adipose tissue and inflammation in rheumatic diseases and OA.pptx

Role of adipose tissue in inflammation and rheumatic diseases

1. Adipose Tissue and Inflammation By DR.B.SASIKALA

2. INTRODUCTION ADIPOCYTES – Initially considered only for storage of fat and thermogenesis and energetic homeostasis But now its is proved that adipocytes also producing complex cohort of cytokines, called adipokines Adipokines have endocrine, paracrine, and autocrine effects . Adipokines are neuromodulators, growth factors, proteins of the complement system, acute phase ,proteins, stress hormones, and proteins involved in glucose homeostasis. Kershaw EE and Flier JS (2004) Adipose tissue as an endocrine organ. The Journal of Clinical Endocrinology and Metabolism89

3. ADIPOSE TISSUE (AT) Brown ( BrAT ) White (WAT) Beige ( BeAT ) NON SHIVERING THERMOGENESIS LIPID OXIDATION ADAPTIVE THERMOGENESIS STORAGE FUNCTION ENDOCRINE FUNCTION

4. Adipose tissue Adipocytes stromal-vascular fraction VASCULATURE, endothelial cells INFLAMMATORY CELLS Eg. , Macrophages , neutrophils, lymphocytes, fibroblast,

5. White adipose tissue ENDOCRINE FUNCTION Adipokines True adipokines Secreted by pre adipocytes and mature adipocytes Adipokines produced by cells from stromal vascular fraction and also by adipocytes

6. Molecules secreted by adipocytes and stromal-vascular fraction HARMONES- ADIPOKINES T hese hormones play a key role over regulatory functions of various mechanisms such as beta-oxidation, fatty acid synthesis, and energy metabolism  Eg. Adiponectine , leptin, visfatin et. Growth factors FGFs (Fibroblast-like growth factor, Insulin-like growth factor (IGF)-1, Hepatocyte growth factor (HGF) Nerve growth factor (NGF) vascular endothelial cell growth factor (VEGF), and Transforming growth factor (TGF)- β growth factors they can induce the adipogenesis ,glucose metabolism , angiogenesis and thermogenesis also implicated in inflammation processes Adipose Tissue and Inflammation, osé Luis Muñoz Carrillo et al 2018

7. Molecules secreted by adipocytes and stromal-vascular fraction Pro inflammatory, Anti inflammatory and fuctions as both Adipose Tissue and Inflammation, osé Luis Muñoz Carrillo et al 2018

8. ADIPOKINES ANTI INFLAMMATORY PRO INFLAMMATORY 1. Adiponectin 2. C1q/TNF-related proteins (CTRPs) 3. omentin 4. secreted frizzled-related protein 5 (SFRP5)  1.LECTIN 2.RESISTIN 3.VISFATIN 4. Chemerin, 5.Retinol binding protein 4 (RBP4), and 6.Lipocalin 2 (LCN2) Peter Mancuso et al., Immuno Targets and Therapy 2016:5

9. Relationship among adipose tissue and immune system In addition to adipocytes, other cells are necessary in adipose tissue to exert its function Cells like macrophages and lymphocytes can infiltrate the adipose tissue There is a difference over the presence of these cells among individuals and the cell number is proportional to the size of the adipocytes. There is more infiltration of macrophages and lymphocytes in obese individual than normal individuals. 1 Even more, there is a significant difference considering the base line number of these cells in normal individuals compared with the number observed in starvation and obese individuals 2  1.Weisberg S et al Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation. 2.Wing E et al Acute starvation in mice reduces the number of T cells and suppresses the development of T-cell-mediated immunity. Immunology .

