Health consequences of obesity

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'Introduction'

Physiological Consequences of Obesity

Cardiovascular Disease in Obesity

Obesity is well known for its association with many serious of diseases, including type 2 diabetes mellitus, coronary heart disease (CHD) amongst many others . BMI has a close correlation with the incidence of several chronic conditions caused by excess fat, and waist circumference correlates with the measure of risk for CHD such as hypertension or blood lipid levels(1).

Obesity increases the risk of cardiovascular disease and premature death which may be indirectly mediated through risk factors associated with the metabolic syndrome . [PICTURE]. Central deposition of adipose tissue increases the risk of cardiovascular morbidity and mortality, including stroke, congestive heart failure, myocardial infarction and cardiovascular death(2). Waist-hip ratios are commonly used to assess this type of body fat distribution. Obesity causes an increase in total body oxygen consumption due to excess lean tissue mass as well as the oxidative demands of metabolically active adipose tissue. This results in an increase in cardiac output1. The left ventricle dilates to accommodate the increased venous return with subsequent development of eccentric hypertrophy to keep the wall stress normal(3). Eventually the ventricle can no longer adapt to volume overload and the dilation of LV results in decreased ventricular contractility(1). With LV hypertrophy, reduced ventricular compliance alters ability of the chamber to accommodate an increased volume during diastole and this results in diastolic dysfunction. A combination of systolic and diastolic dysfunction leads to clinically significant heart failure(1). [PICTURE] Hypertension also becomes more prevalent with increasing severity of obesity(3). In men a BMI of <25 or >30 shows a prevalence of hypertension of 15% and 42%, respectively; in women these are 15% and 38%, respectively(3). Fatal arrhythmias may be the most frequent cause of death among obese people as increased catecholamine and free fatty acid levels may affect repolarization(3). The Framingham Study shows that sudden cardiac death was 40 times higher in obese men and women. In the NHANES III study, 30% of obese patients with glucose intolerance had a prolonged corrected QT (QTc) interval(3). A QTc of more than 0.42 seconds was associated with increased mortality in “healthy” obese patients(3). Schouten et al found that 8% of obese individuals had QTc interval of more than 0.44 seconds and in 2% it was more than 0.46 seconds.

Increased adiposity and reduced physical activity are strong and independent predictors of CHD and death. For each unit increase in BMI, the risk of CHD increases by 8%. However each 1 hour metabolic equivalent increase in activity score decrease CHD risk by 8%(2). Physical activity attenuates the risks of obesity on coronary health and also increases myocardial oxygen supply, improving myocardial contraction and electrical stability(2). Various studies have shown that obesity is an independent predictor of coronary artery disease and this is also linked to BMI(3) and that obesity accelerates atherosclerosis many years before the clinical signs become obvious. In autopsies among 15-35 year olds who died from accidental causes, plaques and ulceration in the coronary arteries and abdominal aorta were found and the extent of damage related to the amount of abdominal fat and BMI(3).

The risk of stroke increases with increased BMI and waist-hip ratio. In the prospective Physician’s Health study, results showed that an increase of 1 BMI unit, increased the rate of ischemic stroke by 4% and 6% for haemorrhagic stroke. The underlying mechanisms linking increased BMI to increased stroke risk are not clear but it is thought that it could be mediated by the prothrombotic and proinflammatory state in obesity(3). Adipose tissue is considered as an active endocrine organ(2). Release of adipokines (e.g. leptin and adiponectin), proinflammatory cytokines (IL-6 and CRP) and hypofibrinolytic factors (PAI-1) might, together, lead to increased oxidative stress and endothelial dysfunction, finally promoting atherosclerosis which then leads to stroke(2). Terao et al (2008) investigated the effect of inflammatory and injury reposonse to ischaemic stroke in obese mice, and discovered that when the middle cerebral artery (MCA) was occluded and reperfused, the inflammatory and injury responses were worse in obese mice (ob/ob) than in wild type mice(4). Monoctye chemoattractant protein-1 appears to be involved in the exaggerated responses to ischaemic stroke in obese mice.

