1. Summary of Metabolic Syndrome
The metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia.[1] This disorder is also known as syndrome X and insulin-resistance syndrome.[1] It is estimated that 20-25% of the world’s adult population have this syndrome and as a result, are twice as likely to die from and three times as likely to have a heart attack or stroke compared to people without metabolic syndrome.[2] In addition, people are five times more likely to develop type 2 diabetes.[2] The three most current definitions of metabolic syndrome, created by the National Cholesterol Education Program – Third Adult Treatment Panel (NCEP ATPIII), the World Health Organization (WHO), and the International Diabetes Foundation (IDF), provide useful guidelines to identify those individuals at increased risk for development of type 2 diabetes, atherosclerotic cardiovascular disease (CVD), and cardiovascular death.[1]
The NCEP ATPIII, WHO and IDF definitions are associated with similar risk for total mortality, cardiovascular disease (CVD) mortality, risk for new CVD events and risk for diabetes despite their different sensitivity and false positive rates.[3] A diagnosis of metabolic syndrome using any of the 2 definitions is correlated with CVD risk in people who are free of CVD and diabetes.[3] Men with metabolic syndrome aged ≥45 years and women aged ≥55 years are also at increased risk for CVD.[3] In addition, the presence of metabolic syndrome predicts diabetes beyond glucose intolerance alone.[3]
Although it is most commonly seen in male adults, the prevalence of metabolic syndrome is increasing in children and female adults.[4] Children with metabolic syndrome are estimated to be 3 times more likely to develop type II diabetes in adulthood.[4] In addition, a recent sub-population of athletes has been identified to be at high risk for the development of metabolic syndrome. Studies have found a high prevalence of metabolic syndrome in collegiate level football lineman, which puts them at high risk for insulin resistance and CVD.[5,6]. Buell et al. found that 34 of the 70 lineman participating in the study fit the diagnostic criteria for metabolic syndrome.[6]
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Table of Contents
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2. Current Definitions of Metabolic Syndrome
| Clinical Features | NCEP ATPIII Criteria[7] (≥3 of the criteria below) | WHO Criteria[1] (Impaired Glucose Regulation/Insulin Resistance and ≥2 other criteria) | IDF Criteria[2] (Central Obesity and ≥2 other criteria) |
|---|---|---|---|
| Impaired Glucose Regulation/Insulin Resistance | Fasting Plasma Glucose ≥ 110 mg/dl | Type 2 DM or impaired fasting glycemia [≥6.1 mmol/L (110 mg/dl) or impaired glucose tolerance or glucose uptake below lowest quartile under hyperinsulinemic euglycemic conditions | Raised fasting plasma glucose ≥100 mg/dl (5.6 mmol/L) or Type 2 DM |
| Abdominal/Central Obesity | Waist Circumference > 102 cm (40 in.) in men, 88 cm (35 in.) in women | Waist/hip ratio 0.90 in. in men, 0.85 in. women or BMI > 30 kg/m2 | Waist circumference within ethnicity specific values or BMI 30 kg/m2 |
| Hypertriglycemia | ≥ 150 mg/dl | ≥ 1.7 mmol/L (150 mg/dl) | ≥ 150 mg/dl or receiving specific treatment for this lipid abnormality |
| Low Levels of HDL Cholesterol | < 40 mg/dl in men, < 50 mg/dl in women | < 0.9 mmol/L (35 mg/dl) in men, <1.0 mmol/L (39 mg/dl) in women | < 40 mg/dl in men, < 50 mg/dl in women or receiving specific treatment for this lipid abnormality |
| Raised Blood Pressure | ≥ 130/85 mm Hg | ≥ 140/90 mm Hg | Systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg or receiving treatment for previously diagnosed hypertension |
| Microalbuminuria | Not Included | ≥ 20µg/min or albumin: creatinine ratio ≥ 30 mg/g | Not Included |
Table 1. Abbreviations: NCEP ATPIII, National Cholesterol Education Program Adult Treatment Panel III; WHO, World Health Organization; IDF, International Diabetes Foundation; DM, diabetes mellitus; BMI, body mass index; HDL, high-density protein; BP, blood pressure
3. Normal Cellular Function
Energy Consumption/Storage and Adipose Tissue
To fully understand metabolic syndrome, it is first important to have a basic understanding of normal energy consumption, storage and usage in the human body. To begin, the human body maintains cellular function by means of consuming energy via the foods we eat. This energy is composed of the three macronutrients: proteins, carbohydrates and fats. Since food intake is intermittent, nutrients must be stored for usage between meals. [8] The amount of stored energy is based upon the overall energy input and output of the human; the amount of excess energy stored is the difference between the energy consumed, or input, and the energy utilized, or output. [8] Carbohydrates are stored as glycogen in the liver and muscles, but as these storage sites are filled, excess glucose is converted into triglycerides and stored in the fat. [8]Proteins are similar in their storage, with excess levels eventually being converted into triglycerides and stored as fat. Thus, the major site for energy storage in the body is in fat cells, or adipocytes, that compose adipose tissue.
Adipose tissue can be divided into two types, brown and white adipose tissue. Brown adipose tissue’s primary role is in non-shivering thermogenesis and is found in much lesser quantities in humans.[8] White adipose tissue is the site of energy storage and neuroendocrine effects. [9] Also, adipose tissue can be further subdivided depending on its location in the body. Adipose tissue can be stored as either subcutaneous fat or visceral fat, surrounding the organs in the thorax including the liver and heart. [10] The role of adipocytes and adipose tissue have changed dramatically with increasing research into the cellular biology of humans. Once thought to be merely a storage site for fat cells, adipocytes have been found to have many endocrine functions as well, which will be discussed in detail.
