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Isfahan University of Medical Science, School of Pharmacy                          Department of Clinical BiochemistryJune...
AdipokinesThe link between obesity and its complications       Supervised by:                         Dr. Mohsen Ani      ...
O u t lin e s         A d ip o s e t is s u e         O b e s it y & r e la t e d c o m p lic a t io n s         A d ip...
Adipose tissue  An overview
Adipose tissue   Adipose tissue or fat is loose connective tissue    composed of adipocytes. Its main role is to store   ...
Two types of adipose tissue exist: white adipose tissue (WAT)and brown adipose tissue (BAT).                              ...
Anatomical features   In humans, adipose tissue is located beneath the skin (subcutaneous fat),    and is also found arou...
Fat cells         Adipose       cells   store          majority of the body’s fat,          vary in size and number      ...
Fat Cell DevelopmentDuring growth,       When energy intake            After fat cells have enlarged and    With fat loss,...
Fat cell number         Fat cell develop:             Last trimester of pregnancy             First year of life       ...
Adipose tissue as an endocrine organ         Adipose tissue has been recognized as the quantitatively most important     ...
The Fat Cell Is a Veritable Endocrine Factory                                                Cytokines       Proteins of t...
Adipokines from adipose tissue                         CytokinesTNF-α                                               Leptin...
Adipokines from adipose tissue           Proteins involved in glucose                  homeostasis  Adiponectin           ...
Adipokines from adipose tissue             Proteins of the alternative                complement system                   ...
Adipokines from adipose tissue                 Proteins involved in                    homeostasis   Plasminogen    activa...
Adipokines from adipose tissue       Proteins for regulation of            blood pressure               Angiotensinogen
Adipokines from adipose tissue               Proteins involved in lipid                     metabolism  Retinol binding   ...
Adipokines from adipose tissue                 Acute phase and stress                   response proteins   Haptoglobin   ...
Cellular origin of the peptides secreted                      by human adipose tissue  Adipocytes  Adipokines           S...
Obesity         Obesity     results    from     an          imbalance between lipogenesis          (fat synthesis) and li...
June 25, 2012   23   Total slides : 51
Musculoskeletal                   Cardiovascular           Problems                         Problems Gastrointestinal     ...
Cardiovascular Problems         Obesity is a significant                risk   factor   for   predicting          cardiov...
Respiratory Problems         Severe obesity may be associated with             Sleep apnea             Obesity hypovent...
Diabetes Mellitus         Hyperinsulinemia         Insulin resistance         Type 2 diabetes               80% of pat...
Musculoskeletal Problems         Osteoarthritis               Trauma to weight-bearing joints         Hyperuricemia    ...
Gastrointestinal and Liver Problems         Gastroesophageal reflux disease (GERD)         Gallstones         Nonalcoho...
Cancer         Obesity is one of the most important known          preventable causes of cancer               Women     ...
History of adipose derived hormones   Communication between adipose and other tissues has been    hypothesized since at l...
leptin   Leptin is a 16 kDa polypeptide    product of the obese (ob) gene.   Leptin, expressed and secreted    primarily...
Leptin expression Leptin expression is influenced by energy stores in  fat. Leptin levels increase within hours after a ...
 Leptin concentrations in the blood are in the range of  several ng/ml, both as an active free form and as an inactive  b...
Signalling Pathway of Leptin Action   Leptin binding to the leptin receptor leads to the formation of    a Ob-R/JAK2 (Jan...
Physiological effects of Leptin Regulation of food intake ,energy expenditure and  body weight . Thermo genesis . Repro...
Role of leptin in regulation of food intake and                  body weight   Decrease hunger and food consumption - inh...
Neuropeptide Y   36 a.a residue produce in the arcuate nucleus of the    hypothalamus . Rich in tyrosine residues .   Ap...
Neuropeptide Y   Found in many organ, high level of NPY are found in    brainstem and hypothalamus .   Stimulates leptin...
Leptin and food intake
Mice with and without LeptinWithout leptin, this mouse     With leptin treatment, this mouseweighs almost three times as  ...
Role of leptin in thermogenesis
Role of leptin in lipid metabolism Leptin activated lipid oxidation, at least partially by  inducing the expression of en...
Leptin resistance   The ability of leptin to decrease body fat content    suggests leptin is an anti-obesity hormone.   ...
Leptin, obesity and diabetes   Disruption of leptin action is thought to play a role in    development of diabetes. This ...
Leptin effects on immune system   Leptin stimulates the proliferation of stem cells and regulates    hematopoiesis.   It...
Adiponectin   A protein is also called ADIPOQ, gelatine-binding 28,    Acrp30, discovered in 1995.   A peptide hormone m...
Plasma concentration   Adiponectin is abundant in human plasma, with concentrations    ranging from 5 to 30mg/ml, thus ac...
Adiponectin and Fat Mass   There seems to be a clear relationship between adiponectin    and fat mass in humans.   Howev...
Adiponectin and Fat Mass   Adiponectin is the only adipose-specific protein known to date    that is negatively regulated...
Adiponectin and DM, CAD   Like plasma leptin levels, adiponectin concentrations seem to    be gender-dependent, being hig...
Adiponectin and DM, CAD   first degree relatives of type 2 diabetic patients have reduced    adiponectin mRNA expression ...
Adiponectin and Serum lipid concentrations   In a large number of non-diabetic women with dyslipidemia,    Matsubara et a...
Adiponectin and Body Weight loss   Recent evidence also suggests that weight loss induces an increase in    adiponectin l...
Adiponectin and TZD   Thiazolidinedione treatment enhances endogenous adiponectin    production   In a group of mildly o...
Adiponectin and TZD   Similar results have been reported with pioglitazone   Furthermore, circulating adiponectin levels...
Adiponectin and CRF, Type 1 DM, Anorexia                 Norvosa   In a study, performed in 227 hemodialysis patients, pl...
Control of the                synthesis of Adiponectin   The only hormone implicated in the regulation of adiponectin    ...
Adiponectin as a Biomarker of the Metabolic                 syndrome   The metabolic syndrome:       common basis for th...
Definition of the Metabolic Syndrome    The presence of at least 3 of the following abnormalities;2.   Abdominal obesity:...
Potential therapeutic applications   Evidence reported so far suggests that adiponectin possesses    antihyperglycemic, a...
Potential therapeutic applications   The anti-inflammatory effects of adiponectin indicate that it is    an interesting p...
Adiponectin - structure
Adiponectin action : activation AMPK
Molecular Mechanisms of Adiponectin Action        Kadowaki et al. Endocrine Reviews 26 (3): 439 - 451, 2005
Adiponectin R1 and R2 are Expressed in Heart,  Liver, Kidney, Skeletal Muscle and Other Tissues                           ...
Resistin   Resistin has been named for the fact that it conveys the    resistance to insulin   Resistin is a cysteine-ri...
Resistin   Resistin is a 114 amino-acid peptide present in humans most    likely in the form of a few splice variants. Mo...
Resistin and obesity   Circulating resistin levels are increased in mouse models of    obesity and in obese humans and ar...
Resistin and inflammation   Resistin mRNA has been found in human PBMC and was increased by    pre-treatment with certain...