Non-alcoholic liver disease and obesity

Definition: Nonalcoholic fatty liver disease can be defined as an accumulation of fat, mainly triglycerides in the hepatocytes that exceeds 5% of the liver weight, this is a condition known as steatosis (5). If left untreated steatosis can lead to the development of steatohepatitis, which can result in fibrosis, cirrhosis and eventual liver failure. NAFLD therefore refers to a wide range of liver damage (6).

Clinical presentation: Patients presenting with NAFLD complain of fatigue, malaise and feelings of discomfort or “fullness” in the upper right abdomen. Laboratory tests reveal a mild to moderate increase in serum levels of alanine aminotransferase, aspartate aminotransferase or both (6). The ratio of aspartate aminotransferase to alanine aminotransferase is usually less than 1, however as the degree of fibrosis in the liver advances, this ratio increases (5).

Risk Factors: Insulin resistance and therefore NAFLD are most commonly associated with the central obesity phenotype. Visceral fat is found to have a greater lipolytic potential than subcutaneous fat. The fatty acids which are released from visceral fat during lipolysis drain straight into the portal circulation. It is the increased lecels of free fatty acids in the circulation which are thought to be responsible for insulin resistance (1-12)

Prevalence: NAFLD is known to affect 10 -24% of the world’s population, however this prevalence increases to 57.5% to 74% in obese persons. Simularly NAFLD is thought to affect 2.6% of children a statistic which rises to 22.5% to 52.8% of obese children. (6)

The role of Insulin Resistance in NAFLD: Insulin resistance, a condition seen in conjunction with obesity and type 2 diabetes mellitus is thought to be the leading cause of NAFLD. It is thought that fat accumulation in the hepatocytes occurs via two distinct mechanisms, namely lipolysis and hyperinsulinaemia. Microsomal ω-oxidation has been found to produce clinically significant amounts of cytotoxic dicarboxdylic acids. This pathway of fatty acid metabolism is closely related to mitochondrial β-oxidation and peroxisomal β-oxidation. A lack in the enzymes associated with peroxisomal β-has been identified as a major cause of steatosis and steatohepatitis. An example of this is deficiency of acyl-coenzyme A oxidase which disrupts disrupt the oxidation of long fatty acid chains and dicarboxilic acids, which in turn leads to microvesicular steatosis and steatohepatitis. Loss of function of acyl-coenzyme A oxidase has also causes sustained hyperactivation of peroxisome proliferator activated receptor-α (PPAR- α), leading to upregulation of PPAR- α regulated genes (6:69). Studies have also been conducted which suggest that PPAR- α is responsible for the promoting the synthesis of uncoupling protein 2 in the liver (6:49). Increased levels of fatty acids in the liver provide a source of oxidative stress, which in turn is thought to be responsible for the progression from steatosis to steatohepatitis and finally to cirrhosis.the reactive oxygen species is found within the mitochondria of the cell and is thought to trigger steatohepatitis and fibrosis via three different mechanisms, lipid peroxidation, cytokine induction and induction of FAS ligand. (6).

The role of the Keratin cytosleleton in NAFLD: Mature and differentiated hepatocytes are the epithelial cells of the liver and normally express the type I keratin keratin 8 anad the type II keratin keratin 18, these are arranged into intermediate filaments in the cytoplasmof the cell. During diseases such as NAFLD disruption to the keratin cytoskeleton is routinely observed in hepatocytes. NAFLD is characterised by steatosis, hepatocyte ballooning, cytoplasmic inclusions such as Mallory bodies, pericellular fibrosis and inflammation (7). Observation of ballooned hepatocytes reveals reduced density and in some cases loss of intermediate filaments, and the Mallory bodies are seen to exist of misfolded and aggregated keratins (7). A study carried out by ….???.... has revealed that disruption of the cytoskeleton is due to oxidative stress. Mallory bodies and ballooned hepatocytes were recrested in hepatocytes of mice by chronic intoxication with Griseofulvin or 3,5-diethoxycarbonyl-1,4 dihydrocollidine (7:29,30). These two reactants were metabolised by cytochrome P450, which in return lead to the formation of methyl radicals(3:31). It is assumed that the mechanism of oxidative injury seen in the study was the same as that which occurs in NAFLD, but in the case of the disease fatty acids are responsible for the production of reactive oxygen species (7)

In conclusion NAFLD is a disease found to be closely linked to both central obesity and insulin resistance which affects a large number of the world’s population

Endocrine Changes in Obesity

It is well documented that obesity is associated with changes in the normal endocrine profile. Many studies have focused particularly on the alterations in the sex steroid profile of obese individuals. This section of the article will briefly discuss the types of changes observed and their consequences on the health of the individual.

