The Road To Metabolic The Road To Metabolic syndromesyndrome

The metabolic syndrome is a constellation of abdominal

obesity, insulin resistance, hyperlipidemia, and hypertension,

all of which increase independently a risk of atherosclerotic

diseases. It is a multi-factorial pathologic condition that arises

from complex interactions between genetic and environmental

factors. However, the molecular basis for the clustering of such

independent risks for atherosclerosis has not been fully

elucidated, with visceral fat obesity considered most important.

why are people so concerned with visceral why are people so concerned with visceral adipose tissue adipose tissue ((fat inside the abdomenfat inside the abdomen ؟؟((

Metabolic syndrome may result due to imbalance in this Metabolic syndrome may result due to imbalance in this tissuetissue..

We used to think of fat as a simple storehouse of energy, but We used to think of fat as a simple storehouse of energy, but

it's much more complicated than thatit's much more complicated than that.. This visceral adipose tissue plays a goodThis visceral adipose tissue plays a good--bad rolebad role. . It makes It makes

beneficial compounds which raise sensitivity to insulin, reduce beneficial compounds which raise sensitivity to insulin, reduce blood pressure and sustain healthy blood vesselsblood pressure and sustain healthy blood vessels. .

But it also makes compounds that promote inflammationBut it also makes compounds that promote inflammation. . When this fat is When this fat is ""healthy,healthy," " it predominantly makes the it predominantly makes the beneficial compounds; when it's unhealthy, it shifts toward beneficial compounds; when it's unhealthy, it shifts toward inflammatory compoundsinflammatory compounds. .

LipocytesLipocytes

AdipocytesAdipocytes

The adipose tissue is not merely an energy The adipose tissue is not merely an energy storage organ but an important endocrine storage organ but an important endocrine organ that secretes many biologically active organ that secretes many biologically active substances such as leptin, free fatty acids substances such as leptin, free fatty acids (FFAs), tumor necrosis factor-a (TNF-a), (FFAs), tumor necrosis factor-a (TNF-a), and adiponectin, which are collectively and adiponectin, which are collectively termed adipocytokines.termed adipocytokines.

Adipocytes and adipocytokinesAdipocytes and adipocytokines

Dysregulation of proDysregulation of pro- - and antiand anti--inflammatory inflammatory

adipocytokine function and production seen in adipocytokine function and production seen in

visceral fat obesity is associated with the metabolic visceral fat obesity is associated with the metabolic

syndrome, suggesting that inflammation may syndrome, suggesting that inflammation may

critically contribute to the development of the critically contribute to the development of the

metabolic syndrome and results in atherosclerosismetabolic syndrome and results in atherosclerosis . .

The adipose tissue as a target organ of the The adipose tissue as a target organ of the metabolic syndromemetabolic syndrome

Leptin is an important adipocytokine that Leptin is an important adipocytokine that acts directly on the hypothalamus, thereby acts directly on the hypothalamus, thereby regulating food intake and energy regulating food intake and energy expenditure.expenditure.

Numerous studies revealed that plasma leptin Numerous studies revealed that plasma leptin concentrations are significantly elevated in concentrations are significantly elevated in obese subjects in proportion to the degree of obese subjects in proportion to the degree of adiposity, suggesting the pathophysiologic adiposity, suggesting the pathophysiologic implication of leptin in obesityimplication of leptin in obesity--related related metabolic syndromemetabolic syndrome. .

Leptin receptorLeptin receptor

The leptin receptor, a single transmembrane protein The leptin receptor, a single transmembrane protein that belongs to the gp130 family of cytokine receptor that belongs to the gp130 family of cytokine receptor superfamilysuperfamily, , is also expressed in a variety of is also expressed in a variety of peripheral tissues, suggesting that leptin works as a peripheral tissues, suggesting that leptin works as a propro--inflammatory cytokine in the peripheryinflammatory cytokine in the periphery..Mutation Mutation in genetic obesities leads to decrease in sensitivity to in genetic obesities leads to decrease in sensitivity to leptin.leptin.

Model of inflammatory and metabolic pathways that Model of inflammatory and metabolic pathways that interact with insulin and leptin actioninteract with insulin and leptin action..

Serum fatty acids trigger inflammation in Serum fatty acids trigger inflammation in macrophages macrophages ((indicated in redindicated in red))..

Circulating inflammatory cytokines increase Circulating inflammatory cytokines increase SOCS3 in skeletal muscle and liver.SOCS3 in skeletal muscle and liver.

This in turn inhibits leptin and insulin signaling.This in turn inhibits leptin and insulin signaling.

Resulting in the accumulation of bioactive Resulting in the accumulation of bioactive lipids and the development of insulin resistance lipids and the development of insulin resistance as a component of metabolic syndrome.as a component of metabolic syndrome.