10. Role of macrophage in adipose tissue Embryonic macrophage Circulating monocyte derived Mainly involved in production of inflammatory cytokine M1 Classically activated M2 alternatively activated Obesity necrosis Proinflammatory cytokines Tnf -alfa, IL 1 ,IL 6 Anti inflammatory cytokines IL 10, IL1RA Lean apoptosis

11. Activation of macrophages and dendritic cells Endogenous or exogenous fatty acids Exogenous LPS Stimulation of TLRS present on adipocytes and macrophages Over all the factors produced by the adipose tissue, both hormones and cytokines, have effect over other cell types including lymphocytes, dendritic cells, and neutrophils  Inflammatory response Lago et al. Adipokines as emerging mediators of immune response and inflammation. Nature. 2007

12. Obesity and inflammation Environmental, humoral, and genetic factors Decrease in physical activity, sedentary lifestyle, and increase in foods with a high index POSITIVE BALANCE Leptin gene and its receptor , proopiomelanocortin gene or in the melanocortin-4 receptor, mutations The development of obesity and obesity-associated insulin resistance, since inflammation caused a significant deterioration in the signaling pathways of insulin and leptin Obesity

13. Role of obesity in shifting adipose tissue milleu from anti-inflammatory to pro inflammatory Excessive nutrition/over eating/other causes Hypertrophy of adipocytes Hyperplasia seen in SCAT not risk factor for increase in inflammation A state of local hypoxia Milleu change from anti- inflammatory to pro inflammatory Migration of macrophages to the necrotic clusters NECROSIS Lumeng CN, et al. (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes57(12 )

14. Obesity Adipocyte hypertrophy and necrosis Macrophage infiltration Increase in TNF alfa and IL-17 Reduction of foxp3+ T-reg cells iNK CELL Decreased th2 cytokines IL10, IL4. IL13 B REG CELLS IL10 AND TGF BETA All this leads to change of inflammatory milleu in adipose tissue from anti inflammatory to pro inflammatory Adipokine role in physiopathology of inflammatory and degenerative musculoskeletal diseases Giardullo et al. 2020 ANTI INFLAMMATORY PROINFLAMMATORY

15. Inflammation and obesity Obesity Increase and extension of adipose tissue molecularly induces the release of signals and protein mediators called adipokines. The inflammatory response is derived from the high production of adipokines that produce the release of inflammatory mediators These factors lead to decrease in downstream signalling pathways of insulin lead to insulin resistance leptin, adiponectin, TNF- α, IL-1 β, IL-6, protein monocyte chemotactic (MCP)-1, macrophage migration inhibitory factor (MIF), NGF, VEGF, plasminogen activator inhibitor (PAI)-1, and haptoglobin

16. Oxidative stress and obesity Adipose Tissue and Inflammation José Luis Muñoz Carrillo et al. intechopen.2018

17. Role of adipokines in chronic inflammation   Peter Mancuso et al., Immuno Targets and Therapy 2016:5 Adiponectin Adiponectin has shown anti-diabetic, anti-inflammatory and anti atherogenic effects , a TNF-alfa inhibitor and vice versa Cardiovascular diseases, such as hypertension have been shown to express an altered balance of adipokines including adiponectin Anti-inflammatory effects of adiponectin, as a decreased expression of IL-8 in aortic endothelial cells stimulated by TNF-alfa Exposure to adiponectin has been shown to reduce the adhesion of monocytes to endothelial cells and the conversion of macrophages to foam cells , thus hampering the genesis of atherosclerosis Achari et al.(2017) Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. International Journal of MolecularSciences Signaling pathways -AMPK and PPAR, after binding to its two receptors: AdipoR1, expressed ubiquitously but mainly in the skeletal muscle, AdipoR2, predominantly described in LIVER

18. The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease Leptin can be produced by multiple cells in the body, including immune cells, but is primarily produced by adipocytes in proportion to adipocyte mass Adipose tissue leptin Leptin receptors highly expressed in hypothalamus Leptin- Regulates APPETITE Decreased nutrient intake and increased energy expenditure leptin may have a role as a nutritional regulator of immunity in the setting of both under- and overnutrition, LEPTIN ALSO HAVE EFFECTS ON IMMUNE SYSTEM Leptin in Immune Cell Function Kiernan and MacIver et al. Frontiers in Immunology January 2021