Glitozones and resistin Rosiglitazone and other glitazones lower glucose and  lipid levels in patients with type 2 diabet...
Visfatin Visfatin is the most recently identified adipocytokine  (known previously as pre-B cell colony enhancing  factor...
   Visfatin binds to the insulin    receptor at a site distinct from    insulin        and         exerts    hypoglycemic...
Angiotensinogen   Angiotensinogen, a precursor to the major proatherogenic    vasoconstrictor angiotensin II (AT-II), is ...
Obesity and inflammationObesity has been suggested to be an inflammatory disease, or at least a disease with an inflammato...
TNFα TNF-α is now recognized as a multi-functional  regulatory cytokine, involved in inflammation,  apoptosis, cell surv...
TNFα and obesity Both mRNA and TNFα protein were elevated in the  adipose tissue of obese animals and humans. Adipose ti...
TNFα and insulin resistance   Several hypotheses have been proposed to explain how TNFα induces    insulin resistance in ...
TNFα and inflammation   TNFα, an inflammatory cytokine released in greater quantities    by obese humans and patients wit...
file:///H:/files/seminar obesity/obesity sites/TNF-alpha_files/tnfpathway.gif
IL-6   IL-6 is another cytokine that has long been    recognized for its effects on the immune system   It is associated...
IL-6, obesity and inflammation   The in vivo release of IL-6 from fat contributes more than one    third of the basal cir...
IL-6 and insulin resistance   IL-6 induces SOCS3 transcription and inhibits JAK/STAT    activation, which caused inhibiti...
JAK-STAT signaling pathway   The JAK-STAT signaling pathway takes part in the    regulation of cellular responses to cyto...
Mechanism
Suppressor of cytokine signaling 3
CRP   cAMP Receptor Protein (CRP) is a dimer of two    identical subunits each of which is 209 amino acids in    length.
CRP   Circulating plasma CRP levels are elevated in obese subjects    and the levels are also directly correlated with th...
CRP   Furthermore, in vascular smooth muscle cells, CRP    upregulates angiotensin type 1 receptor (AT1-R) mRNA and    pr...
CRP CRP may also play a coordinating role by amplifying  the proinflammatory activity of other adipokines. For  example, ...
Elevated CRP Levels in Obesity:                                         NHANES 1988-1994   Percent with CRP > 0.22 mg/dL  ...
Inflammation of coronary artery   Inflammation in a coronary artery produces a cascade of events that can    prove fatal....
Serum Amyloid A   Serum amyloid A (SAA) proteins are a family of apolipoproteins found    predominantly associated with h...
Enzymatic and protein changes within high-density                  lipoprotein (HDL) during an acute phase reactionCopyrig...
Cardiovascular Metabolic Syndrome              (Syndrome X)Low grade inflammation               Prothrombotic stateHypergl...
ObesityI.c. TG accumulationFree radical production        β cell damage      Insulin deficiency
Role of obesity in insulin resistance           ↑ Caloric             intake         ↑ Free                               ...
Fat Cell Products and Hypertension  Visceral                 l Portal                                                H...
Clinical manifestations of insulin resistance                           Type 2 diabetes and                           glyc...
Hypertension   Hyperinsulinemia can enhance renal sodium reabsorption    and vascular reactivity   Angiotensinogen from ...
Metabolic Syndrome, Insulin Resistance, and                 Atherosclerosis                         Hyperinsulinemia/hyper...
Effects of Thiazolidinediones Mediated                      via Adipose Tissue     Thiazolidinediones                     ...
FFA and Adipokines in                           Endothelial Dysfunction                                                   ...
Medical Complications of ObesityPulmonary disease                     Idiopathic intracranialabnormal function            ...
Potential therapeutic strategies associated with Nicotinic   acid                        fatty acid metabolism            ...
adipokines and cardiovascular diseaseBoth abdominal (visceral) fat and insulin resistance may contribute to cardiovascular...
Summary of “adipocyte-vascular axis” and role of major adipocyte - derived factors  (leptin resistin and ghrelin) in in th...
PPAR signaling pathway
Proposed mechanisms for obesity-related            hypertension
ROLE OF ADIPONECTIN IN THE REGULATION OF CARBOHYDRATE                 AND LIPID METABOLISM
The potential effects of adiponectin (and    resistin) on adaptive immunity Tilg and Moschen Nature Reviews Immunology 6, ...
The Role of Adipocytokines in Adipocyte-    Related Pathological Processes
Effects of obesity on growth-factor            production
Effects of obesity on hormone production
Obesity, hormones and endometrial cancer
Molecular links between Obesity and                  Atheroslcerosis   Among the adipokines, CRP and IL-6 are the two mos...
Anti- and proinflammatory adipokines
Effects of the metabolic syndrome of insulin resistance on                 endothelial dysfunction
Adipokines serve as the cellular mediators of the metabolic         syndrome and endothelial dysfunction.
Effects of Adipokines on Vascular Homeostasis and the         Metabolic Syndrome of Insulin ResistanceAdipokines          ...
Effects of Adipokines on Vascular Homeostasis and the          Metabolic Syndrome of Insulin Resistance  Adipokines       ...
Effects of Adipokines on Vascular Homeostasis and the            Metabolic Syndrome of Insulin ResistanceAdipokines       ...
Effects of Adipokines on Vascular Homeostasis and the             Metabolic Syndrome of Insulin ResistanceAdipokines      ...
Effects of Adipokines on Vascular Homeostasis and the          Metabolic Syndrome of Insulin ResistanceAdipokines         ...
Effects of Adipokines on Vascular Homeostasis and the         Metabolic Syndrome of Insulin ResistanceAdipokines          ...
Effects of Adipokines on Vascular Homeostasis and the          Metabolic Syndrome of Insulin ResistanceAdipokines         ...
Effects of Adipokines on Vascular Homeostasis and the         Metabolic Syndrome of Insulin ResistanceAdipokines          ...
Peroxisomes proliferator activated receptors                  (PPAR)    PPARs were originally cloned as nuclear receptors...
PPAR isotypes   PPAR-α is predominantly expressed in brown adipose    tissue and liver as well as kidney heart and skelet...
STAT   The Signal Transducers and Activator of Transcription    (STAT, also, called signal transduction and transcription...
Janus kinase   Janus kinase (JAK, or "Just another kinase") is a family of    intracellular non-receptor tyrosine kinases...
Tank you
AnyAny   question?      question?Any   question?Any   question?Any   question?Any   question?Any   question?Any   question...
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
Obesity & adipokines
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Obesity & adipokines

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Adipose tissue as an endocrine organ:
Adipose tissue has been recognized as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermal insulator. During the last 10 years, adipose tissue has come into focus as an endocrine organ important for development of many diseases related to obesity including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular disease. Adipose tissue secretes a variety of bioactive peptides that play important roles in insulin action, energy homeostasis, inflammation, and cell growth. These secretory proteins from the adipose organ are named adipokines and have many physiological effects on different organs including the brain, bone, reproductive organs, liver, skeletal muscles, immune cells and blood vessels. Adipokines may locally regulate fat mass by modulating adipocyte size/number or angiogenesis and inversely increased fat mass leads to dysregulation of adipocyte functions.

