May 2010 | Vol 7 | N.º 5 | CNIC-20 [PDF (562K)]

Adipose tissue, the metabolic syndrome and atherosclerosis

Martin Laclaustra

Correspondence:
Department of Cardiovascular Epidemiology and Population Genetics, Spanish National Center for Cardiovascular Research (CNIC), C/ Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Email mlaclaustra@cnic.es

Competing interests: The author declared no competing interests.

ABSTRACT
The metabolic syndrome is characterised by a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which commonly occur together. These risk factors include high plasma triglyceride levels, the presence of small low-density lipoproteins in the plasma, low plasma high-density lipoprotein levels, high blood pressure, high fasting blood glucose levels, and the presence of a pro-thrombotic, pro-inflammatory state. The main challenge associated with this syndrome is our lack of understanding of its pathogenesis. The metabolic syndrome needs to be clearly distinguished from obesity. There are two main pathophysiological pathways present, one that is related to lipid and glycaemic disorders and another that is related to hypertension. An imbalance between energy intake and energy expenditure seems to be at the origin of the syndrome. Once the limit of adipose storage has been reached, the lipid buffering function of the tissue is hampered, and hypertriglyceridaemia and hyperglycaemia occur. This situation most commonly occurs with worsening obesity, but it can also happen when the adipose storage capacity is reduced, such as in lipodystrophy, or when hormonal regulation is disrupted, as occurs in type 1 diabetes. The permanent excessive energy inflow damages the adipose tissue and leads to inflammatory cell infiltration. An additional mechanism involves the adipokines that are secreted by adipocytes and inflammatory cells, which play a role in the network that regulates energy homeostasis and in the pathogenesis of the metabolic syndrome.

The metabolic syndrome has been defined as the presence of a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which commonly occur together more often than they should by chance alone.¹ These risk factors include high plasma triglyceride levels, the presence of small and dense LDLs (low-density lipoproteins) in the plasma, low plasma HDL (high-density lipoprotein) levels, high blood pressure, high fasting blood glucose levels, and the presence of a pro-thrombotic [characterised by elevated PAI-1 (plasminogen activator inhibitor type 1) levels], pro-inflammatory state.

Over the past 20 years, this syndrome has received increased attention given the worldwide obesity epidemics and the suspicion that insulin resistance might be the process that links all of these risk factors. However, the pathogenesis of the metabolic syndrome, as well as the pathophysiological sequence of events that lead to atherosclerosis and diabetes, continue to be strongly debated. It has been established, however, that this concept is not useful as a risk prediction tool and that recognising that the syndrome is present has no more clinical value than identifying traditional cardiovascular risk factors.^2;3 Thus, the main challenge that must be overcome with regard to the metabolic syndrome is our lack of a complete understanding of its origins and pathogenesis. If we can discover its origins, we may be to be able to provide aetiological treatments or at least break the chain of events that lead to atherosclerosis and diabetes.

The risk factors that comprise the metabolic syndrome and the actual diseases that they can be used to predict are more prevalent among obese patients.⁴ Based on this fact, obesity, in particular central obesity, which is determined by measuring patients’ waist circumference, has been included in the consensus definition of the metabolic syndrome.¹ Nonetheless, a universal waist circumference cut-off has not been identified, given that this parameter has a different distribution among races, a difficulty that exacerbates the challenge already posed by the sexual dimorphism that fat distribution exhibits.1 Unfortunately, the use of loosely defined terms has led to confusion, and obesity and the metabolic syndrome have often been considered the same thing, which they are not. Obesity is neither a sufficient nor a necessary cause of the metabolic syndrome, as there are obese subjects without these cardio-metabolic disorders and normal-weight subjects who do have them.^5;6 While obesity is defined as an increase in the proportion of adipose tissue in the body, the metabolic syndrome may occur as a consequence of deficient function of that tissue, which is not implied by merely an excess of adipose tissue.⁷

Several pathophysiological models have been proposed since the concept of the metabolic syndrome appeared. Among these, insulin resistance⁸ is no longer seen as the event that starts the syndrome.¹ Other models identify the root of the problem as a saturation of adipose tissue followed by ectopic fat deposits that cause lipotoxicity⁹ and an change in the pattern of secretion of bioactive products produced by the adipose tissue.^10-12
Most statistical factor analysis of cardio-metabolic manifestations show two main association clusters: one cluster includes obesity, dyslipidaemia, and glycaemic control problems and another cluster links obesity and hypertension.^13;14 The first cluster can be explained by an imbalance between energy intake and utilisation, which has direct consequences on the function of adipose tissue. Hypertension may be better explained in terms of vascular dysregulation and may occur as a result of the effects exerted by the hormonal and inflammatory substances that are secreted by the adipose tissue.

