Adiposopathy
Encyclopedia
Adiposopathy refers to certain classes of dysfunction of fat cells. The dysfunctions in question may contribute to many of the adverse metabolic conditions associated with obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

 and the associated metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

.

Diagnosis

Currently, no accepted diagnostic
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

 criteria exist for adiposopathy. Although medical and scientific organizations increasingly acknowledge the central importance of fat tissue in causing metabolic disease, there is no general agreement as yet on how best to diagnose adiposopathy. Proposed criteria include:
Major criteria:
  • Elevated waist circumference or BMI
  • Onset or worsening of high blood sugar with weight gain
  • Onset or worsening of high blood pressure with weight gain
  • Onset or worsening of dyslipidemia with weight gain

Minor criteria:
  • Increase in free fatty acids with weight gain
  • Fatty liver with weight gain
  • Increase in male hormones in women with weight gain
  • Decrease in male hormone in men with weight gain
  • Increase in hormones such as leptin and insulin with weight gain
  • Increase in immune factors (such as C-Reactive protein, interleukin-6, and tumor necrosis alpha) with weight gain
  • Abnormalities in lipoprotein particle size with weight gain

Anatomy

Diseased fat tissue surrounding various organs can cause illness, such as fat surrounding the heart, muscle, vessels, eyes, and bone. Some have suggested that diseased fat tissue surrounding the heart and vessels can contribute to inflammation and plaque rupture. Although not as well recognized, even the so-called “protective” subcutaneous fat tissue has the potential to be “sick” and contribute to metabolic disease. A prime example would be subcutaneous fat tissue found in the abdominal region. Accumulation of fat tissue in this region may have hormonal and immune activity, and thus the potential to cause metabolic disease, between that of visceral fat tissue and other areas of subcutaneous fat tissue.

However, other subcutaneous fat tissues also might contribute to metabolic disease, if the fat cells become too enlarged and “sick.” Admittedly, subcutaneous fat cells typically are larger, and capable of storing more fat when needed. However, subcutaneous fat tissue represents the largest proportion of fat tissue in the body, and is the major source of leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...

.

One potentially unfavorable effect of leptin is to increase blood pressure, as observed in animals. In humans, the observation of leptin-induced hypertension is not as yet conclusive. But to the extent that leptin may increase blood pressure, then the increase in leptin with subcutaneous fat cells (particularly when they become enlarged) could hardly be characterized as “protective.”

Other potentially detrimental effects of enlarged subcutaneous fat tissue relate to free fatty acids. During fasting, the body can obtain energy through the release of free fatty acids from the triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

s in fat cells. The fatty acids thus become available for release into the blood. If too high a concentration of certain fatty acids accumulates in the blood because of sick fat tissue, and the body is unable to recruit more healthy fat cells, then existing healthy fat cells become engorged (and thus also sick). The result is that blood fatty acid concentrations increase to levels toxic to tissues such as liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

, and pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

, and lead to a range of pathological metabolic conditions.

There are grounds for suspicion that sick abdominal fat tissue may produce factors that cause subcutaneous fat tissue to also become “sick” and further contribute to metabolic diseases.

In summary, although abdominal or visceral fat tissue is best described to contribute to metabolic disease, abdominal fat is by no means the only fat tissue depot that has the potential to become “sick” and capable of contributing to metabolic ill health.

Physiology

Fat tissue is an active body organ involved in many processes critical to human health,8 including: (1) promotion of blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

 formation (angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

); (2) fat cell recruitment and development adipogenesis; (3) dissolving and reforming the structures around fat tissue (extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

); (4) generation, storage and release of fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...

; (5) growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

 production; (6) glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 metabolism; (6) production of factors that affect blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...

 (such as those associated with the renin-angiotensin system
Renin-angiotensin system
The renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....

); (7) fat and cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 metabolism; (8) enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 production; (9) hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 production; (10) steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...

 metabolism; (11) blood clotting (hemostasis
Hemostasis
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...

