Health consequences of obesity

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Obesity is conveniently defined according to Body Mass Index (BMI) such that a BMI in excess of 30kg/m2 categorises someone as obese; the main health consequences of obesity are summarised in Figure 1. This article focusses on the cardiovascular consequences, nonalcoholic fatty liver disease (NAFLD), endocrine changes and psychosocial consequences of obesity as these are generally identified as the most significant complications. The implication of the association between type 2 diabetes mellitus and obesity is also of great importance, and is discussed in Diabesity.

Figure 1: (Adapted from [1])

Cardiovascular Disease in Obesity

Obesity is associated with many serious diseases, including coronary heart disease (CHD), and BMI and waist circumference are positively correlated with measures of risk for CHD such as hypertension and blood lipid concentrations[2]. Obesity increases the risk of cardiovascular disease and premature death which may be indirectly mediated through risk factors associated with the metabolic syndrome. Central deposition of adipose tissue increases the risk of cardiovascular morbidity and mortality, including stroke, congestive heart failure, myocardial infarction and cardiovascular death[3]. 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, resulting in an increase in cardiac output. The left ventricle dilates to accommodate the increased venous return with subsequent development of eccentric hypertrophy to keep the wall stress normal[4]. Eventually, the ventricle can no longer adapt to volume overload resulting in decreased ventricular contractility. With left ventricular hypertrophy, reduced ventricular compliance alters the 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 heart failure.

Image Caption

Hypertension also becomes more prevalent with increasing obesity. In men, a BMI of <25 or >30 shows a prevalence of hypertension of 15% and 42%, respectively; in women, 15% and 38%, respectively. Fatal arrhythmias may be the most frequent cause of death among obese people as increased catecholamine and free fatty acid levels may affect repolarization. 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. A QTc of >0.42s was associated with increased mortality in “healthy” obese patients Schouten et al. found that 8% of obese individuals had QTc interval of >0.44s and in 2% it was >0.46s.

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%. Physical activity attenuates the risks of obesity on coronary health and also increases myocardial oxygen supply, improving myocardial contraction and electrical stability Cite error: Closing </ref> missing for <ref> tag. Monoctye chemoattractant protein-1 appears to be involved in the exaggerated responses to ischaemic stroke in obese mice.

Non-alcoholic liver disease and obesity

Nonalcoholic fatty liver disease is an accumulation of fat (mainly triglycerides) in the hepatocytes that exceeds 5% of the liver weight, a condition known as steatosis[5]. If untreated, steatosis can lead to steatohepatitis, which can result in fibrosis, cirrhosis and liver failure. Patients 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, but as fibrosis in the liver advances, this ratio increases.

Risk Factors: Insulin resistance and NAFLD are commonly associated with the central obesity phenotype, as visceral fat has 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 [7].

Prevalence: NAFLD affects 10 -24% of the world’s population, and 58-74% of obese persons. It affects 2.6% of children and 23-53% of obese children. [6]

The role of Insulin Resistance in NAFLD: Insulin resistance is thought to be the leading cause of NAFLD. It is thought that fat accumulation in the hepatocytes occurs via lipolysis and hyperinsulinaemia. Microsomal ω-oxidation has been found to produce clinically significant amounts of cytotoxic dicarboxylic 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 [8]. Studies have also been conducted which suggest that PPAR- α is responsible for the promoting the synthesis of uncoupling protein 2 in the liver [9]. 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 type I keratin (keratin 8) and type II keratin (keratin 18), arranged into intermediate filaments in the cytoplasm. In NAFLD, the keratin cytoskeleton in hepatocytes is disrupted. NAFLD is characterised by steatosis, hepatocyte ballooning, cytoplasmic inclusions such as Mallory bodies, pericellular fibrosis and inflammation [10] apparentlty 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 [11]. These two reactants were metabolised by cytochrome P450, which in return lead to the formation of methyl radicals [12]. It is assumed that the mechanism of oxidative injury seen was the same as in NAFLD, but in the case of the disease, fatty acids are responsible for the production of reactive oxygen species.[10]

Endocrine Changes in Obesity

Obesity is associated with changes in the normal endocrine profile, particularly in the sex steroid profile.

Oestrogens: Oestrogens are synthesized by aromatization of circulating testosterones, catalysed by the enzyme aromatase. This occurs at many sites throughout the body including adipose tissue [13], [14]. An increase in adipose tissue mass results in a greater capacity for aromatization, and an increase in oestrogen levels [15].

