obesity & adipokines

Total slides : 511April 11, 2023

Isfahan University of Medical Science, School of Pharmacy

Department of Clinical Biochemistry

AdipokinesAdipokines

The link between obesity and its complicationsThe link between obesity and its complications

Supervised by:

Dr. Mohsen Ani

Presented by:

A.N. Emami Razavi


Outlines Outlines

Adipose tissue Obesity & related complications Adipocytes as an endocrine cells Adipokines

Adipose tissueAdipose tissue

An overviewAn overview

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.

Two types of adipose tissue exist: white adipose tissue (WAT) and brown adipose tissue (BAT).

WAT

BAT

For letter symbols, see slide 36

Characteristics of brown and white adipocytes

White adipocyte Unilocular adipocyte ( 200µm)Lipid storage and mobilization (+++)Mitochondria (+)Fatty acid oxidation (+)Respiratory chain (+)UCP1 (0)

PGC-1 (+)

Brown adipocyteMultilocular adipocyteLipid storage and mobilization (++)Mitochondria (+++)Fatty acid oxidation (+++)Respiratory chain (+++)UCP1 (+++)

PGC-1 (+++)

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.'


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 hyperplasia

Fat Cell Development

After fat cells have enlarged and energy intake continues to exceed expenditure, fat cells increase in number again.

During growth,fat cells increasein number.

When energy intakeexceeds expenditure,fat cells increase in size.

With fat loss, the size of the fat cells shrinks, but not the number.


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.

The Fat Cell Is a Veritable Endocrine Factory

Fat cell

Cytokines

Proteins involved in

glucose homeostasis

Proteins of the

alternative

complement system


homeostasis

Proteins for

regulation of blood

pressure


lipid metabolism

Acute phase and

stress response

proteins

Fat cells are continually absorbing or releasing substances in response to the body’s energy needs

Fat cell

Cytokines


glucose homeostasis

Proteins of the

alternative

complement system


homeostasis

Proteins for

regulation of blood

pressure


lipid metabolism

Acute phase and

stress response

proteins

Adipokines from adipose tissue

Cytokines

IL-6

IL-1β

TNF-α

IL-8

IL-10

Leptin


Proteins involved in glucose

homeostasis

Adiponectin Resistine


Proteins of the alternative

complement system

Adipsin

Acylation

stimulating

protein



homeostasis

Tissue factor

Plasminogen

activator

inhibitor-1 (PAI-

1)


Proteins for regulation of

blood pressure

Angiotensinogen


Retinol binding

protein

(RBP)

Cholesterol ester

transfer protein

(CETP)

Proteins involved in lipid

metabolism


Metallothionein

Haptoglobin

Acute phase and stress

response proteins

Cellular origin of the peptides secretedby human adipose tissue

Adipocytes Adipokines Stromavascular fraction cells cytokines & chemiokines

Monocyte chemoattractant protein 1 (MCP1)Macrophage inflammatory protein (MIP)Tumor necrosis (TNF)Interleukins 1, 6, 8, 10, ….ChemiokinesResistinApelin…

LeptinAdiponectinSerum amyloidsRetinol binding protein 4 (RBP4)ApelinFIAF/PGAR

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.


Cancer

Gastrointestinal

and Liver Problems

Musculoskeletal

Problems

Diabetes Mellitus

Respiratory

Problems

Cardiovascular

Problems

Complications

of

obesity

Cancer

Gastrointestinal

and Liver Problems

Musculoskeletal

Problems

Diabetes Mellitus

Respiratory

Problems

Cardiovascular

Problems

Complications

of

obesity

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 output


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 capacity


Diabetes Mellitus

Hyperinsulinemia

Insulin resistance

Type 2 diabetes 80% of patients with type 2 diabetes are obese

Weight loss and exercise improve glucose control


Musculoskeletal Problems

Osteoarthritis Trauma to weight-bearing joints

Hyperuricemia

Gout


Gastrointestinal and Liver Problems

Gastroesophageal reflux disease (GERD)

Gallstones

Nonalcoholic steatohepatitis (NASH) Can eventually lead to cirrhosis Weight loss can improve NASH


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: Colon


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.

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.

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.

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.

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.

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.

Physiological effects of Leptin

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 .