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Obesity & adipokines

  1. 1. Isfahan University of Medical Science, School of Pharmacy Department of Clinical BiochemistryJune 25, 2012 1 Total slides : 51
  2. 2. AdipokinesThe link between obesity and its complications Supervised by: Dr. Mohsen Ani Presented by: A.N. Emami Razavi
  3. 3. O u t lin e s  A d ip o s e t is s u e  O b e s it y & r e la t e d c o m p lic a t io n s  A d ip o c y t e s a s a n e n d o c r in e c e lls  A d ip o k in e sJune 25, 2012 3 Total slides : 51
  4. 4. Adipose tissue An overview
  5. 5. Adipose tissue Adipose tissue or fat is loose connective tissue composed of adipocytes. Its main role is to store energy in the form of fat, although it also cushions and insulates the body.
  6. 6. Two types of adipose tissue exist: white adipose tissue (WAT)and brown adipose tissue (BAT). WAT Characteristics of brown and white adipocytes Multilocular adipocyte Brown adipocyte Lipid storage and mobilization (++) Mitochondria (+++) Fatty acid oxidation (+++) Respiratory chain (+++) UCP1 (+++) PGC-1α (+++) White adipocyte BAT Unilocular adipocyte ( 200µm) Lipid storage and mobilization (+++) Mitochondria (+) Fatty acid oxidation (+) Respiratory chain (+) UCP1 (0) PGC-1α (+) For letter symbols, see slide 36
  7. 7. Anatomical features In humans, adipose tissue is located beneath the skin (subcutaneous fat), and is also found around internal organs (visceral fat). Adipose tissue is found in specific locations which are referred to as adipose depots.
  8. 8. Fat cells  Adipose cells store majority of the body’s fat, vary in size and number  Increase in body fatness is due to:  Fat cell hypertrophy  Fat cell hyperplasiaJune 25, 2012 8 Total slides : 51
  9. 9. Fat Cell DevelopmentDuring growth, When energy intake After fat cells have enlarged and With fat loss, the size of thefat cells increase exceeds expenditure, energy intake continues to exceed fat cells shrinks, but not thein number. fat cells increase in size. expenditure, fat cells increase in number. number again.
  10. 10. Fat cell number  Fat cell develop:  Last trimester of pregnancy  First year of life  During adolescent  Average non-obese person: 25-30 bill.  Moderately obese: 60-100 bill.  Massively obese: 300 bill.+  Number of fat cells appears to be biggest factor in determining risk for obesity.June 25, 2012 10 Total slides : 51
  11. 11. Adipose tissue as an endocrine organ  Adipose tissue has been recognized as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermal insulator. During the last 10 years, adipose tissue has come into focus as an endocrine organ important for development of many diseases related to obesity including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular disease. Adipose tissue secretes a variety of bioactive peptides that play important roles in insulin action, energy homeostasis, inflammation, and cell growth. These secretory proteins from the adipose organ are named adipokines and have many physiological effects on different organs including the brain, bone, reproductive organs, liver, skeletal muscles, immune cells and blood vessels. Adipokines may locally regulate fat mass by modulating adipocyte size/number or angiogenesis and inversely increased fat mass leads to dysregulation of adipocyte functions.June 25, 2012 11 Total slides : 51
  12. 12. The Fat Cell Is a Veritable Endocrine Factory Cytokines Proteins of the Proteins involved in alternative glucose homeostasis complement system Fa t c e l l Proteins for Proteins involved in regulation of blood homeostasis pressure Proteins involved in Acute phase and lipid metabolism stress response proteins Fat cells are continually absorbing or releasing substances in response to the body’s energy needs
  13. 13. Adipokines from adipose tissue CytokinesTNF-α Leptin IL-1β IL-10 IL-6 IL-8
  14. 14. Adipokines from adipose tissue Proteins involved in glucose homeostasis Adiponectin Resistine
  15. 15. Adipokines from adipose tissue Proteins of the alternative complement system Acylation Adipsin stimulating protein
  16. 16. Adipokines from adipose tissue Proteins involved in homeostasis Plasminogen activator Tissue factor inhibitor-1 (PAI-1)
  17. 17. Adipokines from adipose tissue Proteins for regulation of blood pressure Angiotensinogen
  18. 18. Adipokines from adipose tissue Proteins involved in lipid metabolism Retinol binding Cholesterol ester protein transfer protein (RBP) (CETP)
  19. 19. Adipokines from adipose tissue Acute phase and stress response proteins Haptoglobin Metallothionein
  20. 20. Cellular origin of the peptides secreted by human adipose tissue Adipocytes  Adipokines Stromavascular fraction cells  cytokines & chemiokines Monocyte chemoattractant protein 1 (MCP1)Leptin Macrophage inflammatory protein (MIP)Adiponectin Tumor necrosis α (TNFα)Serum amyloids Interleukins 1β, 6, 8, 10, ….Retinol binding protein 4 (RBP4) ChemiokinesApelin ResistinFIAF/PGAR Apelin …
  21. 21. Obesity  Obesity results from an imbalance between lipogenesis (fat synthesis) and lipolysis (fat destruction ). Lipogenesis which occurs in liver and adipose tissue involves fatty acid synthesis followed by triglyceride synthesis.  Differentiation of the pre- adipocytes to mature fat cells is referred to as adipogenesis and should not be confused with lipogenesis.June 25, 2012 22 Total slides : 51
  22. 22. June 25, 2012 23 Total slides : 51
  23. 23. Musculoskeletal Cardiovascular Problems Problems Gastrointestinal Complications Respiratoryand Liver Problems Problems of obesity Diabetes Mellitus Cancer
  24. 24. Cardiovascular Problems  Obesity is a significant risk factor for predicting cardiovascular disease  Risks  ↑ Low-density lipoproteins (LDLs)  ↑ Triglycerides  ↓ High-density lipoproteins (HDLs)  Hypertension  ↑ Circulating blood volume  Abnormal vasoconstriction  ↓ Vascular relaxation  ↑ Cardiac outputJune 25, 2012 25 Total slides : 51
  25. 25. Respiratory Problems  Severe obesity may be associated with  Sleep apnea  Obesity hypoventilation syndrome  ↓ Chest wall compliance  ↑ Work of breathing  ↓ Total lung capacity and functional residual capacityJune 25, 2012 26 Total slides : 51
  26. 26. Diabetes Mellitus  Hyperinsulinemia  Insulin resistance  Type 2 diabetes  80% of patients with type 2 diabetes are obese  Weight loss and exercise improve glucose controlJune 25, 2012 27 Total slides : 51
  27. 27. Musculoskeletal Problems  Osteoarthritis  Trauma to weight-bearing joints  Hyperuricemia  GoutJune 25, 2012 28 Total slides : 51
  28. 28. Gastrointestinal and Liver Problems  Gastroesophageal reflux disease (GERD)  Gallstones  Nonalcoholic steatohepatitis (NASH)  Can eventually lead to cirrhosis  Weight loss can improve NASHJune 25, 2012 29 Total slides : 51
  29. 29. Cancer  Obesity is one of the most important known preventable causes of cancer  Women  Breast, endometrial, ovarian, cervical  Possibly from ↑ estrogen postmenopause  Men  Prostate  Both genders: ColonJune 25, 2012 30 Total slides : 51
  30. 30. History of adipose derived hormones Communication between adipose and other tissues has been hypothesized since at least the 1940s to be bidirectional. However, the importance of adipose tissue as an endocrine organ was only fully appreciated in 1994 with the discovery of Leptin, the protein product of the Ob gene.
