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Adiposopathy (or sick fat) refers to the dysfunction of fat cells.[1] This dysfunction may contribute to many of the adverse metabolic conditions associated with obesity and metabolic syndrome.[2][3][4]

Diagnosis

Currently, no accepted diagnostic criteria exist for adiposopathy. Although medical and scientific organizations are increasingly acknowledging the central importance of fat tissue in causing metabolic disease, they have not yet agreed upon how adiposopathy is best diagnosed. Proposed criteria[5] 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

Pathophysiology

Anatomy

Diseased fat tissue surrounding various organs can cause illness, such as fat surrounding the heart, muscle, vessels, eyes, and bone.[6] Some have speculated that diseased fat tissue surrounding the heart and vessels can contribute to inflammation and plaque rupture.[7] 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.[8] 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.[9] However, even other subcutaneous fat tissues might contribute to metabolic disease, if the fat cells become too enlarged and “sick.” Admittedly, subcutaneous fat cells are typically larger, and more capable of storing fat when needed. However, subcutaneous fat tissue represents the large majority of fat tissue in the body, and is the major source of leptin, which is a factor produced by fat cells that has a number of functions. Among the potentially unfavorable effect of leptin is that leptin increases blood pressure, most well described in animals.[10] In humans, leptin-induced hypertension is less conclusive.[11] 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 is in regard to free fatty acids.8 Triglycerides (fats) are the major constituents found and stored in fat cells, and are composed of a glycerol backbone, attached to three carbon chain fatty acids (hence the “tri” in “triglycerides”). During fasting, the body can obtain energy through the release of free fatty acids from the triglycerides in fat cells, which are then released into the blood. If too many certain fatty acids are released into the blood because fat tissue is sick and unable to recruit more fat cells, and existing fat cells become to big (and thus also sick), then the increase in fatty acids are “toxic” to organs such as the liver, muscle, and pancreas, and lead to metabolic disease. 15 Some have suggested that sick abdominal fat tissue may send out factors that cause subcutaneous fat tissue to also become “sick” and further contribute to metabolic diseases.[12] 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.[13] When excessive body weight leads to adiposopathy, this represents a hormone or endocrine disease.[14] Additionally, fat cells and fat tissue also produce many different types of immune factors.[6] 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:[15] (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 [15] 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.[13]

Treatment

Because no accepted diagnostic criteria for adiposopathy exist, then no drugs have received specific treatment indications by regulatory agencies to treat “sick fat.”[16] 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. [17][9] 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.[18] 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 1970’s that when fat cells become too big, they may become bloated and dysfunctional, or “sick.”[19] It has also been known since the 1940’s that if fat gain occurs in the belly or abdominal (visceral) region, that this is another example of sick fat that promotes metabolic diseases.[20] 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.[21] 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,[15] and immune organ.[6] 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.[22] 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.[23] 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.[24] 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.[25] 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.[24][26]

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

Americans, let’s face it: We’ve been a spoiled country for a long time.
Do you know what the number one health risk in America is?
Obesity, obesity
They say we’re in the middle of an obesity epidemic.
An epidemic like its polio.
Like we’ll be telling our grandkids about it one day.
The Great Obesity Epidemic of 2004.
“How’d you get through it grandpa??”
“Oh, it was horrible Johnny, but there was cheesecake and pork chops everywhere.”
Nobody knows why we’re getting fatter? Look at our lifestyles.
I’ll sit at a drive through.
I’ll sit there behind fifteen other cars instead of getting up and making the eight foot walk over to the totally empty counter.
Everything is mega meal, supersize. You want biggy fries with that, you want a jumbo fry, you wanna go large.
You wanna biggie fry,
You want thirty burgers for a nickel you fat mother f****r. There’s room in the bag. Take it!
You want a 55 gallon drum of coke with that? It’s only three more cents.

Given all the problems with medical terms such as overweight, obesity, and metabolic syndrome 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 as 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.[15][17] 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 antiobesity agents must not only reduce fat mass (adiposity) but must also correct fat dysfunction (adiposopathy)."[27] 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.[14] 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.”

