Obesity is considered to be the most common nutritional disorder in the industrialized countries, where it is far more common than all the nutritional deficiencies combined.

Although the prevalence of obesity declines in the elderly, it is possible that this reflects, in part, the increased mortality associated with obesity.

Socioeconomic and cultural factors are important because they influence not only the type and amount of food, but the social acceptability of obesity as well.

Genetic factors may also play a role in some ethnic and racial groups.

It is indisputable that obesity results from a chronic excess of caloric intake relative to the expenditure of energy. Nutritional Pathology Online : click

Although sharp distinctions cannot be made, there are two general types of obesity :

i) that which begins in childhood and is lifelong, and

ii) that which begins in the adult.

Lifelong obesity is associated with a larger than normal number of adipocytes, presumably a genetically determined phenomenon.

By contrast, the obesity that begins in adult life develops against a background of larger - that is, hypertrophied - adipocytes, the number of which remains the same.

These two types of obesity have been referred to as the hyperplastic and hypertrophic types, respectively.

Both types reflect excess caloric intake, but they have different patterns of fat deposition.

In adult-onset obesity fat is deposited principally on the trunk - that is, the hips and buttocks in women and the abdomen (pot belly) in men.

In the type that begins in childhood, weight gain is distributed more peripherally, and is readily measured as an increase in the skin-fold thickness over the triceps muscle or in the subscapular area.

Despite numerous studies, it is not possible to attribute the common varieties of obesity to any specific metabolic or functional disturbance.

In experimental animals, lesions of the hypothalamus have produced obesity, and it has been postulated that an "appetite center " has been damaged.

This concept is supported by the occurrence of overeating and obesity in patients with tumors that impinge on the hypothalamus.

However, it is now known that hypothalamic lesions directly influence lipogenesis and the secretion of insulin, and it is probable that obesity induced by hypothalamic lesions is secondary to these effects.

Since the basal metabolic rate decreases progressively with age, it has been suggested that adult-onset obesity may simply reflect the maintenance of the usual food intake despite decreasing need. However, the decline in basal metabolic rate is not large enough to explain obesity.

Lean body mass decreases with age, while the proportions of water and fat in the body increases.

Thus, the basal metabolic rate per unit of lean body mass may actually not change, although the total caloric requirement seems to decrease.

Under these circumstances, it is likely that the usual food intake becomes excessive in relation to the more sedentary life associated with aging in industrialized countries.

Numerous theories of obesity, invoking hormonal changes, alterations in enzymes, associated with fat metabolism, and decreased thermogenesis, have been proposed, but none has been substantiated.

The many hormonal and metabolic changes seen in obese persons appear to be results of the increased fat stores, rather than the cause of the obesity.

The most important consequence of obesity is maturity-onset (Type II) diabetes, which is associated with normal or high levels of circulating insulin and peripheral resistance to insulin's action.

More than 80% of type II diabetes occurs in obese individuals.

The precise mechanism is not understood, it has been found that weight gain directly stimulates insulin secretion by the beta cells of the pancreas.

Higher levels of circulating insulin decrease the number of insulin receptors on the surface of muscle and adipose cells - a form of negative feedback inhibition. This observation has led to the theory that this peripheral resistance to the action of insulin stimulates insulin production, leading to a further decrease in the number of receptors. Eventually the beta cell is unable to secrete enough insulin to overcome the peripheral resistance to its effect. The final result is "high output failure" of the beta cells of the pancreas.

Weight reduction usually diminishes the glucose tolerance of Type II diabetes, presumably owing to a decrease in the stimulus for insulin secretion by the pancreatic beta cells.

Obesity has also been linked to atherosclerosis and myocardial infarction.

It is noteworthy that obesity is associated with all the major risk factors for myocardial infarction, including hypercholesterolemia, low levels of high-density lipoproteins (HDL), diabetes, and hypertension.

