1. The Road To Metabolic syndrome

2. 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.

4. why are people so concerned with visceral adipose tissue (fat inside the abdomen ؟(
Metabolic syndrome may result due to imbalance in this tissue.
We used to think of fat as a simple storehouse of energy, but it's much more complicated than that.
This visceral adipose tissue plays a good-bad role. It makes beneficial compounds which raise sensitivity to insulin, reduce blood pressure and sustain healthy blood vessels.
But it also makes compounds that promote inflammation. When this fat is "healthy," it predominantly makes the beneficial compounds; when it's unhealthy, it shifts toward inflammatory compounds.

5. Lipocytes

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

11. Adipocytes and adipocytokines

12. Dysregulation of pro- and anti-inflammatory adipocytokine function and production seen in visceral fat obesity is associated with the metabolic syndrome, suggesting that inflammation may critically contribute to the development of the metabolic syndrome and results in atherosclerosis .

14. The adipose tissue as a target organ of the metabolic syndrome
Leptin is an important adipocytokine that acts directly on the hypothalamus, thereby regulating food intake and energy expenditure.

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

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

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

19. Serum fatty acids trigger inflammation in macrophages (indicated in red).
Circulating inflammatory cytokines increase SOCS3 in skeletal muscle and liver.
This in turn inhibits leptin and insulin signaling.
Resulting in the accumulation of bioactive lipids and the development of insulin resistance as a component of metabolic syndrome.

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

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

23. Angiotensinogen (Agt), the precursor of AII, is produced primarily by the liver. It also occurs in the adipose tissue, where it is up-regulated during the development of obesity.
To understand the functional role of Agtr1 in adipose tissue growth and metabolism in vivo, researcher examined the metabolic phenotypes of mice lacking Agtr1a-/- (Agtr1a-/- mice) during a high-fat diet compared to a wild type.

25. The previous experiment proved that high fat diet-induced body weight gain, adiposity and insulin resistance in wild type but not in Agtr1-/- phenotype.
suggesting the role of Agtr1 in the metabolic syndrome. (Endocrinology 146: , 2005).

26. Crosstalk between adipocytes and macrophages in obese adipose tissue
Weight gain is associated with infiltration of fat by macrophages, suggesting that they are an important source of inflammation in obese adipose tissue.
An in vitro co-culture system composed of adipocytes and macrophages demonstrated that a paracrine loop involving FFAs and TNF-α derived from adipocytes and macrophages, respectively, establishes a cycle that aggravates inflammatory changes.
This suggests the pathophysiologic implication of the intimate crosstalk between adipocytes and macrophages in the development of inflammatory changes in obese adipose tissue and thus the metabolic syndrome.

28. The skeletal muscle as a target organ of the metabolic syndrome
A well-balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure that is typically achieved by proper physical exercise is effective against obesity and diabetes.
The skeletal muscle is the largest organ and plays important roles in exercise, energy expenditure, and glucose metabolism.
The mass and composition of the skeletal muscle is critical for its function, and is regulated in response to changes in physical activity, environment or pathologic conditions.

31. How to avoid metabolic syndrome