Leptin /Adiponectin ratioLeptin /Adiponectin ratio

given that leptin and adiponectin are given that leptin and adiponectin are important mediators linking adiposity and important mediators linking adiposity and atherosclerosis in the “adipovascular axis”, atherosclerosis in the “adipovascular axis”, recently it was demonstrated that a high recently it was demonstrated that a high leptinleptin//adiponectin ratio is strongly adiponectin ratio is strongly correlated with correlated with pulsepulse--wave velocity, a wave velocity, a direct measure of arterial stiffnessdirect measure of arterial stiffness and and postulated that the leptinpostulated that the leptin//adiponectin ratio adiponectin ratio may serve as a potential atherogenic may serve as a potential atherogenic index in obese type 2 diabetic patientsindex in obese type 2 diabetic patients ..

Role of angiotensin II type 1 receptor in the Role of angiotensin II type 1 receptor in the

metabolic syndromemetabolic syndrome

The renin-angiotensin system (RAS) plays an important The renin-angiotensin system (RAS) plays an important role in the regulation of body fluid homeostasis and blood role in the regulation of body fluid homeostasis and blood pressure control. Angiotensin II (AII) is a potent pressure control. Angiotensin II (AII) is a potent hypertensive octapeptide that induces blood pressure hypertensive octapeptide that induces blood pressure elevation primarily through the activation of angiotensin II elevation primarily through the activation of angiotensin II type 1 receptor (Agtr1). Clinically, Agtr1 blockers (ARBs) type 1 receptor (Agtr1). Clinically, Agtr1 blockers (ARBs) have been used widely as antihypertensive drugs. Evidence have been used widely as antihypertensive drugs. Evidence has accumulated suggesting that activation of RAS is a has accumulated suggesting that activation of RAS is a common feature in patients with the metabolic syndrome. common feature in patients with the metabolic syndrome. One of the keys to effectively preventing cardiovascular One of the keys to effectively preventing cardiovascular diseases is, therefore, to suppress RAS activation at an diseases is, therefore, to suppress RAS activation at an early stage of the metabolic syndrome.early stage of the metabolic syndrome.

Angiotensinogen (Agt), the precursor of AII, is Angiotensinogen (Agt), the precursor of AII, is produced primarily by the liver. It also occurs in produced primarily by the liver. It also occurs in the adipose tissue, where it is up-regulated during the adipose tissue, where it is up-regulated during the development of obesity.the development of obesity.

To understand the functional role of Agtr1 in To understand the functional role of Agtr1 in adipose tissue growth and metabolism in vivo, adipose tissue growth and metabolism in vivo, researcher examined the metabolic phenotypes of researcher examined the metabolic phenotypes of mice lacking Agtr1a-/- (Agtr1a-/- mice) during a mice lacking Agtr1a-/- (Agtr1a-/- mice) during a high-fat diet compared to a wild type. high-fat diet compared to a wild type.

The previous experiment proved that high The previous experiment proved that high fat diet-induced body weight gain, adiposity fat diet-induced body weight gain, adiposity and insulin resistance in wild type but not in and insulin resistance in wild type but not in Agtr1-/- phenotype.Agtr1-/- phenotype.

suggesting the role of Agtr1 in the metabolic suggesting the role of Agtr1 in the metabolic syndrome. (syndrome. (EndocrinologyEndocrinology 146:3481-3489, 146:3481-3489, 2005).2005).

Crosstalk between adipocytes and macrophages Crosstalk between adipocytes and macrophages

in obese adipose tissuein obese adipose tissue Weight gain is associated with infiltration of fat by Weight gain is associated with infiltration of fat by

macrophages, suggesting that they are an important source macrophages, suggesting that they are an important source of inflammation in obese adipose tissue.of inflammation in obese adipose tissue.

An An in vitroin vitro co-culture co-culture system composed of adipocytes and system composed of adipocytes and macrophages demonstrated that a paracrine loop involving macrophages demonstrated that a paracrine loop involving FFAs and TNF-FFAs and TNF-αα derived from adipocytes and derived from adipocytes and macrophages, respectively, establishes a cycle that macrophages, respectively, establishes a cycle that aggravates inflammatory changes.aggravates inflammatory changes.

This suggests the pathophysiologic implication of the This suggests the pathophysiologic implication of the

intimate crosstalk between adipocytes and macrophages in intimate crosstalk between adipocytes and macrophages in the development of inflammatory changes in obese adipose the development of inflammatory changes in obese adipose tissue and thus the metabolic syndrome.tissue and thus the metabolic syndrome.

The skeletal muscle as a target organ of the The skeletal muscle as a target organ of the

metabolic syndromemetabolic syndrome A A well-balanced body energy budget controlled by well-balanced body energy budget controlled by

limitation of calorie uptake and/or increment of limitation of calorie uptake and/or increment of energy expenditure that is typically achieved by energy expenditure that is typically achieved by proper physical exercise is effective against obesity proper physical exercise is effective against obesity and diabetes. and diabetes.

The skeletal muscle is the largest organ and plays The skeletal muscle is the largest organ and plays important roles in exercise, energy expenditure, important roles in exercise, energy expenditure, and glucose metabolism. and glucose metabolism.

The mass and composition of the skeletal muscle is The mass and composition of the skeletal muscle is critical for its function, and is regulated in critical for its function, and is regulated in response to changes in physical activity, response to changes in physical activity, environment or pathologic conditions.environment or pathologic conditions.

How to avoid metabolic How to avoid metabolic syndromesyndrome