  31. 31. leptin Leptin is a 16 kDa polypeptide product of the obese (ob) gene. Leptin, expressed and secreted primarily by adipocytes, acts via a family of receptor (ob-R) isoforms to mediate an ever growing wide range of physiological effects. These receptors have divergent signaling capabilities, regulating pathways which include JAK/STATs and MAP kinases.
  32. 32. Leptin expression Leptin expression is influenced by energy stores in fat. Leptin levels increase within hours after a meal in rodents and after several days of overfeeding in humans. Insulin stimulates leptin expression and secretion in primary adipocytes. Other factors, such as dexamethasone, thyrotrophin (TSH) , TNF-α and IL-6 also regulate leptin release.
  33. 33.  Leptin concentrations in the blood are in the range of several ng/ml, both as an active free form and as an inactive bound form which occurs by its association with plasma proteins and the leptin receptor isoform. Leptin receptors (OB-R) are expressed in variety of tissues, which suggested that it has a wide range of actions. However, leptin receptor mutations cause early onset obesity in rodents. This is consistent with measurements of high leptin concentration and low leptin receptor expression in most diabetic patients.
  34. 34. Signalling Pathway of Leptin Action Leptin binding to the leptin receptor leads to the formation of a Ob-R/JAK2 (Janusactivated kinase) complex that triggers phosphorylation. JAK2 phosphorylation leads to activation of the PI3K and MAPK pathways that regulate apoptosis, energy homeostasis and gene transcription. Leptin signaling occurs mainly through signal transducers and activators of transcription (STAT3). Phosphorylation of STAT3 triggers dimerization and translocation to the nucleus which leads to activation of gene transcription. The targets include: genes of suppressors of the cytokine signaling family (SOCS3). Therefore, leptin regulates various signaling pathways and impacts gene transcription.
  35. 35. Physiological effects of Leptin Regulation of food intake ,energy expenditure and body weight . Thermo genesis . Reproductive function . Suppressed bone formation . Directly act on the cells of liver and muscles . Related to inflammatory response . Contribute to early hematopoiesis.
  36. 36. Role of leptin in regulation of food intake and body weight Decrease hunger and food consumption - inhibition of neuropeptide Y synthesis . Food intake linked to its ability to regulate the neuroendocrine system .
  37. 37. Neuropeptide Y 36 a.a residue produce in the arcuate nucleus of the hypothalamus . Rich in tyrosine residues . Appetite stimulating hypothalamic peptide
  38. 38. Neuropeptide Y Found in many organ, high level of NPY are found in brainstem and hypothalamus . Stimulates leptin production in adipose tissue by increasing food intake and insulin secretion. Action through the parasympathetic nervous system.
  39. 39. Leptin and food intake
  40. 40. Mice with and without LeptinWithout leptin, this mouse With leptin treatment, this mouseweighs almost three times as lost a significant amount of weight,much as a normal mouse. but still weighs almost one and a half times as much as a normal mouse.
  41. 41. Role of leptin in thermogenesis
  42. 42. Role of leptin in lipid metabolism Leptin activated lipid oxidation, at least partially by inducing the expression of enzymes involved in lipid metabolism. Activate 5 –AMP-activated protein kinase (AMPK) Inhibits acetyl coenzyme-A carboxylase (ACC) Increase insulin sensitivity Inhibits intracellular lipid concentration Leptin also stimulated apoptosis of adipocytes through activation of caspase-8.
  43. 43. Leptin resistance The ability of leptin to decrease body fat content suggests leptin is an anti-obesity hormone. However, high leptin levels have been found in obese and diabetic mice and humans, which is defined as “leptin resistence”. Sometimes it is combined with low-level expression of leptin receptors. Another mechanisms are:  Mutation of the gene for leptin receptors in the brain  Post receptor abnormalities in leptin signal transduction  Impaired leptin transport across blood- brain barrier
  44. 44. Leptin, obesity and diabetes Disruption of leptin action is thought to play a role in development of diabetes. This hypothesis is supported by data showing that mutations of the ob gene cause early onset obesity and type II diabetes in mice and humans. A frameshift/premature stop mutation, c.398delG (Delta133G mutation) caused a congenital leptin deficiency and led to severe early-onset obesity. A homozygous frameshift mutation (delta133) in the human leptin (ob) gene was associated with undetectable serum leptin and extreme obesity.
  45. 45. Leptin effects on immune system Leptin stimulates the proliferation of stem cells and regulates hematopoiesis. It participates in innate immunity by promoting the maturation and survival of dendritic cells (DC) and stimulates macrophage proliferation, phagocytosis, and production of proinflammatory cytokines. Leptin plays a direct role in adaptive immunity by regulating the expression of Ob-R on both T and B cells and promoted the suvival of T and B cells by suppressing Fas-mediated apoptosis. Leptin increase the production of IL-2 and IFN-γ by T lymphocytes.
  46. 46. Adiponectin A protein is also called ADIPOQ, gelatine-binding 28, Acrp30, discovered in 1995. A peptide hormone made by adipocytes in response to high fat reserves:  Increases FA uptake by myocytes and the rate of FA oxidation.  Slows FA synthesis in the liver.  Slows gluconeogenesis in the liver.  Acts through AMP-dependent protein kinase (AMPK). Humans who are obese or who suffer from Type II diabetes show reduced levels of adiponectin. Drugs (thiazolidinediones) used to treat Type II diabetes elevate expression of adiponectin.