The relationship of hypertension to obesity is not understood, but it may involve an increase in circulating blood volume and dietary salt intake.

In addition to its deleterious effect on the heart, hypertension is also responsible for the greater incidence of stroke and vascular disease of the kidneys prevalent in obese individuals.

Atherosclerosis seems to be linked to the disordered lipid metabolism associated with obesity.

Obesity and hypercholesterolemia are also linked to an increased incidence of gallstones, particularly in women.

Severe degrees of obesity result in the deposition of fat in the liver and minor functional changes, but these are of little clinical significance.

For reasons that are not clear, blood uric acid levels are increased in obese individuals, as is the incidence of gout.

A number of complications can be traced simply to the physical effect of an increase on body weight and skin fold thickness.

Osteoarthritis, or degenerative joint disease, is common in weight-bearing joints, such as those of the hip, knee, and spine.

Excessive subcutaneous fat , particularly beneath the breasts and in the crural areas in women, often is responsible for an intertriginous dermatitis owing to an accumulation of moisture and maceration of the epidermis.The moister in the intertriginous areas may predispose to fungal infections of the skin.

Hernias of the ventral abdominal wall and of the diaphragm are not uncommon.

Because the fat deposits place greater pressure on the veins, and possibly because tissue turgor is decreased, varicose veins of the lower extremities are more common in obese persons, and the incidence of thrombophlebitis is increased correspondingly.

Obesity also poses a physical impediment in surgery, which is made more difficult technically. Because of the longer time needed for surgery, the risks of anesthesia, pulmonary complications, and infection are increased, and the overall surgical mortality for the obese is probably twice as great as that for persons of normal weight.

Obesity also has an important effect on the female reproductive system. Oligomenorrhea and amenorrhea are common in premenopausal obese women. Pregnant obese women have a higher incidence of toxemia of pregnancy. Postmenopausal obese women have higher rates of endometrial carcinoma and uterine fibroids.

It has been postulated that the increased body fat provides a larger storage space for estrogens and that the conversion of adrenal androgens to compounds with estrogenic activity is increased. Such mechanisms might lead to greater hormonal stimulation of the endometrium and myometrium.

The treatment of obesity is difficult, especially in those who have been overweight since childhood.

There is no evidence that any particular form of caloric restriction is more effective than others. Any caloric intake that is less than energy expenditure will result in weight loss.

Since some unusual diets (for example, protein hydrolysates) may actually pose health risks, such as cardiac arrhythmias, the most reasonable regimen for most people is a balanced diet containing less than 1000 calories a day.

Recent advances in the relationship between obesity, inflammation, and insulin resistance.Eur Cytokine Netw. 2006 Mar;17(1):4-12.

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.

Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells.Vitam Horm. 2006;74:443-77.