Oestrogens

Oestrogens are synthesized by aromatization of circulating testosterones. This conversion reaction is catalysed by the enzyme aromatase (Ali,) which is expressed at many sites throughout the body, including adipose tissue. Therefore, an increase in adipose tissue mass, results in a greater capacity for aromatization, and oestrogen levels rise.

The effects of obesity on oestrogen concentrations are augmented in postmenopausal women. In premenopausal, non-pregnant women, the principal site at which this takes place is the ovaries (Simpsom 2000) and so the contribution of adipose tissue to overall oestrogen synthesis is minor. However, after the menopause, adipose tissue becomes the main source of oestrogens (Simpson.)

Androgens

The increased capacity for aromatization results in hypoandrogenism in males, as a higher proportion of circulating testosterone is converted to oestrogen (Hammoud et al.) Other factors contributing to the decrease in circulating testoerone include insulin resistance and the suppression of the hypothalamic pituitary testicular axis (Hammoud.)

Most studies in premenopausal women have demonstrated that the concentration of free testosterone in the circulation increases with body weight. It has been proposed that the relationship between body weight and androgens is mediated by insulin and IGF-1, which are both increased in obese subjects.

Furthermore, as is the case for oestrogen, adipose tissue is an important site of peripheral testosterone production, due to local expression of 17 beta hydroxysteroid dehydroenase. Therefore there is a positive association between adipose tissue mass and androgen concentration.

SHBG

Sex steroids are highly lipophilic and are therefore carried in the circulation bound to proteins – sex hormone binding globulins (SHBG.) It is well documented that obesity results in a decreased concentration of SHBG. This is thought to be associated with the rise in insulin levels associated with obesity, as insulin inhibits hepatic synthesis of SHBG. The decreased concentration of binding protein results in an increase in the free fraction of sex steroids. (2)

Obesity and Cancer

It is estimated that 10% of all cancer deaths among non-smokers are related to obesity. Many hypotheses have been proposed to explain this, the most convincing of which is that alterations in endogenous hormone metabolism mediate the effects of obesity on cancer risk Kalle et al. This in part thought to be true due to the fact that sex steroids regulate the balance between cell proliferation, differentiation and apoptosis. 3

Many types of cancer are more prevalent in obese subjects, the most widely studied of which are breast and endometrial cancer. It has been observed that these types of cancer are associated with an increase in oestrogen concentration, decrease in plasma SHBG and an increase in androgen levels. (3, 2) These observations have led to the establishment of the unopposed oestrogen hypothesis. This hypothesis suggests that risk of cancer is due to increased exposure to oestrogen, which is unopposed by progestagens. This results in increased mitotic activity of cells. (Key et al) Increased mitosis, increases the risk of mutation accumulation, and thus the development of cancer.

Infertility

Obesity is thought to account for around 6% of primary infertiliy. (1)

Women

Many studies have observed increased number of atretic follicles in obese women. This reflects the increased risk of anovulatory infertility in obese women. * The anovulation is mainly due to hyperandrogenism. High androgen levels cause increased apoptosis of the granulosa cells, damage to the endometrium and developing oocytes. Excess oestrogen also contributes to infertility. This is partly due to increased negative feedback causing decreased gonadotrophin secretion (1,

There is a well established link between PCOS and obesity. This syndrome is characterized by anovulatory infertility, obesity, hirsutism, multiple ovarian cysts and insulin resistance. ? It is unkown whether PCOS is a cause or effect of obesity (*.)

