A Possible Key in Understanding the Metabolic Mysteries
Osama Hamdy, MD, PhD, FACE
(Note to our readers: we inadvertently skipped a number in this series of text excerpts so there was no "Excerpt #21." Our apologies for any confusion, and thanks to the sharp-eyed reader who pointed this out!)
The week’s excerpt answers the following questions:
- How adipose tissue can function as an endocrine organ.
- The role of adipocytes as an active endocrine organ whose metabolic and secretory products (hormones, prohormones, cytokines and enzymes) play a major role in total-body metabolism.
- How the cytokine hormones play a role in cardiovascular health
- Which treatments may impact adipokines
- Can TZD’s normalize or even increase adiponectin gene expression
- How different treatments impacting adiponectin can be the key as to how certain treatments will respond
Today, we are looking at fat in a whole new light. Until recently, adipose tissue was regarded as a passive depot for lipids that somehow contributed to the metabolic and cardiovascular burden, but in and of itself was an inert bulk. How wrong we seem to have been. There is now increasing evidence which points to an important role of adipocytes as an active endocrine organ whose metabolic and secretory products (hormones, prohormones, cytokines and enzymes) play a major role in total-body metabolism.
This chapter, new to this edition, explores our evolving understanding of the role of adipose tissue as an active organ, producing substances that may play a central role in the development of type 2 diabetes and the vascular dysfunction that often accompanies it. As the concept that adipose tissue can function as an endocrine organ is a relatively new concept for clinicians, we have devoted this chapter to a more in-depth look at what is known in this area. The more practical treatment recommendations follow in Chapter 5, for those who are looking for more of the applicability of nutritional principles to diabetes management. However, the implications of adipose tissue as an active metabolic organ will undoubtedly expand over the next few years, impacting treatments for the hyperglycemia of type 2 diabetes as well as therapies for other components of the metabolic syndrome. Thus, this material sheds an exciting new light on many of the existing treatments discussed elsewhere in this book. Certainly, it provides a rationale for many of the nutritional recommendations that you will find in the chapter that follows. Further, newer treatments are on the horizon which target adipose tissue and the endocrine secretions of this tissue. Thus, it is likely that during the useful lifetime of this book, clinicians will hear more about these potential new treatments. The background information provided by this chapter should be helpful in understanding the importance of such treatments and in putting them into a proper therapeutic and pharmacologic context.
Therefore, in this chapter, we indulge in a discussion of evolving physiologic perspectives — perspectives with a very practical implication which, increasingly, are being recognized as perhaps the etiologic keys to many of the treatments we have been using for decades, and some that are on the horizon.
Understanding the Endocrinologic Role of Adipose Tissue
It has been largely over the past decade that we have learned that the impact of obesity on both insulin resistance and endothelial dysfunction (the early stage of atherosclerosis) is mediated through the release of the cytokine hormones produced in the adipose tissue. Cytokines are proteins produced in hematopoietic and non-hematopoietic cell types, which play a role in immune responses. Their dysfunctional secretion often plays a role in immunological, inflammatory, and infectious diseases. The cytokine hormones produced by adipose are collectively called adipocytokines or adipokines.
It has been evident from studies in recent years that the components of the cardiometabolic syndrome may be mediated through a common underlying cardiometabolic process. The cardiometabolic syndrome is the clustering of metabolic abnormalities, discussed in more detail in Chapters 7 and 15, but defined by the presence of at least three of the following: elevated triglycerides, low HDL, elevated fasting glucose, increased waist circumference, and/or elevated blood pressure. Insulin resistance has been thought to be the common thread in this syndrome, but the role of the inflammatory process has also been implicated in both its etiology and the mechanisms by which the syndrome leads to vascular dysfunction. Therefore, pathophysiologic interrelationships among these vascular risk factors are likely to be of importance, and from a clinical perspective, whatever can be determined to increase insulin resistance and/or the inflammatory response becomes a potential treatment target.
It is for this reason that the products of adipose tissue, the adipokines, have become the focus of a great deal of interest for their potential etiologic role in the cardiometabolic syndrome and vascular disease, and are likely to become even more relevant clinically as treatments targeting them are developed. The adipokines are a group of pharmacologically active proteins which, like other cytokines, are related to inflammatory processes and stimulation of the immune system. They also play an important role in the adipose tissue physiology and in initiating several metabolic and cardiovascular abnormalities, not only in overweight and obese individuals, but also in some lean persons with higher visceral fat mass. These adipokines include adiponectin, leptin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocytes-chemo-attracting protein (MCP-1) and plasminogen-activating inhibitor-I (PAI-1) among many others.
