1. The role of Leptin& Adiponectin in Rheumatologic disorders
Dr Mohammed H AL Osami
CABM,FIBM,FIBM(Rheum)
College of medicine of Baghdad

2. The adipokines
The adipokines or adipocytokines (Greek adipo-, fat; cyto-, cell; and -kinos, movement) are cytokines (cell-to-cell signaling proteins) secreted by adipose tissue .Over 50 adipokines have been identified .The most widely studied adipocytokines is leptin adiponectin is the most abundant human plasma adipocytokine, and levels are reduced in type II diabetes and cardiovascular disease (CVD) Members include:

3. The adipokines
Chemerin Resistin visfatin Leptin Adiponectin Apelin plasminogen activator inhibitor-1 (PAI-1) retinol binding protein 4 (RBP4)

4. The adipokines
the current terminology refers to adipokines as cytokines due to their immunomodulating effects. However, conflicting data exists about what is termed a cytokine and what is termed a hormone

5. The adipokines
The adipokines, have recently been implicated in immune functioning, including proinflammatory properties in the joint.  Adiponectin, in particular, shares sequence homology with tumour necrosis factor (TNF) α and complement C1q, A recent observations derives from in vitro and animal studies demonstrating the ability of adiponectin to mediate damage to cartilage and bone

6. The adipokines
Leptin
is a hormone made by adipocytes .& acts centrally to control body weight .
It conveys information to the brain about the size of energy stores & stimulates the hypothalamic centers responsible for regulation of energy intake & expenditure

7. Its name is derived from the Greek root Leptos, meaning thin
Its name is derived from the Greek root Leptos, meaning thin . It is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. . Leptin (L4146) is the product of the obese (ob) gene The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.In humans, the action of leptin seems to be mediated by tumour-necrosis factor secreted by monocytes

8. The effects of leptin were observed by studying mutant obese mice within a mouse colony at the Jackson Laboratory in These mice were massively obese , When these mice are treated with injections of leptin, they lose their excess fat and return to normal body weight

9. Leptin
Leptin itself was discovered in 1994 by Jeffrey M. Friedman and colleagues at the Rockefeller University

10. Leptin
Human leptin is a protein of 167 amino acids. It is manufactured primarily in the adipocytes of white adipose tissue, and the level of circulating leptin is directly proportional to the total amount of fat in the body.
it can also be produced by brown adipose tissue, placenta , ovaries, skeletal muscle, stomach

11. Leptin
leptin functions as a hypothalamic modulator of food intake, body weight and fat stores.  High circulating leptin levels are seen in overweight individuals,  suggesting that obese patients develop leptin resistance similar to insulin resistance in type II diabetes.

12.   obese patients develop leptin resistance similar to insulin resistance in type II diabetes.

13. Function
Leptin acts on receptors in the hypothalamus where it inhibits appetite by (1) counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus); (2) counteracting the effects of anandamide (another potent feeding stimulant that binds to the same receptors ), and (3) promoting the synthesis of MSH, an appetite suppressant.

14. Leptin melatonin pathway

15. In addition to its endocrine action at a distance (from adipose tissue to brain), leptin also acts as a paracrine mediator

16. Leptin effects on immunity

17. Leptin effects on immunity
leptin also have immunomodulatory roles
& affects both innate and adaptive immunity. In innate immunity, leptin modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals (such as hydrogen peroxide) through direct and indirect mechanisms.
Also In terms of both structure and function, leptin resembles IL-6 .

18. Leptin effects on immunity
In adaptive immunity, leptin affects the generation, maturation and survival of thymic T cells by reducing their rate of apoptosis On naive T-cell responses, leptin increases proliferation and IL-2 secretion through the activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways

19. Adipokines &Rheumatoid arthritis (RA)

20. Adipokines &Rheumatoid arthritis (RA)
in patients with rheumatoid arthritis (RA) a protective effect of obesity has been reported. &increased adipose tissue protects against radiographic joint damage in patients with rheumatoid arthritis (RA) Recently, adipokines were suggested as a molecular link explaining this paradoxical association

21. ADIPOKINES &Rheumatoid arthritis
GILE et al showed that The levels of serum adiponectin and visfatin have been shown to be associated with increased, radiographic joint damage in RA,
while leptin is associated with reduced radiographic joint damage

22. TNFα inhibitors&Adiopkines
There are conflicting data showing a limited influence of TNFα inhibitors on circulating levels of leptin and adiponectin in patients with RA. No change of serum levels of leptin and adiponectin during anti-tumour necrosis factor antibody treatment with adalimumab in patients with rheumatoid arthritis.