Insulin Pathways
Following postprandial increase in blood glucose levels, the pancreas releases insulin into the body. The beta cells of the pancreas produce the hormone insulin, which acts on skeletal muscles, liver and adipose tissue. [11] In response to insulin release, liver gluconeogenisis is suppressed and glucose is taken up by skeletal muscle and adipose tissue in order to maintain homeostasis. [11,12] The transport of glucose into the cell is mediated by glucose transporters (GLUT), with the most important one being GLUT-4. [12] Increased levels of insulin in the blood activates GLUT-4 to be mobilized from intracellular storage and fuses to the cell membrane to allow the internalization of glucose into the cell. [12] By increasing the concentration of GLUT-4 proteins at the cell membrance, more glucose is taken up by the cell. [13] Insulin also plays a role in lipid metabolism by increasing lipid metabolism in the liver and fat cells. [11]
Insulin binds to the cell through an insulin receptor, which consists of two extracellular α subunits and two transmembrane β subunits. [11,13] When insulin binds to a cell, one β subunit tyrosine phopshorylates the other β subunit, that interacts with the proteins known as insulin receptor substrates (IRS).[12,14] Activating the tyrosine kinase pathway leads to phosphorylation of receptor substrates and adapter proteins, which form docking sties for other downstream effects within the cell. [12] From here there are two major pathways that are initiated by the binding of insulin; the phosphatidylinositol 3-kinase (PI3K )pathway and mitogen-activated protein(MAP) pathway [12,14] PI3K is the pathway associated with the metabolic effects of insulin, whereas MAP plays a role in growth and mitogenesis. [12,15]. In the PI3K pathway, IRS that have been tyrosine-phosphorylated interact with the p85 subnit of PI3K, resulting in the synthesis of PIP3 (phosphatidlinotilol 3,4,5 phosphate). [12]. Downstream PIP3 is responsible for the activation of PDK (phosphoinsitide dependent kinase) and Akt (protein kinase 3). [12,14]. Akt’s role related to insulin includes glucose transport and storage, protein synthesis and stopping lipid degradation. [12] The PI3K pathway also helps increase glucose uptake by increasing plasma membrane concentration of GLUT-4. [11,13]
Figure 1. Normal Insulin Signaling [16]
4. Causes of Obesity
Central Obesity
Obesity is defined as excessive fat content in the adipose tissue stores resulting in a bodyweight that is greater than 20% when compared to normal standards. [8] Obesity is becoming one of the biggest problems in the health care system in the United States; over half of the adults in the United States are considered to be overweight and one-third are considered to be obese. [8] Obesity occurs from an overabundance of calories created by a positive energy balance where the body utilizes less calories than it is taking in. [8] Factors related to the cause of obesity include lack of exercise, sedentary lifestyle, accessible energy dense foods, endocrine dysfunction such as hypothyroidism and disturbances in the leptin signaling pathways. [8]
One of the fundamental aspects of metabolic syndrome is the relationship between the disease and increased waist circumference. The definition of metabolic syndrome was created with the use of waist circumference as a measure for obesity, not using Body Mass Index, a very popular measure to quantify obesity. [10] Waist circumference has been shown to have a higher correlation with the presence of metabolic syndrome than body fat percentage and BMI. [17] This measurement tool used to define metabolic syndrome is somewhat controversial among the medical community, with some stating that the different cut-off values established between ethnic groups lack solid epidemiological and metabolic data; some ethinic populations are more or less susceptible to visceral fat than others. [10]
The reason that waist circumference is used as a tool is because it is a more direct measure of the amount of visceral fat in the body.[10] The amount of circulating free fatty acids in the blood is closely associated with insulin resistance, and visceral adipose tissue is thought to be the primary source of these free fatty acids.[10] The lipid overflow-ectopic fat model describes how fat can accumulate in the visceral organs and not subcutaneously. Evidence suggests that if extra energy was stored in insulin-sensitive subcutaneous adipose tissue, the individual would be protected from possibly developing metabolic syndrome. [10]However, with an insufficient amount of subcutaneous adipose tissue or as this tissue becomes more insulin resistant, triglyceride surplus will accumulate at undesired sites such as the liver and heart. [10]The resulting increases in fat to the liver would then lead to increased hepatic glucose production and therefore hyperglycemia. [10]
Genetic Factors
The degree to which metabolic syndrome is caused by genetic factors is under debate, with heritability ranging from approximately 25-60%. [18],[19],[20] Specifically, plasma cholesterol and triglyceride concentrations have been found to be highly heritable (56-77%); waist circumference, plasma glucose and insulin, HOMA-IR, and blood pressure were moderately heritable (43-57%). [21]
Multiple processes have been researched to describe the genetic influence on metabolic syndrome and many hypotheses have been developed. A major component of the genetic influence resides in the mitochondria where expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator (PGC-1) is decreased. This leads to a reduction of oxidative phosphorylation by 30% as the mitochondria are smaller and less efficient without PGC-1, which results in increased levels of triglycerides. Carnitine palmotransferase-1 (CPT-1) is required to transport triglycerides into the mitochondria. In the presence of insulin resistance, the activity of CPT-1 is decreased, which causes an increase of triglycerides in the cytoplasm. Increases of triglycerides in specific tissues such as cardiomyocytes, hepatocytes, and pancreatic beta cells can lead to cardiomyopathy, fatty liver disease, and diabetes, respectively.[18]
In addition to PGC-1α, Mani et al. found that when hyperlipidemia, hypertension, diabetes, and osteoporosis were present, a genetic defect of a short segment on chromosome 12p was present.[22] The defect was a missense mutation in LRP6, which substituted cysteine for arginine. The combination of these traits is often present in metabolic syndrome and therefore this single genetic defect could be a link to the development of metabolic syndrome. [22]
A third genetic trait that has been heavily researched is Toll-like receptor 5 (TLR5). TLR5 is a component of the immune system and is expressed in the gut mucosa. This receptor helps to fight infection, but it also helps to develop hyperlipidemia, hypertension, insulin resistance, and increased adiposity. Vijay-Kumar et al found that transferring the gut microbiota from TLR5-deficient mice to wild-type germ-free mice developed many of the features of metabolic syndrome.[23] They also found that food restriction prevented obesity in these mice, but did not help to prevent insulin resistance, leading to a stronger link between TLR5 and diabetes. [23]
There are many other genetic factors that can contribute to obesity and all of the other factors associated with metabolic syndrome. They continue to be researched and the chart below is a list of some of the genes associated with increased obesity.
| Table 2: Genes Associated with Obesity[24] | ||
| Biological Process | Gene Symbol | Name |
| Upregulated | ||
| Cell proliferation | VEGFB | Vascular endothelial growth factor B |
| FCF1 | Fibroblast growth factor 1 (acidic) | |
| Immune response | FCGR3B | Fc fragment of IgC, low-affinity IIIb, receptor for CD16 |
| Metabolism | LRP5 | Low density lipoprotein receptor-related protein 5 |
| ADRBK2 | Adrenergic, beta, receptor kinase 2 | |
| GSK3A | Glycogen synthase kinase 2 alpha | |
| PGK1 | Phosphoglycerate kinase 1 | |
| Signal transduction | MAPK3 | Mitogen-activated protein kinase 3 |
| NPY1R | Neuropeptide Y receptor Y1 | |
| MAPK3K4 | Mitogen-activated protein kinase kinase kinase 4 | |