An increased amount of adipose tissue, with a disproportionate distribution between central and peripheral body regions, is related to altered serum levels of these cytokines, which can have significant clinical consequences. Except for leptin and adiponectin, other cytokines are produced not only from fat cells but also from the macrophages that infiltrate and reside in the adipose-tissue. It has been seen that when people get older or fatter, more macrophages and mast cells infiltrate the adipose tissue and consequently produce more proinflammatory cytokines.
In contrast to the harmful effect of most cytokines, adiponectin, a cytokine also produced by adipose tissue, has beneficial effects, and protects against the later development of type 2 diabetes. Adiponectin is relatively abundant in plasma and at generally higher levels among women than men. Low plasma adiponectin is found in obese individuals and in patients with coronary artery disease. A ten percent body weight reduction leads to a significant increase in the adiponectin level (40-60%) in both obese individuals with or without type 2 diabetes.
Therefore, one way to look at the pharmacology of the various treatments of type 2 diabetes is to think of how those treatments may impact adipokines. For example, it has been reported that treatment with thiazolidinediones (e.g., pioglitazone and rosiglitazone, see Chapter 8) may normalize or even increase adiponectin gene expression. In one study, the administration of thiazolidinediones for 3 months resulted in increased adiponectin levels in both lean, obese individuals with and without type 2 diabetes. Adiponectin is also involved in the modulation of inflammatory responses, as it seems to attenuate the pro-inflammatory effect of TNF-α and reduce the number of adipose tissue resident macrophages. It has also been shown that adiponectin inhibits many functions of mature macrophage, such as the cytokine production discussed above, as well as phagocytosis. Adiponectin also modulates endothelial function and has an inhibitory effect on proliferation of vascular smooth muscles. Therefore, in trying to understand how the various treatments for type 2 diabetes may work to reduce not only hyperglycemia, but the risk of vascular disease, the impact on adiponectin may hold the key.
Leptin is another adipocyte-derived hormone that circulates in the serum. The physiologic effects of leptin, mediated either through direct stimulation or through activation of specific centers in the hypothalamus, are to decrease food intake, increase energy expenditure, influence glucose and fat metabolism and alter neuroendocrine function. Serum levels of leptin increase with increased fat mass, however it does not seem to suppress the appetite of obese individuals, which raises the possibility of leptin resistance in obese individuals, similar to insulin resistance. Leptin secretion follows a circadian pattern, being the highest during night. Alteration of this circadian pattern or attenuation of leptin secretion by night leads to the night eating syndrome, whereby affected individuals consume a significant amount of calories by night and have a markedly suppressed appetite in the morning.
What is very interesting about leptin is that it is expressed predominantly by subcutaneous rather than visceral fat cells. Women also seem to have higher leptin levels than men, which could be either related to the increased percentage of peripheral body fat in women, or a result of stimulation of leptin production by estrogen/progesterone. Loss of subcutaneous fat as seen in marathon runners results in amenorrhea, which can be corrected by leptin injection. Studies have demonstrated that fat mass and gender are the main independent predictors of leptin concentration in people with type 2 diabetes, and that insulin secretion and the degree of insulin resistance contribute significantly to leptin levels. Leptin therapy in lipodystrophic patients was shown to improve hepatic and peripheral glucose metabolism and reduce hepatic and muscle triglyceride content, suggesting that leptin acts as a signal that contributes to regulation of total body sensitivity to insulin. It was also found that leptin was independently associated with cardiovascular mortality.
Although both adiponectin and leptin are integrally related to the metabolic or "insulin resistance" syndrome, adiponectin is more strongly related to the presence of visceral abdominal fat, while leptin is more closely related to the presence of subcutaneous fat content. The implications of that association are still not fully understood, and in the coming years, further research will undoubtedly shed additional light on the relationships between these two adipokines, as well as their relationships to adiposity and disease. This work may also lead to the prospect of their clinical use as targets or mediators in the treatment of overweight and obese subjects with insulin resistance or the metabolic syndrome. Several trials are ongoing using leptin alone or in combination with other appetite suppressing hormones for treatment of obesity.