In premenopausal, non-pregnant women, the principal site of aromatization is the ovaries, and only a minor proportion of oestrogen comes from adipose tissue. However, in postmenoapusal women, peripheral aromatisation is enhanced and adipose tissue becomes the main site of oestrogen production [16].

Androgens: The increased capacity for aromatization results in hypoandrogenism in males, as more circulating testosterone is converted to oestrogen [17]. Other factors contributing to the decrease in circulating testoerone include insulin resistance and the suppression of the hypothalamic pituitary testicular axis. In contrast, in obese premenopausal women, obesity is associated with an increase in free testosterone levels [18]. This is thought to be partly mediated by the increased levels of insulin and IGF-1 associated with obesity,[19]. Furthermore, as for oestrogen, adipose tissue is an important site of testosterone production, due to local expression of 17 beta hydroxysteroid dehydrogenase. Therefore there is a positive association between adipose tissue mass and androgen concentration.

SHBG:Sex steroids are highly lipophilic and are carried in the circulation bound to proteins – sex hormone binding globulins (SHBG.) Obesity results in a decreased concentration of SHBG [20]. 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 [21].

Female Changes Male Changes
Oestrogen Increase Increase
Androgens Increase Decrease
SHBG Decrease Decrease

Fig 2: Summary of the endocrine changes in obesity

Obesity and Cancer

It is estimated that 10% of all cancer deaths among non-smokers are related to obesity [20]. It is hypothesised that alterations in hormone metabolism mediate the effects of obesity on cancer risk, due to sex steroid hormone regulation of cell proliferation, differentiation and apoptosis. Many types of cancer are more prevalent in obese subjects, the most widely studied of which are breast and endometrial cancer. These cancers are associated with an increase in oestrogen concentration, a decrease in plasma SHBG and an increase in androgen levels. [14][21]. These observations have led to the establishment of the unopposed oestrogen hypothesis, which suggests that mitotic activity of cells is increased in the presence of oestrogen, unopposed by progestogens [22]. Increased mitotic activity leads to a higher prevalence of mutations, thus increasing the risk of cancer.

Obesity and Infertility

Obesity is thought to account for around 6% of primary infertility [20].

Women:Many studies have observed increased risk of anovulatory infertility in obese women Cite error: Invalid <ref> tag; invalid names, e.g. too many. This is thought to be due to hyperandrogenism in which high androgen levels increase apoptosis of the granulosa cells, as well as damaging the endometrium and developing oocytes. Excess oestrogen also contributes to infertility by reducing gonadotrophin secretion through excess negative feedback [17]. One of the commonest reproductive disorders in women is PCOS, which affects 5-10% of women of reproductive age [23]. This syndrome is characterized by anovulatory infertility, obesity, hirsutism, multiple ovarian cysts and insulin resistance. Despite their being a well established association between obesity and PCOS, it remains unknown which is the cause and which is the effect. Figure 2 summarises the proposed endocrine basis of this syndrome.

Men:"Hyperestrogenic hypogonadotropic hypogonadism" in obese men results in high oestrogen levels, low testosterone levels and subsequent subfertility. Many studies have reported a negative association between spermatogenesis and increasing BMI. The mechanism mediating this association is yet to be identified, but it has been suggested that hypoandrogenism in obese males may result in a reduced production of testosterone by the testes. The observed hyperestrogenism may also cause inappropriate suppression of the hypothalamic-pituitary-gonadal axis, resulting in reduced spermatogenesis. Obesity has also been associated with erectile dysfunction. [17]

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 [24]. Early studies exploring the relationship were consistent with the “jolly fat” hypothesis, suggesting that obesity confers a protective role against anxiety and depressive disorders;[24] however, more recent studies contradict the “jolly fat” hypothesis and suggest that depression and obesity are functionally linked. [25] [26].

Recent hypotheses linking obesity and aggression: The underlying mechanisms and direction of an obesity-depression link remain largely unknown, 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.[24] [27][28][29]. These newly discovered mediators give rise to new hypotheses, involving over-activity of the hypothalamic-pituitary-adrenocortical axis.