| MAPK9 | Mitogen-activated protein kinase 9 | |
| MAP2K6 | Mitogen-activated protein kinase kinase 6 | |
| NPY5R | Neuropeptide Y receptor Y5 | |
| Downregulated | ||
| Cell proliferation | FGF4 | Fibroblast growth factor 4 |
| FGF2 | Fibroblast growth factor 2 (basic) | |
| IGF1 | Insulin-like growth factor 1 | |
| FGF7 | Fibroblast growth factor 7 (keratinocyte growth factor) | |
| FIGF | c-fos-induced growth factor (VEGF D) | |
| LDLR | Low-density lipoprotein receptor | |
| AR | Androgen receptor | |
| Signal transduction | ||
| PTGER3 | Prostaglandin E receptor 3 (subtype EP3) | |
| IRS4 | Insulin receptor substrate 4 | |
| ADRB2 | Adrenergic, beta-2, receptor, surface |
Maternal Influences
Maternal diabetes produces an increased risk to their offspring of not only developing diabetes, but also increases their susceptibility to obesity.[25] Intrauterine exposure to higher amounts of glucose occurs in diabetic mothers because glucose is able to freely cross the placenta, while insulin does not. In the fetus this causes an increase in secretion of insulin, which acts as a fetal growth hormone encouraging growth and increased adipocyte development. [25] In a study using pregnant rats with diabetes, the offspring developed decreased insulin sensitivity and secretion as well as impaired glucose tolerance as adults.[25] In a human study of diabetes and pregnancy, children of diabetic mothers at the age of 8 were found to be 30% heavier than their expected weight at their current height.[25] Another theory, known as metabolic imprinting, linking overweight individuals to intrauterine development includes modified neural coding secondary to metabolic alternation in obese mothers.[26] Also increased exposure to excess insulin during the postnatal period can lead to obesity.[26]
Epigenetics, which means inheritance of information based on gene expression rather than gene sequence, may have links to the maternal influences to the development of metabolic syndrome. [28] This hypothesis stems from the idea that offspring undergo incorrect programming of genes during the fetal and postnatal developing due to poor maternal nutrition and metabolic disturbances. One example of this is protein restriction during the fetal development period in a study on rats. A reduction in proteins increased the rate of apoptosis of pancreatic β-cells, resulting in a small mass of β-cells in their offspring; thus increasing the risk of β-cell dysfunction. [28]
Environmental Factors
While genetics and maternal influences can play a role in the development of metabolic syndrome, environmental factors also play a substantial role. Diet is an undeniable factor of insulin sensitivity and therefore metabolic syndrome. Insulin sensitivity can be influenced not only by total energy intake but also by the composition of the diet. The most recognized components of diet studied in regard to metabolic system are the fat content, especially unsaturated vs. saturated fats, and carbohydrate content.[27] In terms of fat content, diets rich in saturated fat have been shown to decrease insulin sensitivity while diets rich in monounsaturated fats cause an increase in insulin sensitivity.[27] Not all carbohydrates are equal, either. Not only the amount of carbohydrates but also the speed at which they are broken down plays a role in avoiding the problems of a high-carbohydrate diet. The glycemic index, or GI, is the measure of how carbohydrate foods affect blood glucose levels.[27] Foods that have a lower GI digest slower than foods with a high GI and can result in less post-prandial hyperglycemia.[27] In general, carbohydrates with higher fiber content, such as whole grain breads and cereals, have a lower GI than white breads and flour.[27]
The Mediterranean style diet has been shown to have an inversely associated relationship with metabolic syndrome.[29] The Mediterranean diet is characterized by high consumption of fruits, vegetables, legumes and grains, moderate alcohol intake, moderate to low consumption of dairy and meat products and a high monounsaturated-to-saturated fat ration.[29]
Several other factors have been shown to be linked to insulin sensitivity and metabolic syndrome. Alcohol intake is also thought to play a role in insulin sensitivity; it is thought to be beneficial to insulin sensitivity as long as it is ingested moderately. Intake beyond 30 grams/day is thought to have a negative effect.[30] Smoking has been linked to an increase in metabolic syndrome, with one study finding a relative risk of 1.9 for those who have 20 pack-year smoking history when compared to non-smokers.[31] The same study found a link between level of education and risk of metabolic syndrome; the higher one’s education level decreased one’s risk of developing metabolic syndrome.[31]
5. Cellular Dysfunction/Dysregulation associated with Metabolic Syndrome
Figure 2. Overview of Metabolic Syndrome Pathways[32]
Abbreviations: NEFA, Non-Essential Fatty Acids; IL-6, Interleukin-6; TNF-α, Tumor Necrosis Factor-Alpha; CRP, C-Reactive Protein; PAI-1, Plasminogen Activator Inhibitor-1; BP, blood pressure
Role of Free Fatty Acids (FFAs)
Plasma levels of free fatty acids (FFAs) are elevated in obesity due to increased visceral adipose tissue.[33,34] Visceral fat has a higher density of β-adrenergic receptors and a lower density of α-1 adrenergic receptors when compared to subcutaneous fat.[18] These receptors, located on the surface of the adipocyte, can lead to increased catecholamine-induced lipolysis and increased release of FFAs into the blood stream.[18] This increase in circulating FFAs can have an effect on liver, pancreas, and muscle function.[18] The effect of increased FFAs on the liver will be discussed later in the section on Non-Alcoholic Fatty Liver Disease (NAFLD). The effect of increased FFAs on the pancreas occurs following chronic elevation (likely due to chronic obesity) as the FFAs induce a state of insulin resistance and impair pancreatic β-cell function.[35] In a study conducted by Lee et al[36], a sustained increase in circulating FFAs on Zucker diabetic fatty rats was responsible for accumulation of triglyceride levels and for elevated cellucar free fatty acyl levels that were cytotoxic, leading to apoptosis and β-cell death.[36] The effect of increased FFAs on muscle can be seen most dramatically when examining the heart muscle. Guenther Boden, M.D. published a manuscript in the National Institutes of Health on the topic of FFAs and their role with obesity. One of his major findings was that acute increases in plasma FFA levels increased the activity matrix metalloproteinases (MMP-2, MMP-9, and MT-MMP) in rat aorta.[34] This is important because increased activity of these specific MMPs combined with increased levels of pro-inflammatory cytokines (discussed below) can lead to progression of atherosclerosis and is a major contributor to increased risk for cardiovascular disease in obese insulin resistant individuals.[34]
Dyslipidemia
The dyslipidemia most commonly associated with metabolic syndrome is labeled hypertriglyceridemia. Hypertriglyceridemia is seen with the combination of abdominal obesity and insulin resistance and is related to the oversecretion of triglyceride-rich very low-density lipoprotein (VLDL) particles.[37] This is due to increased plasma FFA levels, causing the liver to increase FFA uptake, which stimulates the secretion of apolipoprotein B (apo B).[37] Apo B is the structural protein of atherogenic particles, including VLDL, and intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL). The breakdown of VLDL particles by lipoprotein lipase in the blood generates additional FFAs and remnant particles, which are then processed by the liver to form LDL.[37] As this cycle continues in the patient with increased abdominal adiposity, the LDL particles created by the liver become enriched with triglycerides and are smaller and denser.[37,18] These small, dense LDL particles are associated with an increased risk of myocardial infarction and worsened severity of coronary artery disease (CAD).[37]