Harmful Effects of Some Adipokines
Many of the adipokines have harmful physiologic effects that are now being recognized as being of clinical importance in the etiology of vascular disease. As we consider the many treatments discussed later in this book, which seek to reduce the risk of vascular disease, the targeting of the inflammatory process may be a key underlying pharmacologic mechanism. With this in mind, it has become clear that adipose tissue is a major source of such pro-inflammatory cytokines such as TNF-α. Obesity in humans is associated with increased production of TNF-α and also increased gene expression of its receptors. TNF-α is known to be directly linked to cardiovascular disease. Plasma levels of TNF-α have been shown to be increased in individuals with premature cardiovascular disease independent of insulin sensitivity. Table 4-1 below outlines many of the roles in the pathogenesis of the vascular lesion that have been postulated for TNF-α.
TABLE 4-1. Roles of TNF- in the pathogenesis of the vascular lesion
|• Stimulates the production of adhesion molecules on the surface of the vascular endothelium, which work like a glue that traps the circulating monocytes from the blood stream.
• It then stimulates the migration of these trapped monocytes through the endothelial barrier to the subendothelial area where they are transformed into macrophages, which engulf the oxidized LDL and are themselves transformed into the foam cells that form the core of the atheromatous plaque.
• Stimulates the migration and proliferation of the vascular smooth muscle cells.
• Stimulates the production of the proteolytic enzymes that facilitate the rupture of the fibrous cap that would otherwise protect and separate the atheromatous plaque from the vascular lumen. Once exposed to the flowing blood, platelet aggregation and clot formation is likely to occur.
• Increases with obesity; has also been noted to decrease significantly with weight reduction.
PAI-1 is another important bioactive substance produced by adipose tissue. While PAI-1 gene expression has been detected in both subcutaneous and visceral fat, it correlates better with visceral adiposity. High level of PAI-1 is a strong indicator of increased cardiovascular risk. In humans, it has been shown that improvement in insulin sensitivity, either through weight reduction or medications, lowers circulating levels of PAI-1. Such decrease was found to correlate with the amount of weight lost and also with the degree of decline in serum triglycerides.
Body Fat Distribution and Cardiovascular Risk
Over the last few years, it has become evident that central fat distribution (the so-called "apple-shaped" body) is more strongly associated with several metabolic and cardiovascular problems than total adiposity. This relationship between increased visceral adiposity and the risk of developing type 2 diabetes and CAD seems to also be related to the increased presence of the recognized coronary heart disease risk factors such as hyperglycemia, hypertension and dyslipidemia. It is, in fact, the waist circumference that is the key measure relating to risk profiling. For people with the same BMI, those with a larger waist circumference are at a significantly increased risk for coronary artery disease. In clinical practice, the waist circumference and waist to hip ratio (WHR) are the commonly used anthropometric measures to diagnose abdominal obesity. These measures correlate with the total amount of visceral fat measured by abdominal CT scanning.
As a result of the recognition of these relationships, the Adult-Treatment Panel III (ATP-III) of the National Cholesterol Education Program has adopted the increased waist circumference as a major criterion for clinical diagnosis of the metabolic syndrome. A waist circumference of equal to or greater than 102 cm. (> 40") in American men or 88 cm. (>35") in American women is a cut off for increased risk. More importantly, accumulation of visceral fat remains also the major independent cardiovascular risk factor, even within the normal range of body mass index (BMI), and even at lower waist circumference than the above mentioned figures in certain ethic populations such as Asian, Indian and Chinese. This observation leads researchers and clinicians alike to believe that clinical diagnosis of visceral adiposity (metabolic obesity) may be more important than the current diagnosis of obesity using body mass index (BMI), body weight or even percentage of total body fat.
Accumulating evidence also points to a major difference between the intra-abdominal visceral fat and the peripheral or subcutaneous fat in the pathogenesis of these medical problems, both in lean and obese individuals. In contrast to the accumulation of fat in the gluteo-femoral regions, the accumulated fat in the intra-abdominal or visceral depots is strongly associated with all obesity-related complications. The relationship between visceral fat, as quantified by abdominal CT scanning, and CAD seems to be independent of age, BMI and the amount of subcutaneous fat in men with familial hypercholesterolemia. Moreover, abdominal obesity was also found to be associated with accelerated atherosclerosis independent of overall obesity and other risk factors in middle-aged men with no prior atherosclerotic disease.
Next Joslin Excerpt: Visceral Adiposity (Metabolic Obesity)
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