Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #23: Adipose Tissue as an Endocrine Gland

A Possible Key in Understanding the Metabolic Mysteries, Part 2

Osama Hamdy, MD, PhD, FACE

The weeks excerpt answers the following questions:

• What is the liptoxicity theory?
• How best to measure visceral fat?
• Is all fat the same? 
• What is "metabolic obesity"?
• What are the 3 kinds of fat?
• Does liposuction improve diabetes control?
• Which reduces visceral fat more effectively, exercise or caloric restriction?…

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 intra-abdominal 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 testosterone in men)
• growth hormone
• IGF-1
• insulin
• 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
• hypertriglyceridemia
• reduced HDL-cholesterol

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 PPAR_Ý 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. PPAR_Ý 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 PPAR_Ý 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-α. 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.

Next Joslin Excerpt: Chapter 6 Physical Activity for Fitness

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