Experimental evidence: A recent nationally representative Canadian study, whose methodology controlled for sociodemographic factors and comorbid physical health problems, found positive relationships between obesity and an array of lifetime psychiatric disorders and past-year mood and anxiety disorders. These conclusions are consistent with current literature.[27] [29] [30][31][32]. 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)[26] These findings are consistent with previous research, and thus reinforce the notion that obese women have an enhanced vulnerability towards mental disorders. This result may be explained in terms of the increased consciousness amongst women to conform to a socially desirable image and weight. The study also positively linked obesity to suicidal behaviours and negatively linked obesity with past-year drug dependence; both these findings are supportive of existing literature.6,[31][33] 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 [26][34]

Contradictory experimental evidence: At face value, these data appear convincing, but some studies fail to identify mental disorders as a psychosocial consequence of obesity [35][36]. Similarly, whilst much research indicates sex differences between obesity and mental disorders, this is not a unanimous conclusion. In addition, some research only identifies associations amongst the severely obese, who illustrate a BMI of >35kg/m2 [29]. These variable conclusions may in part be attributed to methodological differences between studies.

References

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  2. ↑ Kopelman PG (2000) Obesity as a medical problem Nature 404:635-42
  3. ↑ Gaal LFV et al.(2006) Mechanisms linking obesity with cardiovascular disease Nature 444:875-9
  4. ↑ Mathew B et al. {2008) Obesity: effects on cardiovascular disease and its diagnosis. J Am Board Fam Med 21:562-8
  5. ↑ Angulo P (2007) Obesity and nonalcoholic fatty liver disease, Nutr Rev 65:s57-s63
  6. ↑ 6.0 6.1 6.2 Angulo P (2002) Nonalcoholic fatty liver disease New Eng J Med 346:1221-123
  7. ↑ Stranges S et al.(2004) Body fat distribution, relative weight, and liver enzyme levels: a population based study Hepatology 39; 754-63
  8. ↑ Fan Cet al.(1998)Steatohepatitis, spontaneousperoxisome proliferation and liver tumours in mice lacking fatty acyl CoA ocidase; implications for peroxisome proliferator activated receptor alpha ligand metabolism J Biol Chem 273:15639-45
  9. ↑ Chavin KD et al. (1999) Obesity increases expression of uncoupling protein 2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 274:5692-700
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  12. ↑ Telphy T et al. identification of N-methylprotophorphyran ix in livers of untreated mice and mice treated with 3,5- dieethoxycarbonyl-1.4-dihydorcollidine; source of the methyl group; Arch Bio Chem Biophys 1981; 212; 120-126
  13. ↑ Purohit A, Reed MJ (2002) Regulation of oestrogen synthesis in postmenopausal women. Steroids 67:979-83
  14. ↑ 14.0 14.1 Bianchini F et al. (2002) Overweight, obesity, and cancer risk. Lancet Oncology 3:565-74 Cite error: Invalid <ref> tag; name "Bianchini2002" defined multiple times with different content
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  16. ↑ Simpson ER (2000) Role of aromatase in sex steroid action. J Mol Endocrinol 25:149-56
  17. ↑ 17.0 17.1 17.2 Hammoud AO et al. Obesity and male reproductive potential J Androl 27:619–25 Cite error: Invalid <ref> tag; name "Hammoud" defined multiple times with different content
  18. ↑ Lukanova A et al. (2004) Body mass index, circulating levels of sex steroid hormones, IGF-1 and IGF-binding protein-3: a cross-sectional study in healthy women. Eur J Enodcrinol 190:161-71
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  20. ↑ 20.0 20.1 20.2 Haslam DW, James WP (2005) Obesity Lancet 366:1197-209 Cite error: Invalid <ref> tag; name "Haslam2005" defined multiple times with different content
  21. ↑ 21.0 21.1 Lukanova A et al. (2004) Body mass index, circulating levels of sex steroid hormones, IGF-1 and IGF-binding protein-3: a cross-sectional study in healthy women. Eur J Enodcrinol 190:161-71 Cite error: Invalid <ref> tag; name "lukanova2004" defined multiple times with different content
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  23. ↑ Strauss JF, Dunaif A (1999) Molecular mysteries of polycystic ovary syndrome Mol Endocrinol 13;800-5
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  35. ↑ Hasler G et al.(2004). The associations between psychopathology and being overweight: A 20-year prospective study. Psychol Med 34:1047–157
  36. ↑ Faith MS et al. (2002). Obesity-depression associations in the population. J Psychosom Res 53:935–942
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