyte secretory product that has not yet been identified. Hence, the local environment within adipose tissue would potentiate activation of macrophages to produce inflammatory factors, which in turn would fuel systemic inflammation.

Studies in humans by Meredith Hawkins' group have demonstrated that ATMs appear to be a major source of cytokine production by adipose tissue. These ATM-derived proteins include TNF-α, implicated in insulin resistance, and plasminogen activator inhibitor 1 (PAI-1), which promotes atherothrombosis. Dr. Hawkins' group has shown that increased circulating free fatty acid levels (to levels characteristic of obesity) heighten the production of these deleterious factors from adipose tissue and raise their circulating levels. An intriguing recent finding is that increased free fatty acid levels particularly activate ATMs to increase their production of these factors, yet circulating monocytes show no response. Supplementary in vitro studies of cultured macrophages have confirmed that secretory products contained in adipocyte cell culture medium have direct stimulatory effects on macrophages and potentiate their response to fatty acids. Together, the above data suggest that ATMs play an important role in the systemic inflammation and insulin resistance observed in obesity.

Drawing upon the earlier studies suggesting that anti-inflammatory salicylates (eg, high-dose aspirin) reverse hyperglycemia in patients with diabetes, Steven Shoelson demonstrated that directly activating the NF-κB pathway in fat and liver (as occurs in obesity) causes insulin resistance. NF-κB is well known as a master regulator of gene transcription in white blood cells and lymphocytes involved in inflammation and innate immunity. Previously, however, researchers had not investigated the function of NF-κB in fat, so its relationship to obesity was not known. In recent clinical studies, Dr. Shoelson and his collaborators found that high doses of salicylates lower blood glucose and dramatically reduce circulating triglycerides and free fatty acids as well as inflammatory markers. These changes are accompanied by improvements in glucose uptake and utilization, reductions in hepatic glucose production, and improved first-phase insulin secretion in type 2 diabetes. However, while these studies have shown that targeting the central inflammatory NF-κB pathway is useful, high-dose salicylates have toxic side effects. By pharmacologically inhibiting the NF-κB pathway by more specific means, Dr. Shoelson is working to develop effective new treatments for type 2 diabetes.

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