The characteristic lipid and glycaemic disorders can be explained in the context of impaired fat deposition in fat deposits. Adipose tissue is responsible for the post-prandial buffering of lipids and ensures that their concentration does not reach extreme levels.¹⁵ Adipose tissue can switch between an anabolic state, in which it captures fatty acids mainly from triglyceride-rich lipoproteins in the post-prandial period (triglyceride storage), and a catabolic state, in which it releases fatty acids during periods of fasting (lipolysis).¹⁶ Several factors, including the levels of certain hormones and substrates and the extent to which the adipose tissue is replete, determine the state that the adipose tissue is in and regulate the process of switching between the two states. The local inflow or outflow of fatty acids depends on the rates of lipolysis and triglyceride storage that are present and on the amount of blood that is flowing through the adipose tissue. These parameters differ during the post-prandial period and the fasting period.¹⁶

Insulin suppresses lipolysis and favours the expression and activation of lipoprotein lipase (LPL), thereby promoting fat storage in the adipose tissue. In contrast, catecholamines activate a hormone-sensitive lipase and phosphorylate perilipin, a protein that protects adipocyte fat droplets, which results in the release of fatty acids from the adipose tissue. A new triglyceride lipase that is present in adipocytes has recently been discovered, and its role in the regulation of lipolysis is a topic of current research.¹⁷

In the lipolytic state, the fatty acids that are released are processed in the liver or redistributed as very-low-density lipoproteins (VLDL), which increase in concentration in the plasma when the lipid flow increases. Fatty acids are also used in striated muscle as fuel. Whether fatty acids or carbohydrates are used as fuel at a specific moment depends on their relative abundance. However, this choice is not determined by simple competition for a catabolic pathway alone, but also relies on a complex intracellular regulatory system. For example, an excess of glucose inhibits the transport of acyl-CoA to mitochondria by increasing malonyl-CoA. Conversely, the presence of an abundance of long-chain acyl-CoA inhibits insulin-mediated glucose uptake at the receptor level (through protein kinase C phosphorylation) as well as at the insulin signal transduction pathway and at the enzymatic level, thereby limiting hexokinase activity, which catalyses the initial reaction in glycolysis.¹⁸ It has also been reported that palmitic acid diminishes insulin-mediated glucose uptake in vitro by limiting Akt-kinase phosphorylation and reducing the downstream phosphorylation cascade.¹⁹ Given the way in which this competition for the primary fuel is regulated, situations in which there is high lipid availability can mimic the situation that is present when there is impaired carbohydrate metabolism due to the absence of insulin activity.

With respect to lipid abnormalities, free fatty acids are captured by the liver and released as triglycerides within VLDLs. Under normal conditions, the VLDLs progressively transfer triglycerides to different tissues, transitioning first to IDLs (intermediate density lipoproteins) and ultimately into LDLs.²⁰ The main recipients of VLDL triglycerides are adipose and muscular tissue, but the latter only burns a noticeable amount of fat when it is active. When the adipose tissue is replete with fat, it cannot easily store more triglycerides, causing the transition of lipoproteins from VLDLs to IDLs and LDLs to slow down. As a consequence, lipoproteins accumulate in the VLDL form. In this situation, a certain amount of triglycerides are transferred to HDLs, prompting early degradation of HDLs and producing the typical profile of high triglyceride levels and low HDL levels that characterise the metabolic syndrome.²¹

Any illness or disorder that impairs the body from switching to a triglyceride storage state will cause a functional failure of the system. The most common cause of these lipid and glycaemic disorders is a chronic disequilibrium between food intake and energy expenditure. When a positive energy balance exists over a long period of time, it leads to the development of obesity. Eventually, the storage limit of the adipose tissue is reached. Nonetheless, excessive energy intake is not the only cause of the lipid and glycaemic traits that are part of the metabolic syndrome. When type 1 diabetes is not treated adequately, the functional disorders that appear due to the lack of insulin production lead to the same type of lipid profile that is present in the metabolic syndrome.²² In certain types of lipodystrophy, dyslipidaemia and insulin resistance also exist,^23;24 and the intensity of metabolic alterations depends on the extent and location of the affected regions. In these two illnesses, hypertension is usually absent or else it appears later on as a result of other complications, such as kidney disease. This fact reinforces the hypothesis that there are two separate mechanisms underlying the lipid and blood pressure manifestations of the metabolic syndrome.