The white adipose tissue, especially of humans, is now recognized as the central player in the mild inflammatory state that is characteristic of obesity. The question is how the increased accumulation of lipid seen in obesity causes an inflammatory state and how this is linked to the hypertension and type 2 diabetes that accompanies obesity. Once it was thought that adipose tissue was primarily a reservoir for excess calories that were stored in the adipocytes as triacylglycerols. In times of caloric deprivation these stored lipids were mobilized as free fatty acids and the insulin resistance of obesity was attributed to free fatty acids. It is now clear that in humans the expansion of adipose tissue seen in obesity results in more blood vessels, more connective tissue fibroblasts, and especially more macrophages. There is an enhanced secretion of some interleukins and inflammatory cytokines in adipose tissue of the obese as well as increased circulating levels of many cytokines. The central theme of this chapter is that human adipose tissue is a potent source of inflammatory interleukins plus other cytokines and that the majority of this release is due to the nonfat cells in the adipose tissue except for leptin and adiponectin that are primarily secreted by adipocytes. Human adipocytes secrete at least as much plasminogen activator inhibitor-1 (PAI-1), MCP-1, interleukin-8 (IL-8), and IL-6 in vitro as they do leptin but the nonfat cells of adipose tissue secrete even more of these proteins. The secretion of leptin, on the other hand, by the nonfat cells is negligible. The amount of serum amyloid A proteins 1 & 2 (SAA 1 & 2), haptoglobin, nerve growth factor (NGF), macrophage migration inhibitory factor (MIF), and PAI-1 secreted by the adipocytes derived from a gram of adipose tissue is 144%, 75%, 72%, 37%, and 23%, respectively, of that by the nonfat cells derived from the same amount of human adipose tissue. However, the release of IL-8, MCP-1, vascular endothelial growth factor (VEGF), TGF-beta1, IL-6, PGE(2), TNF-alpha, cathepsin S, hepatocyte growth factor (HGF), IL-1beta, IL-10, resistin, C-reactive protein (CRP), and interleukin-1 receptor antagonist (IL-1Ra) by adipocytes is less than 12% of that by the nonfat cells present in human adipose tissue. Obesity markedly elevates the total release of TNF-alpha, IL-6, and IL-8 by adipose tissue but only that of TNF-alpha is enhanced in adipocytes. However, on a quantitative basis the vast majority of the TNF-alpha comes from the nonfat cells. Visceral adipose tissue also releases more VEGF, resistin, IL-6, PAI-1, TGF-beta1, IL-8, and IL-10 per gram of tissue than does abdominal subcutaneous adipose tissue. In conclusion, there is an increasing recognition that adipose tissue is an endocrine organ that secretes leptin and adiponectin along with a host of other paracrine and endocrine factors in addition to free fatty acids.

Fat as an endocrine organ: relationship to the metabolic syndrome.Am J Med Sci. 2005 Dec;330(6):280-9.

Obesity and the metabolic syndrome have both reached pandemic proportions. Together they have the potential to impact on the incidence and severity of cardiovascular pathologies, with grave implications for worldwide health care systems. The metabolic syndrome is characterized by visceral obesity, insulin resistance, hypertension, chronic inflammation, and thrombotic disorders contributing to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Obesity is a key component in development of the metabolic syndrome and it is becoming increasingly clear that a central factor in this is the production by adipose cells of bioactive substances that directly influence insulin sensitivity and vascular injury. In this paper, we review advances in the understanding of biologically active molecules collectively referred to as "adipokines" and how dysregulated production of these factors in obese states mediates the pathogenesis of obesity associated metabolic syndrome.

The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity.J Am Soc Nephrol. 2004 Nov;15(11):2792-800.

The metabolic effects of obesity have made this highly prevalent disease one of the most common risk factors for diabetes, hypertension, and atherosclerosis, the leading causes of end-stage renal failure. However, obesity per se, as defined by body mass index, is less predictive of the development of these diseases than is the presence of a constellation of obesity-related abnormalities now known as the metabolic syndrome. Recognition of this syndrome, which can readily be identified in clinical settings using defined threshold values for waist circumference, BP, fasting glucose, and dyslipidemia, allows for earlier intervention in these high-risk patients. Systemic insulin resistance has been implicated as one possible factor that links visceral obesity to adverse metabolic consequences; however, the mechanism whereby adipose tissue causes alterations in insulin sensitivity remains unclear. Infection and inflammation are commonly associated with insulin resistance, and visceral obesity is associated with a chronic, low-grade inflammatory state, suggesting that inflammation may be a potential mechanism whereby obesity leads to insulin resistance. Moreover, adipose tissue is now recognized as an immune organ that secretes numerous immunomodulatory factors and seems to be a significant source of inflammatory signals known to cause insulin resistance. Therefore, inflammation within white adipose tissue may be a crucial step contributing to the emergence of many of the pathologic features that characterize the metabolic syndrome and result in diabetes and atherosclerosis. This review describes the role of proinflammatory cytokines and hormones released by adipose tissue in generating the chronic inflammatory profile associated with visceral obesity.