Men

Obese men generally express “hyperoestrogenic hypogonadotropic hypogonadism.” (hAMMOUD, one of other first ref) Essentially the high oestrogen levels, combined with low testosterone levels result in subfertility.

Many studies have reported a negative association between spermatogenesis and increasing BMI. The mechanism mediating this association is yet to be identified. However, it has been suggested that the gerneral hypoandrogenism observed in obese males, may reflect a reduced concentration of testosterone within the testes, which would cause a reduction in sperm count. Furthermore, the observed hyperoestrogenism causes inappropriate suppression of the hypothalamic-pituitary-gonadal axis, resulting in reduced spermatogenesis. The effects of obesity on spermatogenesis is thought to be qualitiative as well as quantitative. For example, .Ghanayem et al . . showed reduced sperm motlity and hyperactivated progression.

Obesity has also been associated with erectile dysfunction (hammoud, first). Feldman et al found that 79% of men suffering erectile dysunction were overweight or obese. Although erectile dysfunction is hought to be in part a result of hypoandrogenism, the main cause is thought to be related to endothelial dysfunction and disruption of the nitric oxide pathway.

In summary, alterations in sex steroid profiles as a result of obesity have many adverse effects on health. The most well documented health consequences are cancer and infertility.

Psychosocial Consequences of Obesity

The relationship between obesity and mental health has been the subject of continuous debate over the past 30 years and remains a topic of extensive deliberation . Early studies exploring the relationship were consistent with the “jolly fat” hypothesis, suggesting that obesity confers a protective role against anxiety and depressive disorders;1 however, the weight of more recent studies contradict the “jolly fat” hypothesis and suggest that the increasing global prevalence of both depression and obesity are functionally linked.2,3 The underlying mechanisms and direction of this link remain largely unknown,3 although recent research has indicated that gender, obesity severity, comorbid physical illness, stress and abdominal fat distribution are important mediating risk factors for the development of an obesity-mental disorder link.1,2,4,5, These newly discovered mediators give rise to new hypotheses, involving over-activity of the hypothalamic-pituitary-adrenocortical axis,1,2 side-effects of medication for depression, and the social stigmatization of obesity.2

A recent nationally representative Canadian study, whose methodology controlled for sociodemographic factors and comorbid physical health problems, found significant positive relationships between obesity and an array of lifetime psychiatric disorders and past-year mood and anxiety disorders.2 These conclusions are consistent with current literature.6,5,7,8 Further subgroup analyses revealed that obese women had a greater susceptibility to specific mental disorders compared to men, including depression, mania, panic attacks, panic disorder, social phobia and agoraphobia (with and without panic).3 These findings are consistent with previous research, and thus reinforce the notion that obese women have an enhanced vulnerability towards mental disorders.2,4,5,7,9 This result may be explained in terms of the increased consciousness amongst women to conform to a socially desirable image and weight.3 The study also positively linked obesity to suicidal behaviours and negatively linked obesity with past-year drug dependence3; both these findings are supportive of existing literature.6,7,10 Mather et al. (2009) suggest that the former may be attributed to the social stigmatization attached to obesity, inducing feelings of decreased self-worth and decreased self-esteem that fuel suicidal thoughts; and the latter due to protective effects of obesity, arising through food and addictive drugs competing for the same reward sites in the brain.3,11 At face value, this data appears convincing, however, it is important to note that some studies fail to identify mental disorders as a psychosocial consequence of obesity.12,13 Similarly, whilst much research is indicative of sex differences between obesity and mental disorders,1,5 this is not a unanimous conclusion.6,7,14 In addition, some research only identifies associations amongst the severely obese, who illustrate a BMI of >35kg/m2.5 These variable conclusions may in part be attributed to methodological differences between studies.5

1 Rivenes, A.C., Harvey, S.B., and Mykltun, A. (2009). The relationship between abdominal fat, obesity, and common mental disorders: Results from the HUNT Study. Journal of Psychosomatic Research, 66: 269-275.

2 Stunkard, A.J., Faith, M.S. and Allison, K.C. (2003). Depression and Obesity. Society of Biological Psychiatry, 54: 330-337.

