VEGF-B Blockade in Muscle Endothelium:A Potential Barrier to Type 2 Diabetes
Obesity and increased lipid deposition in ectopic tissues, such as the heart and skeletal muscle, are linked to insulin insensitivity and type 2 diabetes. Vascular endothelial growth factor B (VEGF-B) is expressed in highly metabolic tissues and acts through endothelial receptors on skeletal and cardiac muscle to increase fatty acid uptake and lipid deposition. Mice lacking Vegfb exhibit lower fatty acid uptake and lipid deposition in muscle, suggesting that VEGF-B blockade at the level of the endothelium could be a novel treatment for type 2 diabetes. In a recent study, Hagberg et al. utilized murine models of diabetes (mice and rats on a high-fat diet [HFD] and diabetic db/db mice) to block VEGF-B action in both skeletal and cardiac muscle endothelia. In these experiments, genetic (deletion of the Vegfb gene) and pharmacologic (neutralizing anti–VEGF-B antibody) approaches were used. Vegfb knockout HFD and db/db mice exhibited decreased blood glucose levels and were more glucose tolerant compared with controls. In addition, Vegfb knockout db/db mice exhibited decreased lipid deposition and increased glucose uptake in skeletal and cardiac muscle compared with their wild-type counterparts. With respect to hyperglycemia, pharmacologic intervention with an anti–VEGF-B antibody was effective as both a preventive treatment in prediabetic db/db mice as well as a therapeutic agent in diabetic db/db mice. The anti–VEGF-B antibody also resulted in decreased lipid deposition in peripheral tissues and improved glucose tolerance in db/db mice relative to controls. The authors also investigated the effect of anti–VEGF-B antibody on insulin resistance and type 2 diabetes using HFD rats. VEGF-B blockade resulted in increased glucose infusion and disposal rates and increased glucose uptake in both skeletal and cardiac muscle. Based on results from both mice and rats, data from Hagberg’s laboratory suggest that prevention of VEGF-B activity could maintain pancreatic islet function and improve insulin resistance. In fact, histochemical analyses of anti–VEGF-B antibody–treated, diabetic db/db mice showed large pancreatic islets and little degeneration, whereas controls had small, disorganized islets. The authors conclude that the anti–VEGF-B antibody may be a novel approach to type 2 diabetes therapy that leverages the natural barrier function of the endothelium to prevent lipid deposition, restore insulin sensitivity, and retain islet functionality. — Eileen M. Resnick, PhD
Hagberg et al. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 2012;490:426–430
A Ternary Complex of Fetuin-A, TLR4, and Free Fatty Acids Promotes Insulin Resistance
Free fatty acids (FFAs) promote chronic inflammation and are linked to insulin resistance in diabetes. The production of proinflammatory cytokines in adipose tissue in response to FFAs is at least partially mediated by signaling via the Toll-like receptor-4 (TLR4) and activation of the nuclear factor-κB (NF-κB). Although it was known that FFAs activate the TLR4 signaling pathway, a direct interaction between FFAs and this receptor has not been documented. Identification of an endogenous ligand for FFA-dependent signaling via TLR4 could be beneficial for development of therapeutic strategies aimed at FFA-induced insulin resistance. FFAs are known to stimulate expression of fetuin-A (FetA), a liver secretory glycoprotein, through NF-κB. Increased FetA has been shown to enhance proinflammatory cytokine production in adipocytes. Pal et al. recently published findings investigating the role of FetA in development of FFA-dependent insulin sensitivity in the TLR4 pathway. To study the effects of either TLR4 or FetA loss on lipid-induced insulin resistance, the authors chose not to use the genetic approaches of TLR4−/− and FetA−/− mice because they are protected from lipid-induced insulin resistance. Alternatively, BALB/c mice were first fed a high-fat diet (HFD), followed by individual knockdown of the two genes by the vivo-morpholino knockdown approach. Compared with wild-type mice, loss of either gene was protective against insulin resistance from HFD and resulted in a reduction in NF-κB activity and IL-6 and TNF-α mRNA expression in adipocytes. Although previous work implicated TLR4 in lipid-induced insulin resistance, these new findings are the first to directly link FetA with this cellular process. Further studies in human adipocytes demonstrated that both TLR4 and FetA were required for this signaling cascade: FFA-induced TLR4 signaling required FetA, and blockade of TLR4 prevented FetA signaling. Additional experiments in various human and mouse primary cells and cultures, including adipocytes and macrophages, defined the importance of the combination of TLR4, FFAs, and FetA for NF-κB activation, thereby providing evidence for the formation of an FFA-FetA-TLR4 ternary complex. The authors demonstrated direct binding between FetA and TLR4, defined the extracellular domain of TLR4 as the binding site for FetA, and showed that the terminal β-galactoside moiety of FetA binds to TLR4. In summarizing the implications of their findings, the authors suggest that FetA acts as an endogenous presenter of FFAs to TLR4 on adipocytes, leading to NF-κB signaling, proinflammatory cytokine production, and insulin resistance. If this is the case, FetA could be a new target for therapeutics in the management of insulin resistance and type 2 diabetes. — Eileen M. Resnick, PhD
Pal et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 2012;18:1279–1285
Myocardial Infarction Exacerbates Atherosclerosis via Enhanced Monocyte Production
