Osama Hamdy, MD, PhD, FACE
This week’s excerpt covers the following topics:
- The role of cytokine hormones
- How cytokines are involved in the inflammatory processes
- The role of leptin and cardiovascular mortality
- How to diagnosis visceral adiposity
- What is the liptoxicity theory
- The protective effect of a large hip circumference
- Why liposuction does not improve metabolic parameters
- The main function of brown fat….
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 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 hematopoetic and non-hematopoetic 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 3 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-chemoattracting 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.
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. (> 40in) in American men or 88 cm. (> 35in) 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 intraabdominal 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.
Visceral Adiposity (Metabolic Obesity)
Visceral adiposity is defined as fat accumulation around the viscera and inside the intra-abdominal solid organs. Although this phenomenon is more common in overweight and obese individuals, as noted above, it can also occur in lean individuals with a normal BMI and, independent of the overall adiposity, this particular type of fat seems to play an important role in the development of type 2 diabetes and atherosclerosis. The progressive accumulation of intraabdominal fat increases hepatic and adipose-tissue insulin resistance and its consequent metabolic abnormalities like glucose intolerance, low HDL-cholesterol, elevated triglycerides and hypertension. This package of metabolic abnormalities is called the cardiometabolic syndrome, and is discussed in other contexts throughout this book, particularly in discussions of type 2 diabetes and cardiovascular complications. Some also refer to this syndrome as the insulin resistance syndrome considering insulin resistance as its fundamental etiology. It is worth mentioning that the definition of metabolic syndrome and its phenotype characteristics is far from firmly established and academic debate is ongoing over which criteria should be included, and their relative etiologic, diagnostic, and prognostic significance.
The most appealing hypothesis to explain the relationship between visceral fat accumulation and insulin resistance is that visceral adipocytes are more lipolytically active, which results in an influx of a large amount of free fatty acids into the portal circulation and to the liver. This hypothesis is called the liptoxicity theory. The other theory that has recently gained a lot of acceptance is that visceral adipose tissue and its resident macrophages and mast cells produce more proinflammatory cytokines like TNF-α and IL-6 that induce insulin resistance.
There are major ethnic and gender differences in the rate of accumulation of visceral fat. For example, African American women have a lower amount of abdominal visceral fat in comparison to white women, but much higher than African American men. Meanwhile, Japanese men and women have a significantly greater amount of abdominal visceral fat compared to Caucasians. Genetic factors like β3-adrenergic receptor polymorphism are another determinant factor of abdominal visceral fat accumulation. People with this common genetic polymorphism (~42% of the population) tend to accumulate more visceral fat. Many other factors also play a role in determining the volume of visceral fat, including:
- environmental factors
- imbalance of sex hormones (in particular low serum-free testosteronein men)
- growth hormone
- excessive intake of carbohydrates and/or saturated fat
- lack of physical activity.
Age is also a major defining factor. At any given waist circumference, older people have a larger amount of visceral fat than younger individuals.
Visceral adiposity is associated with significant lipid abnormalities that include:
- elevated serum levels of small-dense LDL-cholesterol particles
- high apo-B
- reduced HDL-cholesterol
Although central adiposity is associated with impaired insulin sensitivity and blood glucose abnormalities, isolated peripheral adiposity does not have any apparent effect on glucose homeostasis. As excessive accumulation of visceral fat also occurs in lean individuals, the term "metabolic obesity" may be a better new definition of obesity when metabolic and cardiovascular risks are considered. It may identify, more accurately, those individuals at high risk for diabetes and CAD based on their anatomical fat distribution irrespective of their corresponding BMI.
Measurement of Visceral Fat
Current knowledge makes it also possible to subdivide body fat into at least three separate and measurable compartments: subcutaneous, intramuscular and visceral fat. The current gold standard techniques for measuring visceral fat volume are the abdominal CT (at L4-L5) and the MRI. These methods are not widely used because of their cost. Commercial software is currently available for calculating visceral fat volume. Using these techniques has confirmed the original assumption that body fat is mostly localized in the subcutaneous space and only partially in the visceral area. Interestingly, they also showed that fat in the central line (around the waist) is predominately subcutaneous and not visceral. This may explain the difference in clinical value between measuring the volume of visceral fat directly and measuring it indirectly through measuring waist circumference.
Dual-energy X-ray absorptiometry (DEXA) can be used to accurately measure total body fat and regional fat distribution. DEXA is more accurate than anthropometric measures and more practical and cost effective than CT or MRI scans. However, DEXA cannot distinguish between subcutaneous and visceral abdominal fat depots, or between subcutaneous and intramuscular peripheral fat depots.