Neuropeptide Y

36 a.a residue produce in the arcuate nucleus of the hypothalamus . Rich in tyrosine residues .

Appetite stimulating hypothalamic peptide

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.

Leptin and food intake

Mice with and without LeptinWithout leptin, this mouse weighs almost three times as much as a normal mouse.

With leptin treatment, this mouse lost a significant amount of weight, but still weighs almost one and a half times as much as a normal mouse.

Role of leptin in thermogenesis

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.

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

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.

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.

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.

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

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

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

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

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

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

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

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

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

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

Control of thesynthesis 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

Adiponectin as a Biomarker of the Metabolic Adiponectin as a Biomarker of the Metabolic syndromesyndrome

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.

Definition of the Metabolic Syndrome

The presence of at least 3 of the following abnormalities;

1. Abdominal obesity: WC>=85cm in men or >=90cm in women

2. Hypertriglyceridemia: a serum triglyceride concentration>=150mg/dl

3. Low HDL cholesterolemia: a serum HDL cholesterol concentration<40mg/dl

4. Hypertension: SBP>=130mmHg, DBP>=85mmHg and/or having received antihypertensive medication

5. High fasting glucose: serum glucose concentration>=110 mg/dl

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.

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

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

Brain Heart Kidney Liver Lung Skeletal Muscle Spleen Testis

Yamauchi T., et al Nature 423, 762-769

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.

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)

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.

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.

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.

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.

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

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.

Obesity and inflammation

Obesity 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.

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.

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

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.

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.

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-adipose tissue is a major source of plasma IL-6 Adipocytes secretes 2 to 3 times more IL-6 than stromovascular cells

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.

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.

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.

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 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

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.

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

Elevated CRP Levels in Obesity: NHANES 1988-1994

0

5

10

15

20

25

Perc

ent w

ith

CR

P >

0.2

2 m

g/dL

Visser M et al. JAMA 1999;282:2131-2135.

Normal Overweight Obese

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.

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.

Enzymatic and protein changes within high-density lipoprotein (HDL) during an acute phase reaction

Copyright ©2005 American College of Cardiology Foundation. Restrictions may apply.

Cardiovascular Metabolic Syndrome (Syndrome X)

Prothrombotic state

Dyslipidemia Hypertension

CVD

Genetics+Lifestyle

Low grade inflammation

Hyperglycaemia

ObesityI.c. TG accumulation

Free radical production

β cell damage

Insulin deficiency

Role of obesity in insulin resistance

Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.

VisceralObesity

Caloric intake

Sedentarylifestyle

Geneticfactors

Free fatty acids

Glucose

Lipids

Oxidativestress

Inflammation

Insulinresistance

Fat Cell Products and HypertensionFat Cell Products and Hypertension

Hepatic Insulin

Clearance

Portal FFA

Plasma Insulin

Renal Na+ Reabsorption

Hypertension

Visceral Fat Stores

VascularConstriction

Angiotensin I

Angiotensin IIAngiotensinogen

Bray GA. Contemp Diagn Obes. 1998.

Clinical manifestations of insulin resistance

Courtesy of Selwyn AP, Weissman PN.

Type 2 diabetes and glycemic disorders Dyslipidemia – Low HDL – Small, dense LDL – Hypertriglyceridemia

Hypertension

Endothelial dysfunction/inflammation (hsCRP)

Impaired thrombolysis PAI-1

VisceralObesity

Insulinresistance

Glucotoxicity

Lipotoxicity

Adiponectin

Atherosclerosis

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

Metabolic Syndrome, Insulin Resistance, and Atherosclerosis

MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.

Hyperinsulinemia/hyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small, denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

Effects of Thiazolidinediones Mediatedvia Adipose Tissue

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ. Adapted from Goldstein BJ. Am J Cardiol.Am J Cardiol. Suppl 2002. Suppl 2002.

FFA and Adipokines inEndothelial Dysfunction

Adapted from Steinberg H et al. Diabetes. 2000;49:1231.