Additionally, hypertriglyceridemia in individuals with metabolic syndrome is also accompanied by an atherogenic lipoprotein phenotype which is comprised of (1) elevated triglycerides, (2) elevated small LDL particles, and (3) reduced high-density lipoprotein (HDL) levels.[37,38] Elevated triglycerides not only help to form VLDL particles, but some studies have shown that they induce a procoagulant state.[38] Smaller LDL particles, as described above, leads to increased atherogenesis and prevalence of CAD. The mechanisms explaining this phenomena is largely theoretical at this point, though evidence suggests that smaller LDL particles can more easily penetrate the arterial endothelium and gain entry into the subendothelial space where they are more easily oxidized. Following oxidation, these smaller LDL particles can then be more easily picked up by scavenger receptors on macrophages to begin atherogenesis.[18,38] Low HDL levels can independently increase a person’s risk for CAD, after adjustment for confounding risk factors, because raising HDL levels can protect against development of CAD.[38]
Non-Alcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease (NAFLD) is a term used to describe a condition of fat accumulation in the liver in the absence of excessive alcohol consumption.[18,39,40] NAFLD is more frequent in obese subjects (75%) compared with controls (16%) and among patients with type 2 diabetes (34-74%). It is also found in children, particularly obese children (38%) and children with type 2 diabetes (48%).[39] The pathogenesis of NAFLD combines many of the topics outlined throughout this page. With expanding visceral adipose tissue, macrohphages infiltrate the area to bring in proinflammatory cytokines, causing the adipose tissue to likely be insulin resistant.[39]This results in an increase of FFAs from visceral adipose tissue that are released directly into the portal vein and the liver, which are then taken up by hepatocytes and are bound to coenzyme A (CoA).[39] The fatty acyl CoAs (FACoAs) can form triglycerides (creating VLDL particles), interfere with insulin signaling, and can induce inflammation by stimulating nuclear factor κB (NF-κB). The FFAs can also induce insulin resistance by interfering with toll-like receptor 4.[39] In addition, adipose tissue releases high amounts of proinflammatory cytokines (detailed below), which suppress the production of adiponectin.[39,40] adiponectin will be discussed in great detail in proceeding sections, but in general, at this point it is imperative to understand that adiponectin utilizes AMP-activated protein kinase (AMPK) and induction of peroxisome proliferator-activated receptor (PPAR)-α to increase lipid oxidation in the liver.[39] With decreased amounts of adiponectin, lipid oxidation is reduced.[18,39]
Renin-Angiotensin-Aldosterone System (RAAS) Dysregulation
Obesity leads to increased local formation of angiotensin II due to increased secretion of angiotensinogen from adipocytes.[41] Angiotensinogen (AGT) is a precursor to angiotensin II (Ang II), which is a hormone that has endocrine and paracrine effects and is the final product of the renin-angiotensin-aldosterone system (RAAS) within the adipose tissue.[42] Under normal cellular functioning, the RAAS is activated by a decrease in blood volume/pressure. When this occurs, the kidneys release renin, which stimulates the production of Angiotensin I (Ang I), which then is converted to Ang II.[42] Ang II then enhances tubular sodium reabsorption, increases peripheral arterial resistance, and stimulates the sympathetic nervous system.[42] This pathway leads ultimately to an increase in blood pressure. The renin release from the kidneys and the formation of Ang II is then stopped by sodium retention and increased extracellular fluid. Although obesity is associated with sodium retention and increased extracellular fluid volume, continued RAAS activation may occur due to decreased sodium delivery to the kidneys, an increase in renin release by increased sympathetic nerve activity to the kidneys, or by increased generation of AGT within the adipose tissue.[42] This continual activation of the RAAS is a contributor to hypertension in individuals with metabolic syndrome.[42]
Figure 3. Normal Activation and Response of the RAAS.[43]
Mitochondria Dysfunction/Dysregulation
One of the primary mechanisms for mitochondria dysfunction is mitochondrial damage due to ROS.[44, 45]
Decreased Biogenesis
Decreases in mitochondrial biogenesis have been associated with obesity and type II diabetic mice.[46, 47] Kelley et al. [46] demonstrated decreased mitochondria size, by 35% in obese and/or type II diabetic mice. This finding significantly correlated with increased insulin sensitivity as measured by glucose disposal rate. Valerio et al.[47] investigated the tumor necrosis factor-alpha (TNF-alpha) and eNOS content in three models of obesity in mice: ob/ob mutation and fa/fa mutation (genetic), and high-fat induced obesity (environmental). They found that eNOS mRNA and protein levels in skeletal muscle and adipose tissue were significantly reduced in all models, as well as levels of mtDNA, PGC-1α, NRF-1, and Tfam. These results indicate reduced mitochondrial biogenesis in these tissues in with obesity. On the contrary, researchers have also shown increased mitochondrial biogenesis, however new mitochondria were smaller and less efficient.[48,49]
In the same study, Valerio et al.[47] also investigated the effect of TNF-α on eNOS. In obese mouse with partially or fully abolished TNF-α receptors, a restoration in eNOS mRNA and proteins, PGC-1α, NRF-1, and Tfam levels was demonstrated. Therefore, TNF-α was shown to downregulate eNOS, thereby resulting in decreased mitochondrial biogenesis.
Subsarcolemmal mitochondria
Subsarcolemmal mitochondria generate the ATP necessary for membrane processes such as fatty acid oxidation, insulin signaling, glucose transport, and ion exchange. Ritov at al.[50] demonstrated that individuals with obesity and DMII have significantly less subsarcolemmal mitochondria than lean individuals, with DMII greater reductions than obesity. They also found that the decreased in ETC activity was not proportional to the decrease in sarcolemmal mitochondria in those with DMII and obesity.[50] This may implicate subsarcolemmal mitochondria in a possible mechanism for insulin resistance.
Uncoupling
Boudina et al.[49] examined the effects of impaired mitochondrial function on ATP production and cardiac efficiency in mouse hearts. Densitometry measurements of ETC complexes revealed a significantly reduced density of complex I in ob/ob (mice obesity model) compared to wild type, whereas complex II density was comparable between groups. In accordance with these findings, they also found that ob/ob cardiac muscle was unable to significantly increase oxygen consumption in response to an increased workload when glucose was the only fuel source; in contrast, when palmitate (lipid) was the available fuel source, oxygen consumption increased significantly. The increased oxygen consumption, however, did not result in an increase in ATP production, revealing a decreased cardiac efficiency in fatty acid metabolism. Boudina et al.[49] concluded that fatty acid induced uncoupling was the cause for decreased cardiac efficiency in obese mice, the results of which were confirmed by other researchers. [48] The results are also compounded by the increased dependence on fatty acid metabolism in mice with obesity and insulin resistance.[51]
Changes in mitochondrial protein expression and function
PGC-1α
A down-regulation of genes controlled by PGC-1α has been demonstrated in the skeletal muscle of humans with type II diabetes, a disease closely related to metabolic syndrome.[52] Decreased expression of PGC-1α results in insulin resistance and diabetes.[52] PGC-1α null mice demonstrated deficits in cardiac muscle contractility, which relates metabolic syndrome to cardiovascular risk.[48] Patti et al.[52] demonstrated that patients with insulin resistance had decreased expression of many of the genes of oxidative metabolism. PGC-1α was significantly reduced in patients with DM and non-diabetic patients with a positive family history for DM compared to controls.