The relationship between obesity and the metabolic syndrome is not simple. The association between obesity markers and metabolic syndrome factors is weak, and cardiovascular risk in obesity depends mostly on the number of associated risk factors.^2;25 Consequently, there are probably added pathophysiological elements that determine why some obese patients have the syndrome while others do not.

Overall and regional fat storage capacity and the way in which it changes during an individual’s life span are probably determined individually by a combination of genetics, sex, race and environmental exposures. Additionally, not all fat deposits are similarly capable of performing storage or buffering functions.²⁶ Gluteal-femoral subcutaneous fat, abdominal subcutaneous fat and visceral fat have different metabolic activities, a finding that suggests that they may have distinct functional specialisation.²³ Visceral fat is highly active in capturing and releasing fatty acids derived from dietary intake. Its topography is ideal for this task because the liver receives and processes the blood from the digestive system, metabolically protecting the area and preventing exposure of the rest of the body to an excess of free fatty acids.⁷ In contrast, subcutaneous fat is the main long-term energy storage site in the body, and accordingly, this tissue shows a lower lipolytic activity. In particular, the gluteus-femoral area is where the most stable and long-lasting fat deposits are created, as this site of adipose tissue undergoes lipolysis only during high-demand situations, such as breast-feeding.²³

Before body storage capacity is reached, energy is stockpiled as fat in the subcutaneous adipose tissue and the daily lipid buffering of visceral adipose tissue is preserved. However, when subcutaneous deposits are replete due to advancing obesity or to limited initial capacity (as occurs in men), visceral fat must become involved in fat storage, hindering its buffering function.⁷ Sequential fat deposit utilisation could explain why the metabolic syndrome coincides with increased visceral adiposity and why having greater subcutaneous fat deposits seems to confer some protection against it.^23;27;28 Eventually, new alternative locations for fat storage, such as the liver and, to a lesser extent, skeletal muscle, begin to store the excess fat. Fatty liver disease can degenerate into steatohepatitis. These hepatic disorders, known collectively as non-alcoholic fatty liver disease (NAFLD), are considered the hepatic component of the metabolic syndrome. Fatty infiltration of the liver has been shown to be correlated with the different components of the metabolic syndrome, independent of the presence of obesity. When this hepatic condition is present, an increased production of glucose, very low-density lipoproteins, C-reactive protein and coagulation factors may increase the risk of type 2 diabetes and atherosclerosis²⁹. When the liver becomes fatty due to NAFLD, the ability of insulin to inhibit hepatic glucose production is impaired³⁰. An increase in plasma glucose levels also occurs, leading to the stimulation of insulin secretion. Thus, some authors state that hyperinsulinaemia is likely to be the consequence rather than a cause of NAFLD³¹.

The permanent excessive energy inflow that occurs in the metabolic syndrome ultimately causes adipose tissue damage. The tissue, forced into a permanent anabolic state, is infiltrated by macrophages and other inflammatory components, and some adipocytes suffer necrosis as a result.³² These inflammatory alterations are key events in the metabolic abnormalities that appear in obesity.³³ Other morphological changes that occur in obesity that have been proposed to be involved in the metabolic syndrome are increased adipocyte size, increased total adipose tissue mass, and increased visceral adipose tissue mass, but these factors seem to be less important than adipose tissue inflammation.³⁴ The consequence is a chronic low-intensity inflammation that leads to vascular damage, resulting in conditions such as hypertension and atherosclerosis.³⁴ Additionally, injured adipose tissue triggers repair mechanisms that try to increase the tissue’s fat storage capacity. These repair mechanisms include recruiting mesenchymal precursors to become adipocytes.³⁵ In the long run, this situation might deplete the body’s pool of mesenchymal precursors and interfere with other repair mechanisms related to atherosclerosis, such as replacement of damaged endothelial cells or stabilisation of atheromatous plaques.

Adipose tissue also possesses an important secretory activity. In fact, adipose tissue has been recognised to be a very active tissue with endocrine functions. It secretes several bio-active substances known as adipokines.¹⁰ Some adipokines are secreted directly by adipocytes, like leptin and adiponectin, but others are released from the inflammatory cells that are present in the adipose tissue, like TNF-α (tumour necrosis factor-α) and interleukin-6. All of these humoral factors that are secreted from the adipose tissue, together with other hormones, such as insulin, create a complex self-regulatory network that controls energy intake, consumption and storage and, consequently, adipose volume.^36;37 When energy intake and utilisation become unbalanced, several self-regulatory changes³⁸ occur in this network that contribute to the development of the metabolic syndrome.³⁹