Attribution

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References

  1. ↑ Bays H, Dujovne CA (March 2006). "Adiposopathy is a more rational treatment target for metabolic disease than obesity alone". Curr Atheroscler Rep 8 (2): 144–56. PMID 16510049. [e]
  2. ↑ Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004 June;89(6):2548-56. PMID 15181022
  3. ↑ Miner JL. The adipocyte as an endocrine cell. J Anim Sci 2004 March;82(3):935-41. PMID 15032452
  4. ↑ Caspar-Bauguil S, Cousin B, Galinier A, Segafredo C, Nibbelink M, André M, Casteilla L, Pénicaud L. Adipose tissues as an ancestral immune organ: site-specific change in obesity. FEBS Lett 2005 July 4;579(17):3487-92. PMID 15953605
  5. ↑ Bays H, Abate N, Chandalia M. Adiposopathy: Sick fat causes high blood sugar, high blood pressure, and dyslipidemia. Future Cardiology 1[1], 39-59. 2005.Free Text
  6. ↑ 6.0 6.1 6.2 Schaffler A, Muller-Ladner U, Scholmerich J, Buchler C. Role of adipose tissue as an inflammatory organ in human diseases. Endocr Rev 2006 August;27(5):449-67. PMID 16684901
  7. ↑ Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005 June 28;111(25):3481-8. PMID 15983262
  8. ↑ Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 2000 December;43(12):1498-506. PMID 11151758
  9. ↑ 9.0 9.1 Bays H, Blonde L, Rosenson R. Adiposopathy: How do diet, exercise, weight loss and drug therapies improve metabolic disease? Expert Rev Cardiovasc Ther 2006;4(6):871-95. PMID 17173503
  10. ↑ Stenvinkel P. Leptin and blood pressure--is there a link? Nephrol Dial Transplant 2000 August;15(8):1115-7. PMID 10910430
  11. ↑ Brook RD, Bard RL, Bodary PF, Eitzman DT, Rajagopalan S, Sun Y, Depaoli AM. Blood pressure and vascular effects of leptin in humans. Metab Syndr Relat Disord 2007 September;5(3):270-4. PMID 18370781
  12. ↑ Johnson JA, Fried SK, Pi-Sunyer FX, Albu JB. Impaired insulin action in subcutaneous adipocytes from women with visceral obesity. Am J Physiol Endocrinol Metab 2001 January;280(1):E40-E49. PMID 11120657
  13. ↑ 13.0 13.1 Bays H, Ballantyne C. Adiposopathy: why do adiposity and obesity cause metabolic disease? Future Lipidology 2006;1(4):389-420. Abstract
  14. ↑ 14.0 14.1 Bays HE, González-Campoy JM, Henry RR, Bergman DA, Kitabchi AE, Schorr AB, Rodbard HW; The Adiposopathy Working Group. Consensus Statement. Is adiposopathy (sick fat) an endocrine disease? Int J Clin Pract 2008 August 4. PMID 18681905
  15. ↑ 15.0 15.1 15.2 15.3 Bays HE, González-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB, Rodbard HW, Henry RR. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther. 2008;6:343-368. PMID 18327995
  16. ↑ Bays H. Adiposopathy - Defining, Diagnosing, and Establishing Indications to Treat "Sick Fat": What are the Regulatory Considerations? US Endocrine Disease 2006;(2):12-4. Free Text
  17. ↑ 17.0 17.1 Bays HE, Rodbard RW, Schorr AB, González-Campoy JM. Adiposopathy: Treating pathogenic adipose tissue to reduce cardiovascular disease risk. Current Treatment Options in Cardiovascular Medicine 2007;9(4):259-71. PMID 17761111
  18. ↑ Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004 February;89(2):463-78. PMID 14764748
  19. ↑ Bray GA, Glennon JA, Salans LB, Horton ES, Danforth E Jr, Sims EA. Spontaneous and experimental human obesity: effects of diet and adipose cell size on lipolysis and lipogenesis. Metabolism 1977 July;26(7):739-47. PMID 194133
  20. ↑ Vague J. La differenciation sexuelle, facteur determinant des formes de l'obesite. Presse Med 1947;30:339-40.
  21. ↑ Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 2007 December;455(3):479-92. PMID 17609976
  22. ↑ Bays H. Adiposopathy, metabolic syndrome, quantum physics, general relativity, chaos and the Theory of Everything. Expert Rev Cardiovasc Ther 2005 May;3(3):393-404. PMID 15889967
  23. ↑ Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F; American Heart Association; National Heart, Lung, and Blood Institute. Circulation 2005 October 25;112(17):2735-52. PMID 16157765
  24. ↑ 24.0 24.1 Kahn R, Buse J, Ferrannini E, Stern M. The Metabolic Syndrome: Time for a Critical Appraisal: Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005 September;28(9):2289-304. PMID 16123508
  25. ↑ Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM. Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Diabetes Care 2004 November;27(11):2676-81. PMID 15505004
  26. ↑ Grundy SM. Does a diagnosis of metabolic syndrome have value in clinical practice? Am J Clin Nutr 2006 June;83(6):1248-51. PMID 16762931
  27. ↑ Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res 2004 12;8:1197-211 PMID 15340100
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