  47. 47. Plasma concentration Adiponectin is abundant in human plasma, with concentrations ranging from 5 to 30mg/ml, thus accounting for approximately 0.01% of total plasma protein This concentration is three orders of magnitude higher than concentrations of most other hormones
  48. 48. Adiponectin and Fat Mass There seems to be a clear relationship between adiponectin and fat mass in humans. However, in contrast to leptin, adiponectin levels are significantly reduced among obese subjects in comparison with lean control subjects. Arita et al showed that mean plasma adiponectin levels were 3.7 mg/ml in a group of obese patients, whereas in non-obese subjects these values reached a mean of 8.9 mg/ml In a recent longitudinal study, plasma adiponectin concentrations decreased with increasing adiposity in a group of children evaluated at 5 and 10 years of age
  49. 49. Adiponectin and Fat Mass Adiponectin is the only adipose-specific protein known to date that is negatively regulated in obesity In a group of normal weight and obese women plasma adiponectin was negatively correlated not only with body mass index and body fat mass, but also with serum leptin concentration, fasting insulin and calculated insulin resistance Another study, performed in 967 Japanese subjects with normal weight, has shown that plasma adiponectin is negatively correlated with body mass index, systolic and diastolic blood pressure, fasting plasma glucose, insulin, insulin resistance, total and LDL-cholesterol, TG and uric acid, and positively correlated with HDL-cholesterol
  50. 50. Adiponectin and DM, CAD Like plasma leptin levels, adiponectin concentrations seem to be gender-dependent, being higher among women than men plasma adiponectin levels are reduced not only among obese patients but also among patients with some of the disease states frequently associated with obesity, such as type 2 DM and CAD Multivariate analysis demonstrated that hypoadiponectinemia was more intensively related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity or glucose intolerance
  51. 51. Adiponectin and DM, CAD first degree relatives of type 2 diabetic patients have reduced adiponectin mRNA expression in adipose tissue compared with controls, although they have normal levels of circulating adiponectin Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (apM1) is located Evidence of an association between type 2 diabetes and single nucleotide polymorphisms at positions 45 and 276, and in the proximal promoter and exon 3 of the adiponectin gene has been reported Some missense mutations in the globular domain have been also associated with low adiponectin levels and type 2 diabetes
  52. 52. Adiponectin and Serum lipid concentrations In a large number of non-diabetic women with dyslipidemia, Matsubara et al. have shown that plasma adiponectin is negatively correlated with serum triglyceride, atherogenic index, apo B or apo E, and positively correlated with serum HDL-cholesterol or apo A-I levels. These data suggest that low adiponectin concentrations are associated with some of the well-known risk factors for atherosclerosis, such as low HDL-cholesterol levels or hypertriglyceridemia. A relationship between hypoadiponectinemia and the metabolic syndrome seems likely
  53. 53. Adiponectin and Body Weight loss Recent evidence also suggests that weight loss induces an increase in adiponectin levels in obesity. In a group of 22 obese patients, who were treated by gastric partition surgery, a 46% increase in mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index Changes in plasma adiponectin were related to changes in body mass index, waist and hip circumferences, and steady-state plasma glucose levels These data suggest the existence of a negative feedback mechanism between adipose mass and the production of adiponectin in humans
  54. 54. Adiponectin and TZD Thiazolidinedione treatment enhances endogenous adiponectin production In a group of mildly overweight subjects with glucose intolerance the administration of troglitazone for 12 weeks significantly increased the plasma adiponectin concentration in a dose-dependent way In a recent randomized double-blind placebo controlled trial performed in 64 type 2 diabetic patients, rosiglitazone therapy for 6 months was accompanied by a more than 2-fold increase in plasma adiponectin levels
  55. 55. Adiponectin and TZD Similar results have been reported with pioglitazone Furthermore, circulating adiponectin levels were found to be suppressed 5-fold in patients with severe insulin resistance in association with dominant-negative PPAR-g mutations thus suggesting that adiponectin may be a biomarker of in vivo PPAR-g activation
  56. 56. Adiponectin and CRF, Type 1 DM, Anorexia Norvosa In a study, performed in 227 hemodialysis patients, plasma adiponectin levels were 2.5 times higher among dialysis patients than among healthy subjects, and they were higher among women than among men Plasma adiponectin concentrations have been found to be significantly elevated in a group of 46 type 1 diabetic patients in relation to healthy controls Insulin replacement therapy did not affect adiponectin levels in a subgroup of seven patients. A preliminary report also showed that adiponectin levels were moderately elevated in 26 female patients with anorexia nervosa
  57. 57. Control of the synthesis of Adiponectin The only hormone implicated in the regulation of adiponectin expression has been insulin TNF-a is one of the candidate molecules responsible for causing insulin resistance The expression and secretion of adiponectin from adipocytes are significantly reduced by TNF-a Therefore, increased TNF-a might be partially responsible for the decreased adiponectin production in obesity adiponectin itself may increase insulin sensitivity through an inhibition of both the production and action of TNF-a It has also been hypothesized that adiponectin and TNF-a may antagonize each other or perform opposite functions locally in adipose tissue or in the arterial wall
  58. 58. Adiponectin as a Biomarker of the Metabolic syndrome The metabolic syndrome:  common basis for the development of atherogenic cardiovascular diseases. Decreased plasma concentrations of adiponectin:  plays a significant role in the development of the MS. the plasma concentration of adiponectin was significantly correlated with each component of the metabolic syndrome.
  59. 59. Definition of the Metabolic Syndrome The presence of at least 3 of the following abnormalities;2. Abdominal obesity: WC>=85cm in men or >=90cm in women3. Hypertriglyceridemia: a serum triglyceride concentration>=150mg/dl4. Low HDL cholesterolemia: a serum HDL cholesterol concentration<40mg/dl5. Hypertension: SBP>=130mmHg, DBP>=85mmHg and/or having received antihypertensive medication6. High fasting glucose: serum glucose concentration>=110 mg/dl
  60. 60. Potential therapeutic applications Evidence reported so far suggests that adiponectin possesses antihyperglycemic, anti-atherogenic and anti-inflammatory properties. Increased serum adiponectin levels are associated with increased insulin sensitivity and glucose tolerance adiponectin – or drugs that stimulate adiponectin secretion or action –might play a role in the therapeutic armamentarium against disease states associated with insulin resistance, mainly type 2 diabetes mellitus and obesity Low levels of adiponectin have also been implicated in the severe insulin resistance that accompanies lipoatrophy Therapy with adiponectin may also play a role in reversing insulin resistance in lipodystrophic disorders.
  61. 61. Potential therapeutic applications The anti-inflammatory effects of adiponectin indicate that it is an interesting protective factor for atherosclerosis development, especially in those clinical situations associated with low plasma levels of adiponectin. It is conceivable that the use of recombinant adiponectin may become beneficial in the prevention of cardiovascular disease in selected patients. The recent finding that adiponectin deficiency aggravates neointimal thickening, and that supplementation with adiponectin attenuates neointimal thickening in mechanically injured arteries, suggests that increasing plasma adiponectin might be useful in preventing vascular restenosis after vascular intervention
  62. 62. Adiponectin - structure
  63. 63. Adiponectin action : activation AMPK
  64. 64. Molecular Mechanisms of Adiponectin Action Kadowaki et al. Endocrine Reviews 26 (3): 439 - 451, 2005
  65. 65. Adiponectin R1 and R2 are Expressed in Heart, Liver, Kidney, Skeletal Muscle and Other Tissues  Brain  Heart  Kidney  Liver  Lung  Skeletal Muscle  Spleen  TestisYamauchi T., et al Nature 423, 762-769
  66. 66. Resistin Resistin has been named for the fact that it conveys the resistance to insulin Resistin is a cysteine-rich protein secreted by adipose tissue of mice and rats. In other mammals, at least primates, pigs and dogs, resistin is secreted by immune and epithelial cells.
  67. 67. Resistin Resistin is a 114 amino-acid peptide present in humans most likely in the form of a few splice variants. Monomeric peptides may create oligomeric structures It is secreted as a disulfide-linked homodimer via disulfide bonds at cysteine residue (Cys26)
  68. 68. Resistin and obesity Circulating resistin levels are increased in mouse models of obesity and in obese humans and are decreased by the anti- diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity Administration of anti-resistin antibody has been shown to improve blood sugar and insulin action in mice with diet- induced obesity. Similarly resistin has been implicated in the pathogenesis of diabetic complication and diabetes. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin- stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment.