Clear evidence of improved cardiovascular care is the fact that nearly 90% of patients survive a first myocardial infarction (MI). However, reinfarction is common in these patients and is coupled with high mortality. It is intuitively appealing to believe that reinfarction is a downstream event on a linear trajectory of cardiovascular disease progression that begins with the first event. An alternative hypothesis has been proposed in which post-MI inflammation associated with the body’s attempts to repair the damaged heart, actually exacerbates pre-existing atherosclerosis thereby increasing risk of secondary events. It has been established that monocytes and macrophages promote inflammation at the site of atherosclerotic lesions, causing them to be unstable. During MI, monocytes increase and migrate to the site of the myocardial lesion. New studies by Dutta et al. provide evidence that the MI-induced increase in inflammatory cells may itself enhance atherosclerotic disease. The authors’ initial experiments demonstrated that after coronary ligation, Apoe−/− mice developed more severe atherosclerosis than wild-type mice. Findings showed that plaque protease activity, inflammatory cytokine expression in plaques, and the number of monocytes and macrophages in the aorta were all elevated. To determine the origin of the surplus of monocytes in plaques, additional studies focused on monocyte progenitor cells in the spleen because the spleen can accommodate extramedullary hematopoiesis. After MI, expression of inflammatory mRNA differed between monocytes isolated from spleen compared with bone marrow, and the profile of monocytes isolated from post-MI plaques matched spleen progenitor cells. Further studies showed that signaling through β-adrenergic receptors in bone marrow niche cells due to increased sympathetic nervous system (SNS) activity from pain, anxiety, and impaired left ventricular function resulted in release of hematopoietic stem and progenitor cells. β-Adrenergic blockade after MI reduced the number of granulocyte macrophage progenitors in the spleen and also lowered protease activity, myeloid cells, and mRNA levels of inflammatory cytokines in plaques. The authors postulated that increased SNS activity leads to release of upstream progenitors from the bone marrow, as well as receipt and retention of these cells in the spleen. They propose a continuous, circular paradigm that connects MI, SNS activity, progenitor release from bone marrow niches, increased extramedullary monocytopoiesis, and plaque rupture to explain increased reinfarction. The authors note that although knowledge of the role of inflammation in atherosclerosis is increasing, development of therapies targeting specific anti-inflammatory elements is needed. They suggest that one such strategy might be to interrupt monocyte supply. — Eileen M. Resnick, PhD
Dutta et al. Myocardial infarction accelerates atherosclerosis. Nature 2012;487:325–329
Caloric Restriction, Health, and Survival: Surprising New Data From the NIA
Caloric restriction (CR), often defined as a 10–40% reduction in nutritious dietary intake, has long been reported to prolong life span in animal models and to positively impact immune function and motor coordination, improve glucose tolerance, and inhibit development of sarcopenia in nonhuman primates (NHPs). Because of their extended life span in captivity, NHPs are not only a good model of CR and aging but also one that has potential translation to humans. Due to its focus on health across the life span, the National Institute on Aging (NIA) has been studying the effects of CR in NHPs for more than 20 years. In a recent report from the NIA primate study group, Mattison et al. show data on survival in rhesus monkeys and compare their survival data with a seemingly parallel NHP CR study conducted at the Wisconsin National Primate Research Center (WNPRC). Among the NIA primates, CR did not improve survival in old-onset (16–23 years) or young-onset (juvenile, adolescent, and adult) monkeys. However, CR in old-onset monkeys improved certain measures of metabolic health, such as weight, triglycerides, and cholesterol. Although CR monkeys ate and weighed less, prevention of obesity in the CR group did not prevent type 2 diabetes or positively impact cardiovascular disease. In contrast to the NIA NHP findings, data from the WNPRC indicated a survival benefit associated with initiation of CR in adulthood (7–14 years), and the WNPRC study was also suggestive of cardiometabolic protection associated with CR. Mattison et al. suggested that the differing survival data between the NIA and WNPRC studies could be related to differences in various issues associated with study design and animal husbandry. For example, many elements of the studies’ diets differed. The NIA diet was composed of natural ingredients, which contained phytoestrogens and ultra-trace minerals that may influence health. In contrast, the WNPRC diet was purified and contained individually added vitamins and minerals. Protein basis and carbohydrate, vitamin, and mineral content also differed between the groups. Finally, the NIA monkeys were not truly fed ad libitum as they were in the WNPRC study. Additional variables that may play a role in the diverging results include the greater genetic diversity in the NIA group and differences in the ages at which CR was initiated. Because data from lifelong CR in rodents and a recent randomized short-term CR trial in humans have provided evidence for improvement of cardiovascular health with CR, the authors suggest that continued analysis of NHP data will uncover potential mechanisms behind these health effects that may elucidate findings in both the NIA and WNPRC studies. The overall conclusion from various studies in different species is that CR will improve cardiovascular and metabolic health but may not extend the life span in all species. — Eileen M. Resnick, PhD
Mattison et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012;489:318–321
- © 2013 by the American Diabetes Association.
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