3 Mather, A.A., Brian, J.C., Enns, M.W. and Sareen, J. (2009). Association of obesity with psychiatric disorders and suicidal behaviours in a nationally representative sample. Journal of Psychosomatic Research, 66: 277-285.

4 Simon, G.E., Ludman, E.J., Linde, J.A., Operskalski, B.H., Ichikawa, L., Rohde, P., Finch, E.A. and Jeffery, R.W. (2008). Association between obesity and depression in middle-aged women. Gen Hosp Psychiatry, 30(1): 32-39.

5 Scott, K.M., Bruffaerts, R., Simon, G.E., Alonso, J., Angermeyer, M., de Girolamo, G., Demyttenaere, K., Gasquet, I., Haro, J.M., Karam, E., Kessler, R.C., Levinson, D., Mora, M.E.M., Browne, M.O., Ormel, J.H., Villa, J.P., Uda, H. and von Korff, M. (2008). Obesity and Mental Disorders in the General Population: Results from the World Mental Health Surveys. Int J Obes, 32(1):192-200.

6 Simon, G.E., Von Korff, M., Saunders, K., Miglioretti, D.L., Crane, P.K., van Belle, G. and Kessler, R.C. (2006). Association Between Obesity and Psychiatric Disorders in the US Adult Population. Arch Gen Psychiatry, 63: 824-830.

7 Carpenter, K.M., Hasin, D.S., Allison, D.B. and Faith, M.S. (2000) Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study. Am J Public Health, 90:251–257.

8 Onyike, C.U., Crum R.M. and Lee H.B. (2003). Is obesity associated with major depression? Results from the third National Health and Nutrition Examination Survey. Am J Epidemiol, 158:1139–1147.

9 Scott, K.M., Oakley Browne, M.A., McGee, M.A. and Wells, J.E. (2006). Mental-physical comorbidity in Te Rau Hinengaro: the New Zealand Mental Health Survey (NZMHS). Australian and New Zealand Journal of Psychiatry, 40:882–888. 10 Dong, C., Li, W.D. and Li, D. (2006). Extreme obesity is associated with suicide attempts: results from a family study. Int J Obes, 30: 388-390.

11 Kleiner, K.D., Gold, M.S., Frost-Pineda, K. (2004). Body mass index and alcohol use. J Addict Dis, 23:105-118.

12 Hasler, G., Pine, D.S. and Gamma, A. (2004). The associations between psychopathology and being overweight: A 20-year prospective study. Psychol Med, 34:1047–157.

13 Faith, M.S., Matz, P.E. and Jorge, M.A. (2002). Obesity-depression associations in the population. J Psychosom Res, 53:935–942.

14 Onyike, C.U., Crum, R.M., Lee, H.B., Lyketsos, C.G. and Eaton, W.W. (2003). Is obesity associated with major depression? Results from the Third National Health and Nutrition Examination Survey. American Journal of Epidemiology. 158(12):1139–1147. Rachael White 15:09, 23 October 2009 (UTC)

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References

1. Kopelman P.G. (2000) Obesity as a medical problem. Nature. 404:635-642.

2. Gaal L.F.V. et al. (2006) Mechanisms linking obesity with cardiovascular disease. Nature. 444:875-879.

3. Mathew B. et al. (2008) Obesity: effects on cardiovascular disease and its diagnosis. J Am Board Fam Med. 21:562-568.

4. Terao S. et al. (2008) Inflammatory and injury responses to ischemic stroke in obese mice. Stroke. 39:943-950

5. Paul Angulo, Obesity and Nonalcoholic fatty Liver Disease, Nutrition reviews, vol 65, 6, 2007, s57-s63

6. Paul Angulo, Nonalcoholic fatty liver disease, New England Journal of Medicine, vol346, 16, 2002, 1221-1231

7. Kurt Zatloukal, conny Stumptner, Andrea Fuchsbichler, Peter Fickert, Carolin Lackner, Michael Trauner and Helmut Denk, The Keratin cytoskeleton in liver diseases, journal of pathology, 2003 vol 204: 367-376