  69. 69. Resistin and inflammation Resistin mRNA has been found in human PBMC and was increased by pre-treatment with certain cytokines such as IL-6 and TNF-alpha, IL-1, IL-12 or lipopolysacharride. Interestingly resistin itself leads to increased release of numerous pro-inflammatory cytokines TNF-alpha and IL-12, from macrophages and monocytes. Resistin induce the nuclear translocation of NF-kappaB transcription factor and resistin pro-inflammatory effects are reduced in the conditions of NF-kappaB inhibition. Thus pro-inflammatory actions of resistin are related to the activation of NFkappaB pathway, which makes resistin’s actions on the immune system in a direct opposition to adiponectin’s. Finally an important effect of resistin on inflammation is related to it’s ability to induce vascular adhesion molecule expression, thus increasing leukocyte infiltration to tissues, including fat.
  70. 70. Glitozones and resistin Rosiglitazone and other glitazones lower glucose and lipid levels in patients with type 2 diabetes by activating the nuclear receptor peroxisome proliferator- activated receptor g (PPARg)1. Rosiglitazone treatment was shown to reduce resistin expression in 3T3-L1 adipocytes in vitro and in the white adipose tissue (WAT) of mice fed a high fat diet. These data raised the interesting possibility that decreases in resistin levels might be integral to the antidiabetic actions of PPARg agonists.
  71. 71. Visfatin Visfatin is the most recently identified adipocytokine (known previously as pre-B cell colony enhancing factor; PBEF) which appears to be preferentially produced by visceral adipose tissue, and has insulin- mimetic actions. Visfatin expression is increased in animal models of obesity and its plasma concentrations are increased in humans with abdominal obesity or type 2 diabetes mellitus.
  72. 72.  Visfatin binds to the insulin receptor at a site distinct from insulin and exerts hypoglycemic effect by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissues. The latter property could make this molecule very useful in the potential treatment of diabetes. Interestingly, known as PBEF, visfatin was also identified in inflammatory cells and it’s levels were increased in various inflammatory conditions
  73. 73. Angiotensinogen Angiotensinogen, a precursor to the major proatherogenic vasoconstrictor angiotensin II (AT-II), is expressed and produced in adipocytes. AT-II directly stimulates ICAM-1, VCAM-1, MCP-1 and M-CSF expression in vascular cells by activating NF-κΒ-regulated genes. AT-II also promotes the formation of free oxygen radicals from NO, thereby decreasing the availability of NO and incurring damage to the vascular tissue. Augmented angiotensinogen production by adipose tissue in obesity has been linked to angiogenesis and the development of hypertension, both of which are known to be associated with endothelial dysfunction.
  74. 74. Obesity and inflammationObesity has been suggested to be an inflammatory disease, or at least a disease with an inflammatory component to it. Pro-inflammatory molecules as CRP, IL-6, TNF-alpha, Nutrition. 2001 Nov-Dec;17(11-12):953-66; Intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) Circulation. 2002 Feb 19;105(7):804-9 have been shown to be high in overweight or obese subjects.
  75. 75. TNFα TNF-α is now recognized as a multi-functional regulatory cytokine, involved in inflammation, apoptosis, cell survival, cytotoxicity, and insulin resistance. TNF-α is a 26-kDa plasma membrane-bound protein that is cleaved into a 17-kDa biologically active protein. There are two receptors for TNF-α, type I and type II that regulate different functions.
  76. 76. TNFα and obesity Both mRNA and TNFα protein were elevated in the adipose tissue of obese animals and humans. Adipose tissue also expressed both types of TNFα receptors. Long term exposure of cultured cells or animals to TNFα induced insulin resistance, characterized by hyperinsulinemia and an increased prevalence of obesity, hypertension, dyslipidemia and type 2 diabetes
  77. 77. TNFα and insulin resistance Several hypotheses have been proposed to explain how TNFα induces insulin resistance in adipocytes. For example, TNFα inhibited insulin-stimulated IRS-1 phosphorylation. Thus, it might inhibit PI3K and inhibit a pathway that regulates glucose uptake. In addition, TNFα up regulates transcription of many preadipocyte genes and proinflammatory cytokines, such as IL-6 and MCP-1. These proteins were elevated in the plasma or adipose tissue of diabetic patients. TNFα also inhibited adiponectin expression, which may impaire insulin action. Furthermore, TNFα directly stimulated lipolysis, which caused in increased plasma free fatty acids. This also caused hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis.
  78. 78. TNFα and inflammation TNFα, an inflammatory cytokine released in greater quantities by obese humans and patients with insulin resistance, not only initiates but also propagates atherosclerotic lesion formation. TNFα activates the transcription factor nuclear factor-κΒ (NFκΒ), which accelerates experimental atherogenesis, in part by inducing the expression of VCAM-1, ICAM-1, MCP-1 and E-selectin in aortic endothelial and vascular smooth muscle cells. TNFα reduces NO bioavailability in endothelial cells and impairs endothelium-dependent vasodilatation, promoting endothelial dysfunction. TNFα may also promote apoptosis in endothelial cells by dephosphorylating protein kinase B, or Akt, and thereby, contribute to endothelial injury, an effect counteracted by insulin.
  79. 79. file:///H:/files/seminar obesity/obesity sites/TNF-alpha_files/tnfpathway.gif
  80. 80. IL-6 IL-6 is another cytokine that has long been recognized for its effects on the immune system It is associated with obesity and insulin resistance, too Like TNF-o plasma IL-6 Adipocytes secretes 2 to 3 times more IL-6 than stromovascular cells
  81. 81. IL-6, obesity and inflammation The in vivo release of IL-6 from fat contributes more than one third of the basal circulating IL-6 and explains the positive correlation between serum levels of IL-6 and obesity. signals are passed either through (JAK-STAT) or (ERK- MAPK) pathways or both. IL-6 induces fever and the acute phase response, which is defined as the complex series of inflammatory reactions initiated in response to infection, physical trauma, or malignancy. Therefore, enlarged adipose tissue has the potential to exacerate both responses.
  82. 82. IL-6 and insulin resistance IL-6 induces SOCS3 transcription and inhibits JAK/STAT activation, which caused inhibition of insulin receptor (IR) phosphorylation and insulin receptor substrate (IRS) phosphorylation . Thus, increased glyconeogenesis and decreased gluconeogenesis decrease glycogen storage, a consequence of insulin resistance. IL-6 suppresses insulin-induced lipogenesis and reduces expression of GLUT4 via repressed PKB/ERK pathway. Furthermore, IL-6 decreased adiponectin gene expression and secretion in a dose- and time-dependent manner in 3T3L1 adipocytes. All of these changes contribute to a glucose intolerant state.
  83. 83. JAK-STAT signaling pathway The JAK-STAT signaling pathway takes part in the regulation of cellular responses to cytokines and growth factors. Employing Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs), the pathway transduces the signal carried by these extracellular polypeptides to the cell nucleus, where activated STAT proteins modify gene expression. Although STATs were originally discovered as targets of Janus kinases, it has now become apparent that certain stimuli can activate them independently of JAKs. The pathway plays a central role in principal cell fate decisions, regulating the processes of cell proliferation, differentiation and apoptosis. It is particularly important in hematopoiesis - production of blood cells.