19. Role of leptin on IMMUNE CELLS Role in adaptive immunity Leptin in Immune Cell Function Kiernan and MacIver et al. Frontiers in Immunology January 2021 LEPTIN NOT INVOLVED IN CD8 DEVELOPMENT TH1 CYTOKINE (INF gamma , IL2 ) TH2- IL4 PRO INFLAMMATORY EFFECTOR TCELL> TREG CELLS FASTING REDUCES LEPTIN PRODUCTION

20. LRb - receptor variant that is capable of signaling through the JAK-STAT pathway Leptin in Immune Cell Function Kiernan and MacIver et al. Frontiers in Immunology January 2021 INTRA CELLULAR DOMAIN LONG ARM or SHORT ARM LONG ARM IS FUNCTIONAL SEEN IN T CELLS AND NK CELLS class I cytokine receptor

21. Effects of leptin across immune cell types INNATE IMMUNITY

22. Adipokines and innate and adaptive response Adipose Tissue and Inflammation José Luis Muñoz Carrillo et al. intechopen.2018

23. L. Navarini et al. / Cancer Letters 423 (2018) 139e146 Role of leptin in inflammation

24. Clinical Reviews in Bone and Mineral Metabolism (2020 Adipokines and Chronic Rheumatic Diseases: from Inflammation to Bone Involvement

25. Effects of calorie restriction and obesity on adipose tissue leukocyte populations, adipokine secretion, and chronic inflammation 

26. CLASSIC INFLAMMATION IN INFECTION Activation of pattern-recognition receptors The inflammatory response in obesity Initiated by intrinsic signals Nutrient sensing, the unfolded protein response, and endoplasmic reticulum stress STIMULATION OF TLR INFLAMMATION META INFLAMMATION Mancuso et al. Adipokines and inflammation    ImmunoTargets and Therapy 2016

27. Adipokine role in physiopathology of inflammatory and degenerative musculoskeletal diseases Giardullo et al International Journal of Immunopathology and Pharmacology Volume 35: 2021 Resistin levels Greater risk of cardiovascular disease Promote chronic inflammation and insulin resistance by enhancing monocyte recruitment through the induction of CCL2 in inflamed VAT atherosclerosis by promoting monocyte foam cell formation and endothelial cell interactions with the vascular endothelium.

28. Adipokine role in physiopathology of inflammatory and degenerative musculoskeletal diseases International Journal of Immunopathology and Pharmacology The Author(s) 2021 INVERSE CORRELATION WITH TG/HDL AND TC/HDL PREDISPOSE TO ATHEROSCLEROSIS

29. Clinical Reviews in Bone and Mineral Metabolism (2020 Adipokines and Chronic Rheumatic Diseases: from Inflammation to Bone Involvement

30. Adipokine role in physiopathology of inflammatory and degenerative musculoskeletal diseases International Journal of Immunopathology and Pharmacology The Author(s) 2021

31. Conclusion Adipose tissue produces several endocrine factors, cytokines, and chemokines that regulate physiologic processes and immune function. Among these mediators are the adipokines, hormones produced by adipocytes, and cells within the SVF of adipose tissue. There are pro- and anti-adipokines that provide a means of communication between energy stored in adipose tissue and several organ systems to integrate metabolism with several physiologic functions. As adipose tissue shrinks during calorie restriction, anti-inflammatory adipokines rise and proinflammatory adipokines decline, resulting in increased insulin sensitivity and suppressed immune function. As adipose tissue expands during obesity, there is an increase in proinflammatory and a reduction in anti-inflammatory adipokines, which contributes to local and systemic inflammation and disturbances in glucose homeostasis. Future therapeutic interventions may target adipokines and their intracellular signaling cascades to enhance immune function in calorie restriction or ameliorate chronic inflammation and T2D in obese patients

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