It is well known from the medical literature, as well as the day-to-day practice of clinical medicine, that the adverse metabolic consequences associated with excessive body fat (adiposity) vary greatly between individuals and among patient populations. Not everyone who is overweight has Type 2 diabetes mellitus, hypertension or dyslipidemia, and not everyone with Type 2 diabetes mellitus, hypertension, or dyslipidemia is overweight. Emerging evidence supports the fact that it is the dysfunction of fat cells (adiposopathy) that is most associated with promoting metabolic disease [1].
For example, metabolically healthy, but obese patients may have excess fat. However, these patients appear to be (genetically) protected from the adverse metabolic consequences of Type 2 diabetes mellitus, hypertension and dyslipidemia, and appear to have less visceral fat than obese patients with metabolic syndrome [2]. Thus, adiposity alone is often not sufficient for the creation of adverse metabolic consequences and the clinical disease manifestations of adiposopathy.
Conversely, metabolically obese but normal--weight patients may present as younger individuals who express adverse metabolic characteristics such as insulin resistance, hyperinsulinemia and dyslipidemia, all correlating to an increase in intra-abdominal or visceral fat. However, these patients are not overweight [2]. Therefore, in this case, adiposity is not necessarily required for the promotion of these adverse metabolic consequences and diseases. Rather, it is adiposopathy without adiposity that is the underlying causality.
The increased prevalence of Type 2 diabetes mellitus and atherosclerotic cardiovascular disease among nonobese Asian Indians is thought to be due to elevations in free fatty acids (FFAs), elevated leptin, decreased adipo-nectin, elevated C-reactive protein and increased insulin resistance in this ethnic group – all manifestations of abnormal adipocyte and/or dysfunctional adipose tissue [1].
In summary, adiposity is simply an abnormal increase in body fat. Adiposopathy is the pathologic dysfunction of adipocytes and adipose tissue, which may be promoted and exacerbated by fat accumulation (adiposity) and sedentary lifestyle in genetically susceptible patients, and that is a root cause of Type 2 diabetes mellitus, hypertension, dyslipidemia and even metabolic syndrome [1].
However, how might adiposity lead to, or exacerbate adiposopathy in susceptible individuals? It has been suggested that adiposity may often lead to adiposopathy through an increase in fat cell size alone, which subsequently leads to fat dysfunction and then to the release of adipocyte factors that promote metabolic disease [1].
While it is somewhat inexplicable why these causative adipocy-te factors have not yet been better defined, the following is a brief discussion of illustrative and suggested possibilities.
Examples of adipocyte factors that may contribute to Type 2 diabetes mellitus [1]
Leptin and adiponectin are adipocyte cytokines (adipokines) that are associated with increased insulin activity [3]. Impairment of the activity of these adipokines, as might occur with leptin resistance, may decrease insulin action. Interleukin (IL)-6, resistin and tumor necrosis factor-α are examples of other adipokines that are associated with decreased insulin activity [4]. Thus, a dysfunctional increase or decrease in the release or activity of adipokines is associated with changes in insulin activity, and may therefore potentially contribute to glucose abnormalities.
Adipsin and acylation stimulating protein are yet more adipocyte factors that may be involved in the pathogenesis of Type 2 diabetes mellitus.
Adiposopathy is also associated with an abnormal release of FFAs. Long-term, excessive FFA release may contribute to fatty liver, diabetes dyslipidemia, insulin resistance in the liver and muscle, and a decrease in pancreatic insulin release [4]. The detrimental effects of FFA release have sometimes been termed lipotoxicity [4].
Thus, the abnormal release of fat-cell or adipose tissue factors from dysfunctional fat cells may contribute to abnormalities in glucose metabolism.
Adipocyte factors that may contribute to hypertension [1]
Adiposity alone may physically compress the kidney and increase the incidence of other disease conditions such as sleep apnea, which might contribute to hypertension. In addition, adiposo-pathy may result in the abnormal release of adipocyte factors that affect mineralocorticoid release, the renin–angiotensin system (RAS) and the sympathetic nervous system.
For example, adiposopathy is anatomically manifest by an increase in visceral fat [1], which may be associated with the abnormal release of factors associated with the RAS, including angiotensin II, angiotensinogen, angiotensin converting enzyme and cathepsin.
Elevated leptin levels, as might occur in leptin-resistant obese patients, may increase catecholamine release, and thus may affect the sympathetic nervous system.
Adipocyte factors that may contribute to dyslipidemia [1]
Abnormal FFA release from dysfunctional adipocytes or dysfunctio-nal adipose tissue is commonly associated with a dyslipidemia characterized by fasting hypertriglyceridemia, low high-density lipoprotein-cholesterol levels, and abnormalities in lipoprotein particle size and subclass distri-bution. This dyslipidemia is often found in patients with Type 2 diabetes mellitus and metabolic syndrome, and has sometimes been termed diabetes dyslipidemia, and is thought to be particularly atherogenic.
In addition, the abnormal (increased or decreased) secretion or production of other adipocyte factors in the presence of adiposopathy may contribute to a number of lipid abnormalities and a predisposition to atherosclerosis. For example, it is conceivable that dysfunctional fat cells may contribute to dyslipidemia and promote increased atherosclerotic risk through the abnormal release of adipocyte factors such as apolipoprotein E, cholesteryl ester transfer protein, complement factors, endothelin, lipo-protein lipase, lysophospholipid, macrophage inhibitory factor, metalloproteases, nitric oxide synthase, perilipin, phospholipids transfer protein and vascular endothelial growth factor.
Finally, adipokines may potentially increase inflammatory responses that could promote atherogenesis and athero-sclerosis. For example, hepatic synthesis and secretion of C-reactive protein is regulated by IL-6, which is an important cytokine produced by fat cells.
The future
Adipocytes, specifically, and adipose tissue, in general, are both highly active from an endocrine standpoint. Adiposity (excessive body fat) in genetically susceptible patients may lead to adiposopathy (dysfunctional fat), especially when accompanied by a sedentary lifestyle. Adiposopathy is anatomically manifest by the preferential accumulation of visceral fat, and is metabolically manifest by the abnormal release of various adipo-cyte-derived factors that may contribute to the metabolic diseases most associated with obesity: Type 2 diabetes mellitus, hypertension and dyslipidemia.
Determination as to which adipocyte factors are most important in promoting metabolic disease, in the context of adiposopathy, will be an important focus for future studies. For it is only through identifying the metabolic abnormalities that result in the causality of disease that best allows for the pursuit and discovery of interventions to correct these abnormalities. This concept is especially applicable in light of the upcoming wave of new antiobesity agents in development.
For example, as research progresses, it will not be enough for antiobesity agents to demonstrate body-fat reduction alone. Instead, antiobesity agents will be required to demonstrate health benefits beyond weight loss, such as improvement in adipocyte metabolism, and thus improvement in glucose metabolism, blood pressure and dyslipidemia.
In other words:
“The development of any effective antiobesity agent must not only reduce fat mass (adiposity), but must also correct fat dysfunction (adiposopathy) in order to maximize metabolic health” [3].
References
- Bays H, Abate N, Chandalia M. Adiposopathy: sick fat causes high blood sugar, high blood pressure and dyslipidemia. Future Cardiol. 1(1), 39–59 (2005).
- Karelis AD, St-Pierre DH, Conus F et al. Metabolic and body composition factors in subgroups of obesity: what do we know? J. Clin. Endocrinol. Metab. 89, 2569–2575 (2004).
- Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes. Res. 12(8), 1197–1211 (2004).
- Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, FFA and ectopic fat in pathogenesis of Type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 89, 463–478 (2004).