Abdominal ultrasonography is another suitable technique for measuring visceral fat. A good correlation has been found between measuring visceral fat volume using abdominal ultrasound and abdominal CT scanning. Measurements should be performed at the end of quiet inspiration and by compressing the transducer against the abdomen to limit distortion of the abdominal cavity during scanning. The distance between the peritoneum and the lumbar spine is used as a measure of visceral fat. This distance should be measured at 3 positions along the horizontal line between the highest point of iliac crest and the lower costal margin, and each measure should be repeated three times. The reproducibility of this technique is excellent with a coefficient of variability around 4–5%. Using this protocol, it may be possible to easily measure visceral fat volume in clinical practice, which may yield more reliable information than simple anthropometric measurements. Its accuracy is closer to abdominal CT or MRI while being less costly.
However for the time being, since these methods are not usually performed to assess visceral adiposity; waist circumference seems to be the easiest anthropometric measurement that can be used by healthcare professionals in order to diagnose visceral adiposity, or at least to get a rough impression of the visceral fat volume.
The Paradoxical Effect of Peripheral Fat Accumulation
There is much less data on the physiologic and clinical role of the peripheral fat mass. Interestingly, large hip circumference has been found to be an independent predictor of lower cardiovascular and diabetes-related mortality. It also seems that fat depots exhibit different influences on lipid metabolism, with central fat mass promoting and peripheral fat mass counteracting atherogenicity. Peripheral fat mass has been found to negatively correlate with both atherogenic metabolic risk factors and aortic calcification in women. Hip circumference and leg fat also showed a strong negative association with atherogenic lipid and glucose metabolites. It is interesting that a relative lack of peripheral fat leads to significantly poorer insulin sensitivity.
It is postulated that increased leg fat may reflect underlying hormonal factors (e.g. estrogen) that regulate preferential deposition of fat in the hip and thigh area. The protective effect of a large hip circumference may be due to the high lipoprotein lipase activity and low fatty acid turnover of gluteo-femoral adipose tissue. There is also evidence to suggest that peripheral fat accumulation plays an important role in modulating insulin resistance through regulating visceral fat accumulation and visceral fat production of TNF-α. In an experiment with animals, removal of peripheral fat resulted in excessive accumulation of visceral fat and more production of TNF-α. Thus, from a clinical and endocrinologic perspective, all fat is not alike!
Biological and Genetic Differences between Visceral and Subcutaneous Body Fat
It has recently been shown that the functional differences between visceral and the subcutaneous adipocytes are related to their anatomical location. The severity of atherosclerosis is significantly lower in generally obese people compared with those with predominantly central obesity. Adipocytes from the visceral abdominal region are more sensitive to lipolytic stimuli and are more resistant to suppression of lipolysis by insulin than the adipocytes from gluteo-femoral subcutaneous region. The metabolic characteristics of the adipocytes from the subcutaneous abdominal region tend to be intermediate. Consequently, the systemic flux of free fatty acids is higher in individuals with a preponderance of abdominal fat. An overexposure of hepatic and extra hepatic tissue to FFA promotes abnormal insulin dynamics and action. Moreover, abdominal fat may directly impact hepatic free fatty acid flux due to its proximity to the portal circulation, and consequently increases triglyceride synthesis and decreases hepatic insulin clearance. Other contributing mechanisms include abnormal expression and secretion of fat-derived cytokines including resistin, leptin, adiponectin, TNF-α and IL-6.
Recent evidence also indicates that there are several gene loci which determine the propensity to store fat in the abdominal region. Differences in several gene expressions in visceral fat in comparison to subcutaneous fat may account for the differences in the metabolic risks between the two fat depots. Many of those genes that are involved in glucose homeostasis, insulin action, or in lipid metabolism are expressed more in visceral fat than in subcutaneous fat.
Modification of Body Fat Distribution
Lifestyle modifications in the form of caloric restriction and increased physical activity, and medications such as metformin and PPARÝ agonists like pioglitazone and rosiglitazone, are the most common modalities used for treating insulin resistance. Except for metformin, reduction of visceral adiposity is a common feature of these interventions. Caloric restriction and exercise result in weight loss, lower W/H ratio and improvement of insulin sensitivity through reducing visceral fat and total body fat volume. In contrast, treatment with the thiazolidinediones, pioglitazone or rosiglitazone, results in weight gain but also lowers W/H ratio and improves insulin sensitivity through selective increase of subcutaneous body fat with possible reduction in visceral fat volume. PPARÝ agonists selectively stimulate adipocyte proliferation, but mostly in peripheral adipose tissue so consequently the result is body fat redistribution. This observation also confirms a site-specific responsiveness of these compounds and suggests that the improvement in insulin sensitivity with PPARÝ agonists may be a result of favorable fat redistribution in association with reduction in both intrahepatic and intramuscular fat. Treatment with these medications is discussed in more detail in Chapter 8.
