Adiposopathy

Adiposopathy (or sick fat) is a proposed cardiovascular disease (CVD)[1] caused by diseased fat tissue which may explain the anatomical and/or functional changes to fat cells which may indirectly increase other CVD risk, and may be a contributor to the metabolic syndrome.[2][3][4]

Pathophysiology

Anatomy

Diseased fat tissue surrounding various organs can cause illness, such as fat surrounding the heart, muscle, vessels, eyes, and bone.[5] Some have suggested that diseased fat tissue surrounding the heart and vessels can contribute to inflammation and plaque rupture.[6] 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.[7] 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.[8]

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.

One potentially unfavorable effect of leptin is to increase blood pressure, as observed in animals.[9] In humans, the observation of leptin-induced hypertension is not as yet conclusive.[10] 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 triglycerides 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, muscle, and pancreas, 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.[11]

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 formation (angiogenesis); (2) fat cell recruitment and development adipogenesis; (3) dissolving and reforming the structures around fat tissue (extracellular matrix); (4) generation, storage and release of fat; (5) growth factor production; (6) glucose metabolism; (6) production of factors that affect blood pressure (such as those associated with the renin–angiotensin system); (7) fat and cholesterol metabolism; (8) enzyme production; (9) hormone production; (10) steroid metabolism; (11) blood clotting (hemostasis); (12) element 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.[12] When excessive body weight leads to adiposopathy, this represents a hormone or endocrine disease.[13] Additionally, fat cells and fat tissue also produce many different types of immune factors.[5] Inflammation 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:[14] (1) adipokines with cytokine activity such as leptin, interleukins, and tumor necrosis factor alpha; (2) acute phase proteins / reactants such as C-reactive protein; (3) adipokines of the alternative complement system; (4) chemotactic/chemoattractant adipokines; and prostaglandins (eicosanoids). From an anti-inflammatory standpoint, fat tissue produces various anti-inflammatory factors [14] with the most commonly described being adiponectin. 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.[12]

History

It has been known since the 1970s that when fat cells become too big, they may become bloated and dysfunctional, or "sick".[15] 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.[16] 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.[17] 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 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,[14] and immune organ.[5] 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". The metabolic syndrome 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.[18] 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.[19] However, different scientific and medical organizations have different definitions for the "metabolic syndrome". Also, the term "metabolic syndrome" does not describe, nor is it intended to describe a unifying cause of any disease.[20] Since "metabolic syndrome" is not a disease, regulatory agencies (such as the Food and Drug Administration) do not approve drugs to treat metabolic syndrome, as a specific indicated use. Finally, the "metabolic syndrome" may be no better at predicting atherosclerotic coronary heart disease than an assessment of its individual components.[21] As such, major scientific and medical organizations have questioned the usefulness of the metabolic syndrome, sometimes in open conflict with other major scientific and medical organizations.[20][22]

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)."[23] 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 adiposopathy 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.[13] Their final conclusion was that "adiposopathy is an endocrine disease".

See also

References

This article incorporates material from the Citizendium article "Adiposopathy", which is licensed under the Creative Commons Attribution-ShareAlike 3.0 Unported License but not under the GFDL.

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  2. Kershaw, EE; Flier, JS (2004). "Adipose tissue as an endocrine organ". The Journal of Clinical Endocrinology and Metabolism. 89 (6): 2548–56. doi:10.1210/jc.2004-0395. PMID 15181022.
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