Contradictory evidence was found in cardiac muscle of insulin-resistant mice. UCP-DTA mice, an mice model for metabolic syndrome, demonstrated increased mitochondrial density and mtDNA content over controls.[48] The mitochondria, however, also demonstrated decreased efficency, evidenced by decreased ATP/O2 ratio and attributed to increased uncoupling. The study also showed that UCP-DTA mice have increased PPAR-α, which in turn increased PGC-1α, NRF-1, and TFAM. These results were not seen in PPAR-α null mice.[48]
NRF-1
Nuclear respiratory factor-1 (NRF-1) is a regulator of mitochondrial genes, including mitochondrial transcription factor A (Tfam) and the genes of oxidative phosphorylation.[44,53] PGC-1α expression regulates NRF-1 expression. Patti et al. demonstrated decreased NRF-1 levels in individuals with insulin resistance, which may be attributed to decreased PGC-1α levels.[52] In contrast, increased PPAR-α has been found in UCP-DTA mice, which in turn increased NRF-1 levels.[48
eNOS
Endothelial nitrous oxide synthase (eNOS) regulates PGC-1α expression; however the cellular mechanism of this regulation is unknown.[44] eNOS null mice demonstrated insulin resistance, hypertension, decreased mitochondria, and defective fatty acid metabolism.[54] eNOS has also been shown to be down regulated by TNF-α, which can result in mitochondrial biogenesis.[47]
ATM Protein
ATM (ataxia telangiectasia mutated) protein is required for DNA repair and to maintain genomic homeostasis. Therefore, it is important in regulation of mitochondrial biogenesis and mtDNA content. Dysfunction in the ATM protein promotes atherosclerosis, whereas increased activation of the ATM protein is associated with decreased atherosclerosis.[55]
Mercer et al.[55] demonstrated that mice with ATM+/- (haploinsufficiency) developed atherosclerosis at a faster rate compared to ATM+/+. ATM+/- mice also demonstrated increased serum cholesterol, triglycerides and low-density lipoproteins on high-fat and chow feedings. Mercer et al. also investigated DNA damage in ATM+/- mice and found increased genomic instability. Therefore, Mercer et al. proposed that the mitochondrial dysfunction and apoptosis caused by mtDNA damage and dysfunction in DNA repair results two primary clinical features of metabolic syndrome: obesity and hyperlipidemia.[55]
Endoplasmic Reticulum Dysfunction
During normal cell function within the adipocyte, the endoplasmic reticulum (ER) has three main functions: protein synthesis and secretion, energy storage in the form of triglyceride droplet formation, and nutrient sensing that are particular to the differentiated fat cell.[56] These three functions contribute to the maintenance of cellular homeostasis. When the number of nutrients reaches a pathological level, the ER activates the unfolded protein response (UPR). The UPR has been indicated as one of the causes of insulin resistance and adipocyte dysfunction in metabolic syndrome.[56]
The UPR is activated by the ER when proteins are released that are improperly folded, causing a build up in the ER lumen.[56] Improper folding of proteins can be caused by many cellular stresses including glucose and energy deprivation, increased protein synthesis, inhibition of protein glycosylation, imbalance of ER calcium levels, and the presence of mutant or misfolded proteins.[56] When the ER senses any of these cellular stresses, the UPR is activated through 3 main pathways, denoted by the three stress-sensing proteins found in the ER membrane: PKR-like eukaryotic initiation factor 2α kinase (PERK), inositol-requiring enzyme-1 (IRE-1) and activating transcription factor-6 (ATF-6).[56] Under normal cellular conditions, these 3 proteins are usually bound by a protein chaperone, BiP. When there are too many proteins, there is not enough BiP to bind the stress-sensing proteins. When unbound, PERK and IRE-1 auto-oligomerize and undergo autophosphorylation which starts the cellular cascades involved in these 2 parts of the UPR.[56] When ATF-6 is unbound, it is released to the Golgi apparatus where it undergoes 2 cleavages to produce an active transcription factor.[56]
When the PERK pathway is activated, selective suppression of protein translation occurs, causing an increase in expression of many genes involved in apoptosis.[56] When ATF-6 is activated, it translocates to the nucleus and increases the expression of protein chaperones, ER degradation-enhancing α-mannosidase-like protein (EDEM) and X-box protein 1 (XBP-1), thereby increasing ER biogenesis and secretion. Activation of the IRE-1 pathway results in upregulation of chaperone proteins, ER biogenesis and enhanced secretory capacity via XBP-1.[56]
The pathways that lead to apoptosis caused by ER stress are unknown but C/EBP homologous protein (CHOP) induction, caspase-12 activation from the ER membrane, and IRE-1α activation of c-jun N-terminal kinase (JNK) and regulation of the proapoptotic Bcl-2 family of proteins are hypothesized to play major roles.[56] It is known that phosphorylation of IRE-1α leads to the recruitment of tumor necrosis factor receptor-associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1)to the cystolic leaflet of the ER membrane.[56] This activates the JNK pathway which leads to many downstream effects including apoptosis, cell survival, inflammation and insulin resistance.[56]
It has been shown that increased activation of JNK can cause pancreatic islet dysfunction as well as further inhibition of insulin signaling through the phosphorylation of the insulin receptor substrate 1 (IRS-1), making IRS-1 incapable of serving as a substrate, disrupting the insulin receptor-IRS-1 interaction and, after prolonged activation, IRS-1 degradation.[56] Within the nucleus, JNK phosphorylates PPARγ, a major regulator of glucose and lipid homeostasis in the adipocyte and major effector of insulin sensitivity in mammals.[56]
Prolonged activation of the UPR generates oxidative stress which causes a toxic accumulation of ROS within the cell, as well as upreglation of many inflammatory genes (including IL-6 and TNF-α).[56] When the PERK pathway, which can activate an antioxidant program, is unable to control the accumulation of ROS, either an inflammatory response is seen or cell death occurs.[56]
Figure 4. Obesity and Endoplasmic Reticulum Response.[57]
Inflammation
Obesity causes a chronic proinflammatory state that contributes to the development of insulin resistance, glucose intolerance, atherogenesis[1] and hypertension.[58] The inflammatory response that is seen in metabolic syndrome is directly linked to the presence of obesity and seems to stem from the adipose tissue itself.[61] In addition to its role in specialized storage and mobilization of lipids, adipose tissue has been shown to play an integral role in the immune system.[59] Specifically, adipose tissue has been established as an endocrine organ that releases numerous cytokines and proinflammatory molecules such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α).[60]
The chronic systemic inflammatory response associated with metabolic syndrome is characterized by abnormal cytokine production, increased acute-phase reactants and other mediators and activation of a network of inflammatory signaling pathways.[61] The proinflammatory markers that have been directly linked to the inflammation component of metabolic syndrome include two cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and C-Reactive Protein (CRP).[62] The proinflammatory state seen in metabolic syndrome induces insulin resistance,[63] high blood pressure,[42] and ultimately leads to an increased risk of cardiovascular disease.[64]
Figure 5. Inflammation Pathways in Metabolic Syndrome.[65]
Cytokines (Adipokines)
The oxidative stress from accumulated fat has been found to be an important factor in metabolic syndrome primarily through the dysregulation of adipocytokines. Increased fat accumulation has been correlated with systemic oxidative stress in humans and mice. Oxidative stress results in ROS. In Furukawa et al.’s study cultured adipocytes increased levels of FFA increased oxidative stress via NADPH oxidase activation and this caused dysregulated production of adipocytokines including adiponectin, PAI-1, and IL-6. When NADPH oxidase inhibitor was used in obese mice, ROS were reduced, which resulted in decreased dysregulation of adipocytokines and improved diabetes, and hyperlipidemia.[66] The roles of each adipocytokines are explained in greater detail below.