23. TNFα inhibitors&Adiopkines
However, recent study showed that treatment with Etanercept is rather associated with a significant increase in leptin and decrease in adiponectin in adipose tissue in RA patients.

24. Adipokines&radiographic joint damage in patients with RA
An inverse association between the levels of leptin and CRP in the circulation of patients with active RA has been reported & increase in adipose tissue leptin levels is a consequence of the improvement of systemic inflammation, which may support the data showing that higher circulating leptin levels are associated with reduced radiographic joint damage in patients with RA

25. Adipokines &SLE

26. Adipokines &SLE
Young women with SLE have up to a 50 times higher risk of cardiovascular events than age-matched controls, It has increasingly become evident that inflammation and immune mechanisms play an important role in the pathogenesis of atherosclerosis in SLE

27. ADIPOKINES &SLE
leptin functions as a hypothalamic modulator of food intake, body weight and fat stores.  suggesting that obese patients develop leptin resistance similar to insulin resistance in type II diabetes. Hyperleptinaemia in the general population is also associated with atherosclerosis, hypertension and metabolic syndrome  
adiponectin level is reduced in type II diabetes and cardiovascular disease (CVD).   .

28. ADIPOKINES &SLE
leptin and adiponectin also have immunomodulatory roles.  The dual roles of adipokines in the regulation of metabolism and the immune system have led some investigators to postulate that adipokines may provide a link between immune responses and atherosclerosis in SLE patients.

29. ADIPOKINES &SLE
Several studies found that plasma adiponectin levels are similar or raised in patients with SLE compared with controls. A recent study by Reynolds et al, also found an association between high adiponectin levels and carotid plaque in SLE.

30. ADIPOKINES &SLE
Several cohort studies have shown elevated leptin and adiponectin levels in adult and paediatric patients with SLE. McMahon et al study shows that high leptin levels contribute to a 2.8-fold increased odds for the presence of atherosclerosis in female patients with SLE

31. ADIPOKINES & OA

32. ADIPOKINES & OA
Epidemiological studies have shown obesity to be an important risk factor for the development of knee osteoarthritis (OA),  and there is a definite association between weight bearing in both knee and hip joints and the development of OA.

33. ADIPOKINES & OA
adipokines have recently been implicated in immune functioning, including proinflammatory properties in the joint. Adiponectin, in particular, which shares sequence homology with tumour necrosis factor (TNF) α and complement C1q, has been cross-sectionally linked to erosive damage in RA  and erosive osteoarthritis.  

34. ADIPOKINES & OA
The basis for these observations derived from in vitro and animal studies demonstrating the ability of adiponectin to activate pro- inflammatory pathways in synoviocytes  leading to activation of proteases  and osteoclasts  that may mediate damage to cartilage and bone.

35. ADIPOKINES & OA
Recently, adipokines have been proposed as relevant mediators of cartilage degeneration in both OA and RA. There is a positive association between serum levels of leptin and hip-radiographic OA, and of adiponectin and erosive OA.

36. ADIPOKINES & OA
also leptin and adiponectin, contribute significantly to cartilage damage, due to their ability to induce nitric oxide (NO), pro-inflammatory cytokines and matrix metalloproteinases (MMPs).

37. ADIPOKINES & OA
recent study showing that leptin and adiponectin can increase IL-8 expression in human synovial fibroblasts. these results depict a scenario in which both adipokines enhance the chemotactic environment in the joint.and enhance joint destruction in OA .

38. ADIPOKINES & OA
The infrapatellar fat pad has been suggested as an in vivo intra-articular source of adipokines and is indeed becoming recognised as an active joint tissue. It would therefore be reasonable to hypothesise that increased adipokine secretion by the infrapatellar fat pad in obese OA patients contributes to damage of the adjacent cartilage, which in turn leads to increased NO, MMP and IL-8 production

39. The infrapatellar fat pad

40. ADIPOKINES & OA
In conclusion, in recent studies demonstrated that leptin and adiponectin induce IL-8 secretion in human primary chondrocytes. adiponectin and leptin have a pro-inflammatory role, increasing IL-8 levels and thus contributing significantly to the chemotactic gradient seen in inflamed joints

41. Summary
The adipokines are cytokines secreted by adipose tissue . adipokines have recently been implicated in immune functioning, including proinflammatory properties in the joint. And has been linked to erosive damage in RA and erosive osteoarthritis and there is an association between high adiponectin levels and carotid plaque in SLE

42. thanks