Leptin limits the extent of fat deposition that occurs by inhibiting appetite and consequently leading to a decrease in food intake. Leptin levels depend on adipose tissue volume, and its levels are higher in obese subjects than in normal weight subjects. As a parallel to the insulin resistance concept, acquired leptin resistance has been suggested as a possible cause for common obesity, but it seems more probable that, among obese individuals, the leptin signal is overcome by environmental pressures and lifestyle. Presumably, a decreased leptin effect is not a primary problem in common obesity. In fact, administration of exogenous leptin supplementation to obese patients did not improve their weight control or their clinical characteristics.⁷ In contrast, leptin levels are low in lipodystrophy, given the reduced number of adipocytes that produce it. In these patients, leptin replacement with exogenous leptin helps regulate energy intake and control of glycaemic and lipid abnormalities.^7;40 Adiponectin modifies metabolism so that free fatty acids are removed from the bloodstream and mainly enter fat deposits, leading to an overall insulin-sensitising effect. The serum adiponectin concentration is low among obese subjects and among those with the metabolic syndrome, and it increases with extended fasting. Adiponectin levels are inversely correlated with adipose volume. This relationship is particularly true for visceral fat compared to subcutaneous fat. Low adiponectin levels are predictive of diabetes development. Furthermore, adiponectin promotes nitric oxide production and reduces inflammation, resulting in an overall anti-atherogenic effect.⁴¹

The mechanisms linking obesity to vascular disorders and hypertension are not yet fully understood. In normal subjects, vascular beds in the adipose tissue vasodilate and have increased blood flow after meals, promoting the clearance of circulating fats by transferring them to adipose tissue droplets. In obese subjects, this post-prandial vasodilatation is reduced. This finding could be explained by an impairment in the insulin-dependent vasodilatation process, which is mediated by nitric oxide.⁴² However, this vasodilatation is also dependent on adrenergic signalling. In obese subjects, adrenergic tone rises after meals, and it rises even further in hyperinsulinaemic subjects. However, initiation of the vasodilatory signal probably requires an additional intermediate step that remains to be identified. A possibility is that adipose tissue-related factors that regulate vascular tone⁴³ are inhibited in obese subjects and that ultimately they, together with the increase in adrenergic tone that occurs, affect systemic blood pressure. Additionally, adiponectin levels decrease as blood pressure increases, suggesting that adiponectin may be another contributing factor to this process.⁷

The Aragon Worker’s Health Study (AWHS) at CNIC will follow approximately 5000 industrial workers between 20 and 65 years of age for ten years. It will focus on how cardiometabolic risk factors appear and the way in which they are associated with the obesity epidemic and the rise of diabetes. This ongoing study has already recruited 5000 participants. The follow-up includes yearly medical visits, imaging studies every 3 years (computerised tomography coronary calcium scanning and carotid and abdominal ultrasonography), and DNA extraction. We are currently analysing the association that higher levels of inflammatory cytokines and the presence of oxidative damage in lipids have with insulin sensitivity. We will also study the association that physical inactivity and weight gain have with the progression of the metabolic syndrome and the development of subclinical atherosclerosis.

The Progression of Early Subclinical Atherosclerosis (PESA) study will include 4000 office workers between 40 and 54 years of age. Over a 9-year period, these workers will be evaluated 3 times. These evaluations will include taking detailed histories regarding patients’ dietary habits and performing objective measurements of physical activity through portable accelerometers. Blood and urine samples will be taken to perform genomic, transcriptomic and metabolomic studies and to chart the development of metabolic and cardiovascular risk factors and subclinical atherosclerosis. This study will be possible due to computerised tomography coronary calcium scanning studies and 3D ultrasound studies of the carotid artery and abdominal aorta. In one subgroup, magnetic resonance imaging will allow us to study the inflammation of atherosclerotic plaques as well as whole body fat distribution. Additionally, one million SNP microarrays will be used to evaluate the genetic characteristics of the participants.

In summary,an imbalance between caloric intake and energy expenditure seems to be a determinant of the metabolic syndrome, regardless of whether obesity is present. Accordingly, treatment should primarily consist of caloric restriction and promotion of physical activity. The volume of each one of an individual’s fat deposits and personal differences in their capacity to increase the size of these deposits may help explain inter-individual differences in patients’ susceptibility to the metabolic syndrome. Given that adipokines participate in the network that regulates energy homeostasis and intervenes in the pathogenesis of the metabolic syndrome, they may be used as therapeutic targets or as markers of the metabolic syndrome in the future. At CNIC, we are currently gathering data from the AWHS and PESA studies that will allow us to gain a better understanding of the dynamics of metabolic cardiovascular risk factors and their relationship to the development of subclinical atherosclerosis.