Adiponectin
Adiponectin a protein which is located on chromosome 3q27 and codes for a 244 amino acid polypeptide plays an important role in metabolic syndrome.[67] Adiponectin is the most abundant adipose tissue protein in plasma.[68] Several studies have shown that decreases in adiponectin levels result in decreased insulin sensitivity.[69],[70],[71] Adiponectin enhances insulin sensitivity by activating insulin-receptor substrate 1 (IRS-1) associated with PI3-kinase and glucose uptake.[71] Adiponectin gene expression is reduced by obesity.[72],[73] Negative correlations were found between BMI and plasma adiponectin levels in humans in various studies.[74],[75],[76] The addition of oxidative stress has been found to suppress mRNA expression and secretion of adiponectin.[66] Reduced plasma adiponectin levels have also been found in cardiovascular disease and hypertension, which are two of the major components of metabolic syndrome.[69]
A study in which the gene that encodes for adiponectin was disrupted in mice ( known as ACR3P0 knockout mice or KO mice) found that adiponectin deficiency and high TNF-α levels reduced muscle fatty-acid transport protein 1 (FATP-1) mRNA and insulin-receptor substrate 1 (IRS-1) mediated insulin signaling, which resulted in severe diet-induced insulin resistance.[71] These findings suggest that adiponectin accelerates FFA clearance and fatty-acid oxygenation. The KO mice showed high levels of plasma TNF-α. The research suggests that adiponectin and TNF-α mutually inhibit each other’s production. The KO mice were infected with adenovirus which produced high plasma adiponectin levels and resulted in decreased plasma glucose, insulin, FFA, and TNF-α.[71]
Besides adiponectin's important role in insulin sensitivity, it also plays an important role in the prevention of atherosclerosis and cardiovascular disease. Adiponectin downregulates vascular adhesion molecules and inhibits smooth muscle migration and foam cell formation, which can be seen in the image below.[77] As discussed earlier, adiponectin levels are decreased in obesity, so it can be seen how the risk of cardiovascular disease and the presence of hypertension found in metabolic syndrome are related to adiponectin levels. Okamoto et al.'s study in mice found that increasing plasma adiponectin levels suppressed the uptake of LDL into foam cells and protected the endothelial cells from vascular injuries from hypercholesterolemia.[78]
Figure 6. Adiponectin's role with atherosclerosis and inflammation[79]
Tumor Necrosis Factor - Alpha (TNF-α)
TNF-α is a proinflammatory cytokine that stimulates endothelial cells and leukocytes to secrete cytokines, chemokines and growth factors.[80] TNF-α is mostly produced by macrophages that reside within adipocytes[81] but is also produced by monocytes, T Cells, B Cells and fibroblasts.[80] It has 2 receptors that it binds through to affect immune system responses: TNF-R1 and TNF-R2.[80] Through these receptors, TNF-α can stimulate death domain proteins in order to mediate apoptosis and programmed cell death.[80]
Stimulation of cells with TNF-α causes activation of nuclear factor-kappa beta (NF-kB) through signaling molecules including, TNF-R associated factor 2 (TNRF2), receptor interacting protein (RIP), mitogen-activated protein kinase kinase kinase (MAP3K) and the IKK (IκB Kinase) complex.[82] NF-kB is inhibitor of NF-a transcription factor that controls the expression of various genes involved in inflammatory, anti-apoptotic and immune responses. Once activated, IKK is activated resulting in a phosphorylation of inhibitor of NF-κB (IκB).[83] This targets IκB for degradation in the proteasome and frees the NF-kB dimer, which then relocates to the nucleus and binds to consensus κB sequences in the enhancers region of κB target genes.[83] The products of these target genes include cytokines (e.g., IL-1, IL-2, IL-6, IL-12, TNF-α, LTα, LTβ, and GM-CSF), chemokines (e.g., IL-8), inducible enzymes (e.g., iNOS and COX-2), adhesion molecules (e.g., intercellular adhesion molecule, vascular cell adhesion molecule, and endothelial leukocyte adhesion molecule), anti-apoptotic genes (c-IAP1, c-IAP2, IXAP, TRAF1, TRAF2, the Bcl-2 homologue A1/Bfl-1, Bcl-XL and IEX-IL) and pro-apoptotic genes (TNF-α, c-myc, and FasL).[83] Upregulation of TNF-α leads to upregulation of the NF-kB pathways resulting in a positive feedback loop that further contributes to the chronic systemic inflammation response seen in metabolic syndrome.[61]
It has been shown that TNF-α levels are increased in obese individuals and that this expression can contribute to systemic insulin resistance.[84] In a study done by Kern et al., it was found that subjects with low insulin sensitivity had a 3.0-fold increased level of TNF- α secretion from adipose tissue, indicating that the local expression of TNF-α is high in subjects with obesity-related insulin resistance.[85] TNF-α is known to decrease insulin receptor signaling[86] through paracrine or endocrine mechanisms that occur within adipose tissue and skeletal muscles.[81] TNF-α induces serine phosphorylation of IRS-1 which causes serine phosphorylation of the insulin receptor.[87] This prevents the normal tyrosine phosphorylation of the insulin receptor which interferes with insulin signal transduction, leading to insulin resistance.[87]
TNF-α also plays a role in the induction of suppressor of cytokine signaling-3 (SOCS-3)[88] which interferes with cytokine signal transduction, tyrosine phosphorylation of the insulin receptor and IRS-1, and to cause ubiquitination and proteosomal degradation of IRS-1.[89] This causes a reduction in the activation of Akt (protein kinase B) which normally causes the translocation of the insulin-responsive glucose transporter, GLUT-4, to the plasma membrane.[63] TNF-α may also contribute to insulin resistance through induction of lipolysis and stimulation of hepatic lipogensis which causes elevations in free fatty acid levels.[81] Also, TNF-α signaling decreases adiponectin secretion by adipocytes through a paracrine mechanism that could contribute to the systemic insulin resistance.[81]
Figure 7. The roles of TNF-α, adiponectinand NF-κB in the metabolic syndrome.[90]
Interleukin - 6 (IL-6)
IL-6 is an endocrine cytokine and the effects of IL-6 are correlated with serum concentration.[81] It is responsible for the acute-phase immune system response to tissue damage or infection designed to recruit host defense mechanisms, eliminate damaged cells, contain pathogens and begin tissue repair.[81] Within adipose tissue, IL-6 can be secreted from either macrophages or adipocytes with adipocyte secretion of IL-6 accounting for up to 30% of the circulating IL-6 plasma concentration.[81] Increased adiposity is directly correlated with an increase in this circulating plasma concentration.[81]
IL-6 has a direct effect on endothelial cells and vascular smooth muscle cells that can result in an increased expression of adhesion molecules and activation of the local renin-angiotensin pathways that leads to vascular wall inflammation and damage.[81] IL-6 also directly regulates CRP production within the liver.[81]
IL-6 can contribute to insulin resistance through a variety of mechanisms. It can increase basal glucose uptake, alter insulin sensitivity, increase the release of adhesion molecules by the endothelium, increase the hepatic release of fibrinogen and has a procoagulant effect on platelets.[64] Rodent models have shown that in vivo infusion of human recombinant IL-6 can induce gluconeogenesis, subsequent hyperglycemia and compensatory hyperinsulemia.[91] In a study done by Kern et al., it was found that subjects who had low insulin sensitivity demonstrated a 2.3-fold higher plasma IL-6 level.[85] A research study done by Pradhan et al found that elevated levels of CRP and IL-6 predicted the development of insulin resistance and Type 2 Diabetes Mellitus.[91]
Resistin