ThiazolidinedionesThiazolidinediones

InsulinInsulin NO productionVascular dilationNO production

Vascular dilationShear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

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Decreased adiponectinDecreased adiponectin

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Pulmonary diseasePulmonary diseaseabnormal functionabnormal functionobstructive sleep apneaobstructive sleep apneahypoventilation syndromehypoventilation syndrome

Nonalcoholic fatty liver Nonalcoholic fatty liver diseasediseasesteatosissteatosissteatohepatitissteatohepatitiscirrhosiscirrhosis

Coronary heart diseaseCoronary heart disease

DiabetesDiabetes

DyslipidemiaDyslipidemia

HypertensionHypertension

Gynecologic abnormalitiesGynecologic abnormalitiesabnormal mensesabnormal mensesinfertilityinfertilitypolycystic ovarian syndromepolycystic ovarian syndrome

OsteoarthritisOsteoarthritis

SkinSkin

Gall bladder diseaseGall bladder disease

CancerCancerbreast, uterus, cervixbreast, uterus, cervixcolon, esophagus, pancreascolon, esophagus, pancreaskidney, prostatekidney, prostate

PhlebitisPhlebitisvenous stasisvenous stasis

GoutGout

Medical Complications of Obesity

Idiopathic intracranial Idiopathic intracranial hypertensionhypertension

StrokeStroke

CataractsCataracts

Severe Severe pancreatitispancreatitis

A combination of PGC-1 inducers and nuclear receptor

ligands may constitute a strategy to combat obesity

PGC1

Lipidutilization

Fat mass?

Nuclearreceptors

LigandsInducers

Potential therapeutic strategies associated withfatty acid metabolism

HM74a

cAMP

AC

Gi

HSL

PKA

Lipolysis

ATGL

Nicotinicacid

Inhibitors

Antilipolysis as a strategy to combat the

metabolic syndrome

Trends Endocrinol Metab 2003;14 :439-441.Trends Endocrinol Metab 2006 ;17 :314-320.

adipokines and cardiovascular disease

Both abdominal (visceral) fat and insulin resistance may contribute to cardiovascular

disease in obesity.

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.

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, 772–783 (October 2006) | doi:10.1038/nri1937

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 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.

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 Resistance

Adipokines Vascular action Insulin action and resistance

Adiponectin ↓ ICAM-1, VCAM-1, E-Selectin

↓NFκB

↓transformation of macrophages to foam cells

↓ VSMC proliferation and migration

Plasma levels inversely correlated with obesity and insulin resistance

↑ insulin sensitivity

↓ TNF-induced changes in adhesion molecule expression



Angiotensinogen ↓ NO availability

↑ NFκB

↑ ICAM-1, V-CAM-, MCP-1 and M-CSF

↓ angiogenesis

↑ development of hypertension



CRP ↓ NO by destabilizing eNOS mRNA and ↓ protein expression

↑ ET-1 and IL-6 release

↑ 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 73

↑ AT1-R on VSMC 11

↑ PAI-1 expression and activity in endothelial cells

CRP levels correlate with the metabolic syndrome and predicts future CHD

predicts development of diabetes

Hyperglycemia potentiates proatherogenic action of CRP



IL-6 ↑ ICAM-1, E-Selectin, VCAM-1, MCP-1

↑ SMC proliferation and migration

↑ preadipocyte differentiation

↓insulin receptor signal transduction

↑ systemic insulin resistance

↑ hepatic CRP production



Leptin ↑ NO by increasing eNOS production

↑ ET-1

↑ proliferation and migration of EC and VSMC

↑ ROS accumulation and oxidative stress

↑ VSMC apoptosis

↑ angiogenesis

↑ release of monocyte colony-stimulating factor

↑ cholesterol accumulation under

hyperglycemia

↑ glucose transport

Reverses insulin resistance in lipodystrophy

↑ sympathetic tone

↑ blood pressure



PAI-1 ↑ thrombus formation

↑ restenosis

PAI-1 expression stimulated by TNF-α, ang II, FFAs



Resistin ↑ ET-1 release

↑ expression of adhesion molecules and chemokines

↓ TRAF-3

↑ insulin resistance in muscle and liver

↓ glucose uptake and insulin action

TZD downregulates resistin expression



TNF-α NO bioavailability

↓ vasodilatation

↑ NFκB via ROS

↑ VCAM-1, ICAM-1, E-selectin and MCP-1 in EC and VSMC

↑ apoptosis in EC

↓ adipose cell differentiation

↓ insulin signal transduction

↑ systemic insulin resistance

↑ lipolysis

↑ FFAs

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.

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.

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.

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.

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