  84. 84. Mechanism
  85. 85. Suppressor of cytokine signaling 3
  86. 86. CRP cAMP Receptor Protein (CRP) is a dimer of two identical subunits each of which is 209 amino acids in length.
  87. 87. CRP Circulating plasma CRP levels are elevated in obese subjects and the levels are also directly correlated with the amount of body fat, Elevated plasma levels of C-reactive protein (CRP) have become one of the strongest independent predictors of CHD CRP induces the expression of VCAM-1, ICAM-1, selectins, and MCP- 1 in cultured endothelial cells via increased secretion of ET-1, a potent endogenous vasoconstrictor, and IL-6 CRP downregulates eNOS mRNA and protein expression. The diminished NO activity may in turn inhibit angiogenesis, an important compensatory response in chronic ischemia
  88. 88. CRP Furthermore, in vascular smooth muscle cells, CRP upregulates angiotensin type 1 receptor (AT1-R) mRNA and protein levels and increased AT1-R expression on the cell surface. AT1-R is a key atherosclerotic switch that facilitates angiotensin-II induced reactive oxygen species production, vascular smooth muscle cell migration and proliferation, and vascular remodeling. The effect of CRP on endothelial dysfunction is potentiated by hyperglycemia and these effects are attenuated by rosiglitazone, an insulin sensitizing thiazolidinedione anti- diabetic drug.
  89. 89. CRP CRP may also play a coordinating role by amplifying the proinflammatory activity of other adipokines. For example, it increases the expression and activity of PAI-1 in endothelial cells Plasminogen activator inhibitor-1 (PAI-1) suppresses fibrinolysis by inhibiting plasminogen activation, and is an active contributor to atherogenesis by promoting thrombus formation. Plasma PAI-1 levels are positively correlated with cardiovascular risk and mortality, and recently, the development of diabetes
  90. 90. Elevated CRP Levels in Obesity: NHANES 1988-1994 Percent with CRP > 0.22 mg/dL 25 20 15 10 5 0 Normal Overweight ObeseVisser M et al. JAMA 1999;282:2131-2135.
  91. 91. Inflammation of coronary artery Inflammation in a coronary artery produces a cascade of events that can prove fatal. Pretreatment with the antithrombotic agent clopidogrel prior to angioplasty and stenting reduced rates of myocardial infarction and death in patients with the highest levels of C-reactive protein, a marker of inflammation.
  92. 92. Serum Amyloid A Serum amyloid A (SAA) proteins are a family of apolipoproteins found predominantly associated with high-density lipoprotein (HDL) in plasma, with different isoforms being unequally expressed constitutively and in response to inflammatory stimuli. Serum amyloid A (SAA) is an acute phase reactant like CRP, which has been associated with systemic inflammation, linked to atherosclerosis and used as a predictor for coronary artery disease and cardiovascular outcome. SAA levels correlate significantly with insulin resistance and obesity in type 2 DM patients. Adipose tissue has been shown to express SAA at low levels under normal conditions but expression in adipose tissue is dramatically upregulated in the diabetic state. The increase in acute phase reactant proteins may affect lipid metabolism and thus contribute to the dyslipidemia associated with diabetes. Serum amyloid A displaces apolipoprotein A1 from HDL cholesterol, increasing HDL binding to macrophages, and thus, decreasing cardioprotective HDL cholesterol.
  93. 93. Enzymatic and protein changes within high-density lipoprotein (HDL) during an acute phase reactionCopyright ©2005 American College of Cardiology Foundation. Restrictions may apply.
  94. 94. Cardiovascular Metabolic Syndrome (Syndrome X)Low grade inflammation Prothrombotic stateHyperglycaemia CVD Dyslipidemia Hypertension Genetics+ Lifestyle
  95. 95. ObesityI.c. TG accumulationFree radical production β cell damage Insulin deficiency
  96. 96. Role of obesity in insulin resistance ↑ Caloric intake ↑ Free OxidativeVisceral Sedentary fatty acids stress InsulinObesity lifestyle ↑ Glucose resistance Inflammation Genetic ↑ Lipids factors Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.
  97. 97. Fat Cell Products and Hypertension  Visceral l Portal  Hepatic  Plasma Insulin Fat Stores FFA Clearance Insulin Vascular  Renal Na+ Constriction Reabsorption Angiotensinogen Angiotensin II Angiotensin I HypertensionBray GA. Contemp Diagn Obes. 1998.
  98. 98. Clinical manifestations of insulin resistance Type 2 diabetes and glycemic disorders Atherosclerosis Dyslipidemia Insulin resistance – Low HDL – Small, dense LDLVisceral Glucotoxicity – HypertriglyceridemiaObesity Lipotoxicity Hypertension ↓ Adiponectin Endothelial dysfunction/ inflammation (hsCRP) Impaired thrombolysis ↑ PAI-1 Courtesy of Selwyn AP, Weissman PN.
  99. 99. Hypertension Hyperinsulinemia can enhance renal sodium reabsorption and vascular reactivity Angiotensinogen from fat cells can increase angiotensin II and thus blood pressure Both systolic and diastolic blood pressure increase with increasing body mass index
  100. 100. Metabolic Syndrome, Insulin Resistance, and Atherosclerosis Hyperinsulinemia/hyperproinsulinemia Insulin resistance Glucose Increased Decreased Increased BP intolerance triglycerides HDL cholesterol Endothelial dysfunction Increased Small, dense PAI-1 LDL Atherosclerotic cardiovascular diseaseMacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.
  101. 101. Effects of Thiazolidinediones Mediated via Adipose Tissue Thiazolidinediones Adipose tissue PPARγ Decreased FFA and TNFα release Decreased tissue triglycerides Increased adiponectin Muscle Liver β-cell Vascular Increased Decreased Increased Increased glucose glucose insulin endothelial utilization output secretion functionAdapted from Goldstein BJ. Am J Cardiol. Suppl 2002.
  102. 102. FFA and Adipokines in Endothelial Dysfunction Increased visceral fat Thiazolidinediones Increased lipolysis Increased TNFα Decreased adiponectin Increased FFA levels - - - Insulin NO production Shear stress Endothelium Vascular dilationAdapted from Steinberg H et al. Diabetes. 2000;49:1231.
  103. 103. Medical Complications of ObesityPulmonary disease Idiopathic intracranialabnormal function hypertensionobstructive sleep apnea Strokehypoventilation syndrome CataractsNonalcoholic fatty liver Coronary heart diseasedisease Diabetessteatosissteatohepatitis Dyslipidemiacirrhosis HypertensionGall bladder disease Severe pancreatitisGynecologic abnormalities Cancerabnormal menses breast, uterus, cervixinfertility colon, esophagus, pancreaspolycystic ovarian syndrome kidney, prostate Osteoarthritis Phlebitis Skin venous stasis Gout
  104. 104. Potential therapeutic strategies associated with Nicotinic acid fatty acid metabolism HM74a Inducers Ligands A C Gi PGC1α Nuclear Inhibitors cAMP receptors PKA Fat Lipid mass? utilization ATGL HSL Lipolysis A combination of PGC-1α inducers and nuclear receptor Antilipolysis as a strategy to combat the ligands may constitute a strategy to combat obesity metabolic syndromeTrends Endocrinol Metab 2006 ;17 :314-320. Trends Endocrinol Metab 2003;14 :439-441.