); (12) element
Chemical element
A chemical element is a pure chemical substance consisting of one type of atom distinguished by its atomic number, which is the number of protons in its nucleus. Familiar examples of elements include carbon, oxygen, aluminum, iron, copper, gold, mercury, and lead.As of November 2011, 118 elements...

 binding; (13) and immune response (described below). When fat cells and fat tissue remain healthy during fat weight gain, patients may avoid metabolic ill health. However, if enlargement of fat cells and fat tissue causes them to become “sick,” then important fat tissue functions are disrupted, and deranged responses contribute to metabolic disease.
When excessive body weight leads to adiposopathy, this represents a hormone or endocrine disease. Additionally, fat cells and fat tissue also produce many different types of immune factors. Inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 is a contributing cause to metabolic disease, and the ultimate contribution of fat tissue to inflammation is determined by the production of both inflammatory and anti-inflammatory factors. From a pro-inflammatory standpoint, fat tissue (which includes fat cells and other cells, such as immune cells) produces factors including: (1) adipokines with cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

 activity such as leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...

, interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...

s, and tumor necrosis factor alpha); (2) acute phase proteins / reactants such as C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

; (3) adipokines of the alternative complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

; (4) chemotactic/chemoattractant adipokines; and prostaglandins (eicosanoids). From an anti-inflammatory standpoint, fat tissue produces various anti-inflammatory factors with the most commonly described being adiponectin
Adiponectin
Adiponectin is a protein which in humans is encoded by the ADIPOQ gene.- Structure :...

. If fat cells or fat tissue becomes “sick,” then the release of too many pro-inflammatory factors and a decrease in too many anti-inflammatory factors often result in a net pro-inflammatory response can contribute to metabolic disease.

Treatment

Because no accepted diagnostic criteria for adiposopathy exist, then no drugs have received specific treatment indications by regulatory agencies to treat “sick fat.” However, weight loss therapies in overweight patients not only improve, or sometimes normalize various fat tissue factors that may cause or contribute to metabolic disease, but also improve and sometimes “cure” metabolic diseases such as type 2 diabetes mellitus, hypertension, and dyslipidemia.
By doing so, these therapies (which includes appropriate diet and physical exercise) effectively treat adiposopathy or "sick fat."
Additionally, drugs that increase the recruitment of new, healthy fat cells may also help treat metabolic diseases. For example, peroxisome proliferator-activated receptor (PPAR) gamma agents are commonly used drugs to treat type 2 diabetes mellitus. Pioglitazone is an example of a PPAR gamma agonist drug that lowers blood sugar and improves lipid levels. As part of PPAR gamma drugs’ mechanism of action is increasing the amount of functional or healthy fat tissue. As a result, many patients treated with these types of drugs increase body fat. Initially, it may seem odd and almost paradoxical to use a drug that increases fat tissue to treat metabolic diseases that are caused by too much fat tissue. However, when explained through the concept adiposopathy, no such paradox exists. Because PPAR gamma agents work by increasing the amount of healthy, functional fat, decreasing the proportion of sick abdominal fat tissue, and decrease “fatty liver.” All of these effects upon fat tissue are effective in treating sick fat and improving metabolic disease. Thus, it is within the framework of “sick” versus “healthy” fat, that the rationale behind the use of these drugs is easier to understand.

History

It has been known since the 1970s that when fat cells become too big, they may become bloated and dysfunctional, or “sick.” It has also been known since the 1940s that if fat gain occurs in the belly or abdominal (visceral) region, that this is another example of sick fat that promotes metabolic diseases. Finally, if fat growth exceeds its blood vessel supply, then the lack of oxygen delivery by the blood may also result in pathologic responses from fat tissue. In summary, it has been known for decades that adverse changes in fat cell and fat tissue anatomy result in sick fat which causes metabolic disease.
More recently, an additional event that has prompted the concept and term of “adiposopathy” is the evolving recognition of the profound hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 and immune importance of fat tissue. In the past, fat cells and fat tissue were considered by many as being inert, or hormonally and immunologically inactive. However, this has been proven incorrect, and it is now generally accepted that fat tissue is an active hormone, and immune organ.
Yet another historical event that moved medical science towards recognizing fat tissue as an underlying cause of metabolic disease has been the problematic issues that have arisen with the “metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

.” The metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

 is a commonly used medical term to describe atherosclerotic coronary heart disease risk factors that tend to cluster together. Over the years, there have been at least 15 other similar terms used to generally describe the same clustering. According to one common definition, a patient is said to have “metabolic syndrome” if he or she has 3 or more the 5 following criteria: (1) abdominal obesity, (2) elevated triglycerides, (3) reduced high density lipoprotein cholesterol levels, (4) high blood pressure, and (5) high blood sugar. However, different scientific and medical organizations have different definitions for the “metabolic syndrome.” Also, the term “metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

