Adipose Tissue as an Endocrine Organ. Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University

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1 Adipose Tissue as an Endocrine Organ Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University

2 Functions of Adipose Tissue Adipose tissue expresses and secretes a variety of bioactive peptides, known as adipokines, which act at both the local (autocrine/paracrine) and systemic (endocrine) level In addition to these efferent signals, adipose tissue expresses numerous receptors that allow it to respond to afferent signals from hormone systems and CNS.

3 Regulator of food intake Hypothalamus Blood Vessels Leptin Vasoconstriction Endothelial dysfunction Thrombosis AGE, PAI-1 I.R. Blood Vessels Liver Anti atherogenic effects Adiponectin IL-6, TNF-α?? I.S. Skeletal Muscle I.R. Resistin Adipocytokines implicated in energy homeostasis, insulin sensitivity (IS), insulin Resistance (IR) and atherothrombosis.

4 Actions of leptin on the hypothalamus and peripheral organs (pancreas, liver and skeletal muscle

5 Effects of Leptin on vascular homeostasis and the metabolic syndrome of insulin resistance Vascular Action NO by increasing enos production ET-1 Proliferation and migration of EC and VSMC ROS accumulation and oxidation stress VSMC apoptosis Angiogenesis Cholesterol accumulation in macrophages under hyperglycemia. Insulin Action and Resistance Glucose uptake Reverse erse insulin resistance in lipodystrophy Sympathetic tone Blood pressure Lau, et al., Am J Physiol Heart Circ Physiol 2005, 288: H2031-

6 Pro-inflammatory cytokines Adipose tissue is a rich source of pro- inflammatory mediators that contribute to vascular injury, insulin resistance, and atherogenesis These pro-inflammatory adipokines include: TNF-α α, IL-6 6, leptin, PAI-1 1, angiotensinogen, and CRP. On the other hand, NO and adiponectin protect against inflammation and obesity-linked insulin resistance,

7 Effects of TNF-α on vascular homeostasis and the metabolic syndrome of insulin resistance Vascular Action NO bioavailability Vasodilatation NFκB via ROS VCAM-1, ICAM-1, E-selectin, and MCP-1 in EC and VSMC Apoptosis in EC Insulin Action and Resistance Adipose cell differentiation Insulin signal transduction Systemic insulin resistance Lipolysis FFAs Lau, et al., Am J Physiol Heart Circ Physiol 2005, 288: H2031-

8 Effects of IL-6 on vascular homeostasis and the metabolic syndrome of insulin resistance Vascular Action VCAM-1, ICAM-1, E-selectin, and MCP-1 SMC proliferation and migration Insulin Action and Resistance Preadipocyte differentiation Insulin receptor signal transduction Systemic insulin resistance Hepatic CRP production Lau, et al., Am J Physiol Heart Circ Physiol 2005, 288: H2031-

9 Effects of CRP on vascular homeostasis and the metabolic syndrome of insulin resistance Vascular Action NO by destabilizing enos mrna and decreasing protein expression ET-1 and IL-6 release ease VCAM-1, ICAM-1, selectins, and MCP-1 in EC LDL uptake in EC angiogenesis apoptosis in EC ROS SMC proliferation and migration and restenosis AT1-R on VSMC PAI-1 expression and activity in ECs. Insulin Action and Resistance CRP correlates with metabolic syndrome and predicts future CHD Predicts the development of diabetes Hyperglycemia potentiates proatherogenic action of CRP Lau, et al., Am J Physiol Heart Circ Physiol 2005, 288: H2031-

10 Visfatin Visfatin is the most recently identified adipokines that is secreted by adipocytes in visceral fat. Visfatin has insulin-mimetic actions. It decreases insulin resistance. Visfatin binds and activates the insulin receptor, but does not compete with insulin. Insulin and visfatin bind different sites on the insulin receptor.

11 Effects of resistin on vascular homeostasis and the metabolic syndrome of insulin resistance Vascular Action ET-1 release Expression of adhesion molecules and chemokines TRAF-3 Insulin Action and Resistance Insulin resistance in muscle and liver Glucose uptake and insulin action TZDs downregulate resistin expression TZDs: Thiazolidinediones Lau, et al., Am J Physiol Heart Circ Physiol 2005, 288: H2031-

12 Serum Retinol-binding Protein 4 (RBP4) RBP4 is another recently characterized adipokine It is the only specific transport protein for retinol (vitamin A) in the circulation. Elevated RBP4 levels have been reported in people with IGT or type 2 diabetes RBP4 is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated CV risk factors in subjects with varied clinical presentations. Lowering serum RBP4 may be a rationale for antidiabetic therapies

13 Vaspin (visceral adipose-tissue-derived serine protease inhibitor) Vaspin is a visceral adipose tissue- derived d factor with potential ti antiprotease t properties. It is similar to adiponectin in improving insulin resistance It suppresses the production of TNF, leptin, and resistin (i.e., it has anti- inflammatory effects)

14 Plasminogen activator inhibitor-1 (PAI-1) Adipocytes synthesize and produce PAI-1 PAI-1 expression and secretion are greater in visceral relative to sc adipose tissue, decline with caloric restriction, exercise, weight loss and metformin treatment. PAI-1 expression stimulated by TNFα, ANG II, and FFAs. PAI-1 is the primary inhibitor of fibrinolysis, thereby favouring thrombus formation upon ruptured atherosclerotic plaques.

15 Angiotensinogen (AGE) Adipose tissue is the major extrahepatic source of ANG. Epidemiological studies reported a significant positive correlation between BP and circulating levels of AGE Angiotensinogen: i 1. NO bioavailability 2. NF-κB, ICAM-1, VCAM,-1, MCP-1, and M-CSF 3. Angiogenesis 4. Development of HTN

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