Visceral fat is also sensitive to exercise. Regular exercise that is balanced between cardiovascular and resistance exercise has been shown to reduce visceral fat volume. Interestingly, most of the fat loss during the first 2 weeks of caloric restriction and exercise is from the visceral fat. But if one compares a given level of caloric deficit brought on either by caloric restriction or increased energy expenditure by exercise, the deficit brought on by the increased exercise more effectively reduces the volume of visceral fat.
Recent evidence has also shown that reducing the caloric intake from carbohydrates from 55–60% down to around 40% is associated with significant reduction of visceral fat and improvement of insulin sensitivity. If this change is associated with caloric reduction and increased protein intake from 15% to around 20–30% in patients with no microalbuminuria or impaired kidney function, it results in more weight reduction, a decrease in triglycerides and an increase in HDL.
So far, it is unclear how much reduction in visceral adipose tissue is required to induce favorable metabolic changes. It seems that even moderate reduction of visceral fat, as seen with short-term weight reduction programs, yields great metabolic benefits with regard to lipid profile, insulin sensitivity and blood pressure.
Effects of Selective Removal of Visceral or Subcutaneous Fat
Surgical removal of visceral fat in experimental animals reversed hepatic insulin resistance. It also prevented age-related deterioration in peripheral and hepatic insulin action. Meanwhile it decreased gene expression of TNF-α and leptin in subcutaneous adipose tissue. Furthermore, removal of visceral fat delayed the onset of diabetes in the Zucker fatty rats, the model of obesity and diabetes.
In contrast, surgical removal of subcutaneous adipose tissue of similar amount did not have any noticeable effect on any of the metabolic parameters. Similarly, surgical removal of large amount of abdominal subcutaneous fat by liposuction in a group of diabetic and non-diabetic individuals did not improve insulin sensitivity in muscles, liver or adipose tissues, and did not change plasma concentrations of circulating mediators of inflammation, including C-reactive protein, IL-6, and TNF-a. It also did not change blood pressure, plasma glucose, and serum insulin or lipid profile. Interestingly, the weight loss observed in this liposuction study was equal or even far more than weight loss observed in many lifestyle modification studies, yet the weight loss brought on by lifestyle changes resulted in significant improvement in insulin sensitivity and improvement of cardiovascular risk factors. The only explanation for this observation is that liposuction only reduces subcutaneous fat mass without changing visceral, intramuscular, or hepatic fat mass, which is only reduced by weight reduction brought about by diet and exercise.
Brown fat is different from white fat not only in color but also in function. Instead of being a depot for fat storage, brown fat is very efficient in burning calories. A few ounces of brown fat are enough to burn ~500 calories per day. The main function of brown fat is to keep the body warm. It is abundant in animals, including primates, and is also present in infants between their shoulder plates. Its volume reduces significantly as people age. Recent evidence shows that adults, especially lean individuals, still have very little amounts of brown fat in different areas of the upper chest area. Researchers are currently working on finding a way to increase the amount or function of brown fat as a way to increase energy expenditure and to reduce body weight in obese individuals.
So how will this growing knowledge base impact the efficacy of the clinician in his or her efforts to blunt the impact of the metabolic syndrome and its related conditions? In the past, clinicians, faced with patients who had diabetes, dyslipidemia, or other stigmata of this syndrome would tell people to "lose weight" knowing fully that the likelihood of success was small. Fad diets abounded, with their fast-off and then faster-back-on patterns. Yet, now we are on the brink of an era where many of the concepts described above, included for the first time in this edition at the risk of being more theoretical than most chapters, may very shortly be taking that final leap into daily clinical care in a very relevant way.
The understandings described above help us better appreciate how existing treatments work, both at reducing a targeted metabolic parameter for which they have a specific indication, as well as for pleiotropic effects on other metabolic manifestations mediated through underlying mechanisms which are only now beginning to be understood. New treatments are currently being developed to target these specific factors, the adipokines, and their target tissues. Dietary modifications, which address these issues more precisely, are being designed and initiated, and pharmacologic agents that target abdominal adiposity, at this writing, are undergoing FDA review. These treatments may lead to more successful weight loss programs, and more effectively blunt the impact of the endocrine effects of adipose tissue. And, certainly, understanding the issues mechanistically helps put the treatment principles discussed in the next few chapters into a perspective that is more understandable and logical. The principles of medical nutrition therapy, exercise, and pharmacologic treatment for type 2 diabetes and its macrovascular complications take on a new light in the context of the mechanisms discussed above, and a new relevance as we better understand the etiologic targets and downstream implications of our therapeutic interventions.
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