  105. 105. adipokines and cardiovascular diseaseBoth abdominal (visceral) fat and insulin resistance may contribute to cardiovascular disease in obesity.
  106. 106. Summary of “adipocyte-vascular axis” and role of major adipocyte - derived factors (leptin resistin and ghrelin) in in the regulation of vascular and immune functions. Detailed description is provided in individual sections in the text of the paper.
  107. 107. PPAR signaling pathway
  108. 108. Proposed mechanisms for obesity-related hypertension
  109. 109. ROLE OF ADIPONECTIN IN THE REGULATION OF CARBOHYDRATE AND LIPID METABOLISM
  110. 110. The potential effects of adiponectin (and resistin) on adaptive immunity Tilg and Moschen Nature Reviews Immunology 6, 772–783 (October 2006) | doi:10.1038/nri1937
  111. 111. The Role of Adipocytokines in Adipocyte- Related Pathological Processes
  112. 112. Effects of obesity on growth-factor production
  113. 113. Effects of obesity on hormone production
  114. 114. Obesity, hormones and endometrial cancer
  115. 115. Molecular links between Obesity and Atheroslcerosis Among the adipokines, CRP and IL-6 are the two most strongly associated with increased cardiovascular disease risk and the prediction of future cardiovascular disease or type 2 diabetes. The wide-ranging direct effects of CRP on endothelial and smooth muscle cells argue favorably for CRP as a key cellular mediator linking obesity, the metabolic syndrome of insulin resistance and type 2 diabetes, to increased atherogenesis. Emerging data suggest the beneficial effects of TZDs, and possibly statins and ACEIs, may in part be mediated via the reduction of the levels and the direct effects of the adipokines on atherogenesis. Further investigations into the molecular links between obesity and atherosclerosis will unravel innovative therapeutic strategies to improve cardiovascular health in people affected by obesity linked insulin resistance, the metabolic syndrome and type 2 diabetes.
  116. 116. Anti- and proinflammatory adipokines
  117. 117. Effects of the metabolic syndrome of insulin resistance on endothelial dysfunction
  118. 118. Adipokines serve as the cellular mediators of the metabolic syndrome and endothelial dysfunction.
  119. 119. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceAdiponectin ↓ ICAM-1, VCAM-1, E-Selectin Plasma levels inversely correlated with obesity and insulin resistance ↓NFκB ↑ insulin sensitivity ↓transformation of macrophages to foam cells ↓ TNF-induced changes in adhesion molecule expression ↓ VSMC proliferation and migration
  120. 120. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin Resistance Adipokines Vascular action Insulin action and resistanceAngiotensinogen ↓ NO availability ↑ development of hypertension ↑ NFκB ↑ ICAM-1, V-CAM-, MCP-1 and M-CSF ↓ angiogenesis
  121. 121. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceCRP ↓ NO by destabilizing eNOS mRNA ↑ PAI-1 expression and activity and ↓ protein expression in endothelial cells ↑ ET-1 and IL-6 release ↑ VCAM-1, ICAM-1, selectins and CRP levels correlate with the MCP-1 in EC metabolic syndrome and predicts ↑ LDL uptake in EC future CHD ↓ angiogenesis ↑ apoptosis in EC predicts development of diabetes ↑ ROS ↑ SMC proliferation and migration Hyperglycemia potentiates and restenosis 73 proatherogenic action of CRP ↑ AT1-R on VSMC 11
  122. 122. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceIL-6 ↑ ICAM-1, E-Selectin, VCAM-1, ↑ preadipocyte differentiation MCP-1 ↓insulin receptor signal ↑ SMC proliferation and migration transduction ↑ systemic insulin resistance ↑ hepatic CRP production
  123. 123. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceLeptin ↑ NO by increasing eNOS ↑ glucose transport production ↑ ET-1 Reverses insulin resistance in ↑ proliferation and migration of EC lipodystrophy and VSMC ↑ ROS accumulation and oxidative ↑ sympathetic tone stress ↑ VSMC apoptosis ↑ blood pressure ↑ angiogenesis ↑ release of monocyte colony- stimulating factor ↑ cholesterol accumulation under hyperglycemia
  124. 124. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistancePAI-1 ↑ thrombus formation PAI-1 expression stimulated by TNF-α, ang II, FFAs ↑ restenosis
  125. 125. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceResistin ↑ ET-1 release ↑ insulin resistance in muscle and liver ↑ expression of adhesion molecules and chemokines ↓ glucose uptake and insulin action ↓ TRAF-3 TZD downregulates resistin expression
  126. 126. Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceTNF-α NO bioavailability ↓ adipose cell differentiation ↓ insulin signal transduction ↓ vasodilatation ↑ systemic insulin resistance ↑ lipolysis ↑ NFκB via ROS ↑ FFAs ↑ VCAM-1, ICAM-1, E-selectin and MCP-1 in EC and VSMC ↑ apoptosis in EC
  127. 127. Peroxisomes proliferator activated receptors (PPAR) PPARs were originally cloned as nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. Three PPAR isotypes have been described: α, β, and γ. Binding of the ligands to these receptors results in activation of target gene transcription. Endocr Rev. 1999 Oct;20(5):649-88. The target genes of PPARs are involved in lipid transport and metabolism, including trans-membrane fatty acid uptake , fatty acid binding in cells, fatty acid oxidation in microsomes peroxisomes and mitochondria, as well as lipoprotein synthesis and transport. PUFA binds to all three receptors, while long chain unsaturated fatty acids (linoleic acid), branched chain fatty acids, Leukotriene B4 and eicosanoids bind mainly to PPAR α. Prostaglandin J2 and Prostaglandin 15-deoxy-D are the endogenous ligands for PPAR-γ.
  128. 128. PPAR isotypes PPAR-α is predominantly expressed in brown adipose tissue and liver as well as kidney heart and skeletal muscle. PPAR β has greatest expression in gut, kidney and heart. PPAR-β is linked to colon cancer . PPAR-β regulates the expression of acyl-CoA synthetase2 in the brain, thus playing a role in basic lipid metabolism. PPAR γ is mainly expressed in adipose tissue, and at lower levels in the colon, and immune system. No significant expression of PPAR-γ has been demonstrated in the skeletal muscle the main site of glucose disposal.
  129. 129. STAT The Signal Transducers and Activator of Transcription (STAT, also, called signal transduction and transcription) proteins regulate many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis, enhanced survival of tumors and immunosuppression. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
  130. 130. Janus kinase Janus kinase (JAK, or "Just another kinase") is a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases[1]), but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of doorways, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other negatively regulates the kinase activity of the first.
  131. 131. Tank you
  132. 132. AnyAny question? question?Any question?Any question?Any question?Any question?Any question?Any question?Any question?Any question?Any question?Any question?Have a good day

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