The degree of a role resistin plays in metabolic syndrome is one of some controversy. In Utzschneider et al.’s study of 177 non-diabetic adults, plasma resistin levels were found to not have a correlation with insulin sensitivity, intra-abdominal fat, and subcutaneous fat.[92] However, another study of 123 non-diabetic patients found resistin concentrations were 1.21 times higher in subjects with metabolic syndrome and regression analysis revealed that resistin concentrations were associated with circulating markers of inflammation.[93] Furthermore, resistin was found to be a strong up-regulator of pro-inflammatory cytokines, IL-6 and TNF-α.[94] A study evaluating resistin’s effect on insulin-stimulated glucose uptake and insulin signaling in rat skeletal muscle cells found that resistin decreases insulin-stimulated glucose uptake but does not affect insulin signaling.[95] The investigators of this study suggest that resistin decreases the insulin-stimulated glucose uptake by decreasing the intrinsic activity of GLUT-4 and GLUT-1.[95] In Steppan et al.’s study, administration of resistin to normal mice impaired glucose tolerance and insulin action, and the administration of an anti-resistin antibody improved glucose tolerance and insulin action.[96] A study of cultured endothelial cells discovered that resistin increased the expression of vascular cell adhesion molecule (VCAM-1) and monocyte chemoattractant chemokine (MCP-1) and down regulated tumor necrosis factor receptor–associated factor-3 (TRAF3), an inhibitor of CD40 ligand signaling.[97]
Ghrelin and Leptin
Ghrelin is a peptide hormone produced by P/D1 cells of the stomach and epsilon cells of the pancreas.[98] Ghrelin’s primary action is the stimulation of hunger.[98] Ghrelin is released and acts upon the hypothalamus which in turn stimulates the anterior pituitary gland to secrete growth hormone.[98] Ghrelin is found to be in lower concentration in patients with metabolic syndrome when compared to the normal population.[98] The mechanism behind this is thought to be that hyperinsulinemia, and not increased adiposity, acts as a feedback mechanism for the down-regulation of circulating ghrelin. [99]
Leptin is another peptide hormone, released by adipocytes, whose receptors are found on the arcuate nucleus on the hypothalamus.[100] Leptin acts by stimulating the sensation of satiety, thus ghrelin and leptin have opposite purposes.[100] Leptin’s role in regulating body weight becomes more complex as adipose tissue is increased. Leptin levels are found to be in higher concentrations in obese patients simply because there is more adipose tissue that is secreting the hormone.[100] It is thought that leptin resistance mechanisms occur on the target cells of the hormone. Increased levels of Suppresor of cytokine signaling-3 (SOCS-3), an inhibitor of leptin signaling, is seen with increased leptin levels. [100] Therefore, the effects that leptin would produce in a normal functioning system, the sensation of satiety, are inhibited with increased obesity.[100] Leptin also plays a role in reproduction, wound healing and bone development. (Kershaw 2004)
Recent research has shown that ghrelin and leptin are inversely related in fasting plasma levels in the presence of insulin resistance; the lower the ghrelin that exists, leptin levels will increase.[98] Therefore, high leptin and low ghrelin have been associated with increased risk of metabolic syndrome.[98] In a study of over 600 subjects, low ghrelin levels were a statistically significant predictor of the development of type II diabetes.[98] Low ghrelin levels were also associated with increased waist circumference, hypertension and fasting blood glucose, all criteria of metabolic syndrome.[98] This same ratio of leptin and ghrelin has also been associated with early atherosclerosis.[101]
PAI-1
Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of tissue-type plasminogen activator and functions to regulate fibrinolysis both in blood and in tissues.[102, 103] PAI-1 is produced by visceral adipocytes and works against tissue plasmingoen activator (TPA) to decrease the formation of plasmin.[18] Increased levels of PAI-1 are associated with thrombotic phenomena while decreased levels are result in increased likelihood of hemorrhagic events.[102] This is because plasmin is needed to breakdown thromboembolic events in the blood stream.[18] Since circulating PAI-1 is increased in obese subjects with metabolic syndrome, the formation of plasmin is decreased and plaque build-up cannot be slowed, increasing a patient’s risk for atherosclerosis.[18,102]
The mechanisms linking PAI-1 and metabolic syndrome are complex and interrelated. Overall, it appears that increased PAI-1 levels are associated with central obesity and fat redistribution rather than with IL-6 driven inflammation or with dyslipidemia.[104,105] This is because increased plasma PAI-1 originates primarily from adipocytes in response to chronically elevated levels of TNF-α, insulin, and transforming growth factor (TGF)-B and not acute-phase reactions.[103] In fact, obese patients expressed 5-fold more PAI-1 in abdominal visceral fat than subcutaneous fat.[106] Additionally, a link between PAI-1 and TNF-α has been found during obesity. A study by Samad et al (1999) found that deletion of TNF receptors in mice significantly reduced the plasma PAI-1 levels as well as the adipose tissue PAI-1 mRNA levels, which proves a direct link between TNF-α and PAI-1 during obesity.[103,107]
RBP-4
Retinol-binding protein 4 (RBP-4) is another protein secreted by adipocytes that has a role in insulin resistance in metabolic syndrome. Elevated serum RBP-4 is associated with increased BMI, waist-to- hip ratio, serum triglycerides, and systolic blood pressure.[108] Elevated serum RBP-4 levels were found in humans to be correlated with decreased GLUT-4 expression, however the mechanism of this interaction is not known.[108] Injection of RBP-4 into normal mice resulted in insulin resistance, whereas deletion of RBP-4 improves insulin sensitivity.[109]
A study of 36 adults looking at the effects of weight loss on RBP-4, visceral fat, and metabolic syndrome found that after bariatric surgery visceral fat decreased by 60.6% and as result of decreased visceral fat RBP-4 serum levels decreased by 16.6%.[110] At baseline, 19 of the subjects met the IDF’s guidelines for metabolic syndrome and at follow-up only 9 of the subjects had metabolic syndrome.[110] The greatest predictor of not having metabolic syndrome at follow up was change in RBP-4 serum levels as the group without metabolic syndrome decreased 28.1% versus 6.3% in the group that continued to have metabolic syndrome.[110]
Insulin Resistance and Pathway Dysregulation
Insulin resistance occurs when peripheral tissues no longer respond to the insulin hormone to decrease glucose levels. [15,111]. In the case of insulin resistance, there is a decrease in the immediate insulin response following a meal which results in hyperglycemia. The body responds to this by releasing more insulin, which overtime causes chronic hyperinsulinemia. Chronically raised levels of insulin in the blood, decrease the response of insulin at the tissue level. [12]. Since this condition develops in individuals with type 2 diabetes and obesity, insulin resistance has also been linked to surplus lipids in the body. [111]
Insulin Receptor
Insulin resistance can be directly related to malfunction of the insulin receptor. This can include poor expression, binding, phosphorylation or kinase activiation. [11] Problems with the insulin receptor can also be caused by genetics, with lesions in both insulin receptor alleles causing insulin resistance. [11].
GLUT-4
GLUT-4 concentration in cells is decreased in adipose as people age, along with being obese or diabetic. In individuals that are obese or diabetic, skeletal muscle does not respond as well to insulin because GLUT-4 is dysfunctional. GLUT-4 expression can be increased through exercise or increased adiponectin, therefore increasing the sensitivity of the tissues to insulin. [12]
DAG
Diacylglycerol (DAG), a gylceride found in skeletal muscle, is directly related to levels of nonessential fatty acids (NEFA). When excess NEFA exist in the body, levels of DAG increase in the muscle causing serine phosphorylayion of IRS. [12] Early phosphoryltation of IRS disrupts the normal pathway of insulin signaling, adding to insulin resistance.