” does not describe, nor is it intended to describe a unifying cause of any disease. Since “metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

” is not a disease, regulatory agencies (such as the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

) do not approve drugs to treat metabolic syndrome, as a specific indicated use. Finally, the “metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

” may be no better at predicting atherosclerotic coronary heart disease than an assessment of its individual components. As such, major scientific and medical organizations have questioned the usefulness of the metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

, sometimes in open conflict with other major scientific and medical organizations.

Society and culture

The scientific and medical organizations are not alone in grappling with if and/or when too much body fat is actually a “disease.” Many patients and clinicians have the same uncertainties. This is reflected by the attitude of many of the public as well. Many are often resistant to the idea that gaining too much fat is a disease, for a number of reasons. One illustrative example in pop culture would be the “song” entitled: " Underwear Goes Inside the Pants
Underwear Goes Inside the Pants
"Underwear Goes Inside the Pants" is a song by Lazyboy, which is a musical project combining spoken word with hip-hop beats and other musical styles, with vocals on this track by stand-up comedian Greg Giraldo...

 " performed by Lazyboy in the album Lazyboy TV (2004). An excerpt of the publicly disclosed lyrics includes:

Given all the problems with medical terms such as overweight
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...

, obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

, and metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

in describing when excessive body fat is a disease, adiposopathy has emerged as a term that reflects the fact that adipose (fat) tissue is no less capable of being diseased than any other body organ. The addition of the suffix “pathy” to an organ is not only accepted, but an historic universal identifier as to when a body tissue is diseased. Cardiomyopathy describes heart (cardiac) disease; myopathy describes muscle disease; encephalopathy describes brain disease; ophthalmopathy describes eye disease; retinopathy describes eye disease; enteropathy describes intestine disease; nephropathy describes kidney disease; neuropathy describes nerve disease; and dermopathy describes skin disease. Adiposopathy describes the disease of fat cell and fat tissue that frequently occurs with excessive fat weight gain.

Research and future directions

Regarding drug therapies, it has been stated that: "An emerging concept is that the development of anti-obesity agents must not only reduce fat mass (adiposity) but must also correct fat dysfunction (adiposopathy)." This is in recognition that the use of weight loss therapies and drugs in overweight patients must not only improve the weight of patients, but must also improve the health of patients. Unfortunately, not everyone understands the central role that sick fat plays in the development of metabolic disease. This is partly because in the past, most of the attention of what causes metabolic disease was given to other body organs. In the past, the importance of fat tissue was often ignored, even as the obesity epidemic was contributing to the epidemic of metabolic diseases such as type 2 diabetes mellitus, hypertension, and dyslipidemia.
This has placed many clinical scientists at odds with basic researchers, clinicians and patients. The animal data supporting adiposopathy as a contributing cause to metabolic disease is overwhelming. Clinicians and patients well know through “real life” experiences that gaining body fat often causes patients to develop or worsen high blood sugar (diabetes mellitus), high blood pressure (hypertension), and dyslipidemia (abnormal cholesterol or fats in the blood). In fact, clinicians often recommend, and patients often expect that weight reduction efforts will improve, if not cure these metabolic diseases. However, many clinical scientists and even medical organizations continue to resist what is obvious to others, and that is that fat cells and fat tissue are hormonally and immunologically active. Many refuse to acknowledge the scientific and clinical evidence that too much body fat can cause or worsen metabolic disease, if the fat becomes sick.
In order to give greater recognition to the “adipocentric” (fat tissue as a central cause) paradigm of metabolic disease, a “Adiposopathy Working Group” was assembled to develop a consensus regarding whether adipospathy was truly an endocrine disease. In 2008, this group of experts in both the scientific and clinical field of Endocrinology reported their opinions in the International Journal of Clinical Practice. In this consensus paper encompassing approximately 2 years of research, the authors addressed the many philosophical misconceptions, and unfounded/uninformed facts regarding the relationship of adiposopathy to metabolic disease. Their final conclusion was that: “Adiposopathy is an endocrine disease.”
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