Beta-Cells
In normal healthy individuals, beta cells are able to adapt by either increasing function or mass to sustain homeostatic glucose levels within the body. [112] In metabolic syndrome, increased blood glucose levels secondary to decreased peripheral sensitivity to insulin leads to increased production of insulin. Chronically high levels of glucose can also lead to glucotoxic effects on the beta cells due to poor regulation. [112] Overworking the beta cells begins to add to their dysfunction and clinical type 2 diabetes occurs when the cell is performing at 25% or less of its normal function. [112} Exposure to prolonged high levels of NEFAs not only contributes to peripheral insulin resistance but it has also been found to decrease the compensatory mechanism of beta cells in response to high glucose levels. [112] IRS proteins have also been linked to beta cell dysfunction in metabolic syndrome, specifically the IRS-2 protein. [13] In IRS-2 knockout mice, not only do the mice develop insulin resistance at the tissue level, but eventually develop full diabetes secondary to decreased beta cell function. [13]
Protein Dysfunction/Dysregulation
C-Reactive Protein (CRP)
CRP is a calcium dependent ligand-binding protein that is involved in the acute-phase immune system response.[113] Plasma CRP is produced by hepatocytes and regulated by proinflammatory cytokines, especially IL-6.[114] CRP binds with phosphocholine residues as well as a variety of autologous and extrinsic ligands and it aggregates the cellular, particulate or molecular structures bearing these ligands.[113] In this way, CRP may contribute to host defense against infection, function as a proinflammatory mediator and participate in the physiological and pathophysiological handling of autologous constituents.[113]
Because IL-6 is induced by TNF-α in various cells and TNF-α plasma levels are known to be increased with increased adiposity, serum levels of IL-6 are also at higher levels in obese individuals.[114] This increased serum level of IL-6 causes an upregulation of CRP, which also indicates that obese individuals will have high levels of serum CRP concentration.[114] A positive correlation has been found between serum CRP concentration and many elements of metabolic syndrome including obesity, hypertriglyceridemia, hyper-LDL-cholesterolemia, diabetes, hyperinsulinemia, and hyperuricemia.[114] CRP is also a predictor of the development of type 2 diabetes independent of traditional risk factors.[113]
Lipid droplet associated proteins
Lipid droplets are small intracellular fat cells filled with triacylglycerol (TAG). TAG is a primary form of stored energy in the body. Initially thought to be inert storage molecules, research has shown that lipid droplets are active organelles. TAG hydrolysis results in free fatty acids (FFA) and diacylglycerol (DAG), components that can affect signaling pathways, gene expression, disrupt the phospholipid bilayer, and induce apoptosis. [116]
Lipid droplet-associated proteins have been identified in the phospholipid monolayer of lipid droplet molecules. The most abundant and well-studied lipid droplet associated proteins belong to the PAT family, which consist of five members: perilipin, ADRP (adipose differentiation-related protein/adipophilin), TIP47, MLDP/OXPAT and S3-12. These proteins protect the molecule from hydrolysis by lipases in the cytoplasm. [115]
Perilipin
Perilipin (PLIN) is the most abundant and best characterized lipid droplet-associated protein. It is a central regulator in lipid metabolism, as it has a role in TAG hydrolysis. [116] The role of perilipin continues to the studied, however one theory is that PLIN, when phosphorylated by protein kinase A (PKA), modulates the activity of hormone-sensitive lipase (HSL), which in turn mediates and catalyzes the hydrolysis of TAG. [117]
- Tansey et al. [117] demonstrated that PLIN null mice are resistant to diet induced obesity. With an equal consumption of a chow diet, PLIN null mice demonstrated decreased adipose tissue compared to PLIN mice of equal weight. With equal consumption of a high fat diet, PLIN null mice accumulated 25% of the adipose tissue of that accumulated by the PLIN mice. The decrease in adipose to attributed to increase FFA release under basal conditions. Tansey et al. [117] also identified increased insulin and plasma glucose levels in the PLIN null mice.
- Zhai et al. [118] further researched plasma concentrations of metabolic factors in PLIN null mice and found increased FFA, glycerol, glucose and insulin after a 4 hour fast. They also identified increased lipolysis in adipose tissue, with increased levels of adipocyte lipases, HSL and ATGL. They concluded that the increased circulating FFA from increased lipolysis causes insulin resistance, as increased system FFA is thought to decrease glucose utilization.
- Miyoshi et al. [119] examined the effects of PLIN overexpression in mice fed chow and high fat diets. They found that when fed chow diets, there was no significant difference between experimental and control groups. However, when fed a high fat diet, PLIN overexpressed mice demonstrated significantly reduced body weight, adipocyte size, and adipocyte mass compared to controls. A suggested mechanism for the resistance to obesity is an upregulation of genes for oxidative metabolism, however the connection between PLIN expression and oxidative metabolism gene expression is not yet known.
ADRP
ADRP is believed to be the primary lipid droplet-associated protein prior to PLIN gene expression. A study has shown that in PLIN null mice, ADRP increases in abundance and becomes the primary membrane-bound protein. [117] The same study demonstrated ADRP does not limit basal FFA release to the same extent as PLIN.
Heat Shock Protein
Heat shock proteins (HSP), or stress proteins, have been linked to the inflammation process of metabolic syndrome as well as the development of type 2 diabetes. [120] HSPs at normal levels help to improve insulin signaling as well as reducing inflammation; but levels are decreased in individuals with metabolic syndrome. Obesity begins the cycle of decreasing HSP, by the inflammation mediators released from adipose decreasing insulin sensitivity. When tissues are not responding to insulin appropriately, the expression of HSP is reduced. Lower levels of HSP leave cells vulnerable to damage and accumulation of harmful proteins within the cells that start to damage beta cells. Beta cell dysfunction increases insulin resistance, reducing HSPs. The decline in HSP allows inflammation to continue uninhibited and further continues the cycle of progressive disease. [120]
HPA Axis Hyperactivity
The hypothalamus-pituitary-adrenal (HPA) axis is a part of the neuroendocrine system that is involved in the response to stress and helps to regulate the body’s level of cortisol. [121] When stress is perceived in the body, the hypothalamus produces and releases corticotrophin-releasing hormone (CRH) which in turn stimulates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary.[121] ACTH then stimulates the release of cortisol from the adrenal cortex.[121] Cortisol is then either converted at the tissue level by one of two enzymes; 11-B hydroxysteroid dehydrogenase 1 (11β-HSD1) converts cortisol into the active form while 11-B hydroxysteroid dehydrogenase 11 converts cortisol into the inactive form.[121] Cortisol binds to two types of receptors that have different functions; glucocorticoid receptors (GR) have influence on fluctuations of the HPA via negative feedback loops, while mineralcorticoids (MR) have influence on the basal level of the HPA.[121]
Hypercortisolism is associated with visceral obesity, a marker of the metabolic syndrome and Cushing’s disease alike.[122] This state of hypercortisolism is thought to have effects on obesity from several fronts. First, increased circulating cortisol may act on the foods that people desire; in a study on rats, increased corticosterone increased the levels of lard eaten when the rats were given a choice of what food to eat.[123] Secondly, glucocorticoids have been shown to induce resistance to leptin, the hormone that stimulates the sensation of satiety.[124]In rats that have had adrenalectomies performed, and thus decreased cortisol production, the anorexic effects of leptin were increased. With cortisol replacement, these anorexic effects were diminished.[124]Thirdly, hypercortisolism has been shown to increased the breakdown of muscle in Cushing’s syndrome.[125] Thus, since muscle mass is directly correlated to resting energy expenditure, patients with metabolic syndrome may not be able to expend the excess energy needed to maintain homeostatic balance. [121]
In addition to hypercortisolism resulting from the HPA, local production of cortisol also occurs through enzymes located in adipose tissue. The enzyme 11β-HSD1 may provide a possible target for the treatment of visceral obesity in patients with metabolic syndrome, as it is located within and is produced in excess by adipocytes.[103] 11β-HSD1 facilitates conversion of metabolically inactive cortisone to metabolically active cortisol thus raising glucocorticoid levels.[103,126] Coincidentally, 11β-HSD1 levels in adipose tissue mirror the levels of PAI-1 indicating a possible link between 11β-HSD1, PAI-1, metabolic syndrome, and atherosclerosis. In fact, a study found that by inhibiting the activity of 11β-HSD1 in obese mice, lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol resulted.[126] This inhibition also slowed plaque progression, decreasing the risk of atherosclerosis.[126] Utilizing the knowledge of this enzyme may lead to a possible treatment option for patients with metabolic syndrome in the future.
6. Medical Management
The primary approach to the treatment and prevention of metabolic syndrome is lifestyle change. With a substantial component of metabolic syndrome attributed to unhealthy diet and sedentary lifestyle, improvements in these areas will likewise improve clinical manifestations of this disease such as hypertension, dyslipidemia, insulin sensitivity, and glucose tolerance. [1]
The secondary approach for treatment is to treat the clinical manifestations individually. Since metabolic syndrome is a cluster of symptoms that presents uniquely between individuals, treatment with medication is handled similarly, unique to each individual. [1]
There is currently no drug therapy to treat metabolic syndrome, as a whole disease, however extensive research continues to be published yearly. As the pathophysiology of the disease becomes more understood, high volumes of research will likely shift towards drugs that target these mechanisms. For now, evidence in this area remains weak. [1]
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