Health consequences of obesity: Difference between revisions

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''''Introduction''''
{{Image|Obesity final.jpg|right|450px|(Adapted from <ref>Boon NA ''et al.'' (2006) ''Davidson's Principles and Practice of Medicine'' p 111</ref>)}}
{{Image|Obesity final.jpg|right|250px|Summary of the health consequences of obesity (Adapted from 1)}}
[[Obesity]] is conveniently defined according to [[Body Mass Index]] (BMI) such that a BMI in excess of 30kg/m<sup>2</sup> categorises someone as obese; the main  '''health consequences of obesity''' are summarised below. 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 discussed in [[Diabesity]].


='''Physiological Consequences of Obesity'''=
===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<ref name=Kopelman2000> Kopelman PG (2000) Obesity as a medical problem ''Nature'' 404:635-42 PMID 10766250</ref>. Obesity increases the risk of cardiovascular disease and premature death, and this 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<ref name=Gaal2006>Gaal LFV ''et al.''(2006) Mechanisms linking obesity with cardiovascular disease ''Nature'' 444:875-9</ref>. Waist-hip ratios are commonly used to assess this type of body fat distribution.


==Cardiovascular Disease in Obesity==
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]]. As a result, the [[left ventricle]] dilates to accommodate the increased venous return with subsequent development of eccentric hypertrophy to keep the wall stress normal<ref name=Mathew2008>Mathew B ''et al.'' {2008) Obesity: effects on cardiovascular disease and its diagnosis ''J Am Board Fam Med'' 21:562-8 PMID 18988724</ref>. 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|slide1.jpg|right|500px|}}
[[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. [[Arrhythmia]]s 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.


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(2).
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 decreases CHD risk by 8%. Physical activity increases myocardial oxygen supply, improving myocardial contraction and electrical stability. <ref name=Gaal2006/>  Obesity is an independent predictor of [[coronary artery disease]], and this is also linked to BMI; 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 was related to the amount of abdominal fat and BMI.<ref name=Mathew2008 />


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(3).  Waist-hip ratios are commonly used to assess this type of body fat distribution.
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 haemorrhagic stroke by 6%. The underlying mechanisms linking increased BMI to increased stroke risk are not clear but it is thought that they could involve the prothrombotic and proinflammatory state in obesity. Adipose tissue is as an active endocrine organ: release of [[adipokine]]s (including [[leptin]] and [[adiponectin]]), proinflammatory cytokines (IL-6 and CRP) and hypofibrinolytic factors (PAI-1) might, together, lead to increased oxidative stress and endothelial dysfunction, promoting atherosclerosis which then leads to [[stroke]].<ref name=Gaal2006 /> Terao ''et al.'' (2008) investigated the effect of inflammatory and injury reposonse to ischaemic stroke in obese mice; when the middle cerebral artery was occluded and reperfused, the inflammatory and injury responses were worse in genetically obese mice (''ob/ob'') than in wild-type mice<ref name=Terao2008>Terao S ''et al.'' (2008) Inflammatory and injury responses to ischemic stroke in obese mice ''Stroke'' 39:943-50</ref>.  Monoctye chemoattractant protein-1 appears to be involved in the exaggerated responses to ischaemic stroke in obese mice.
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 output (2).  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 and the dilation of LV results in decreased ventricular contractility(2).  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(2). [PICTURE] Hypertension also becomes more prevalent with increasing severity of obesity(4).  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(4).
Fatal arrhythmias may be the most frequent cause of death among obese people as increased catecholamine and free fatty acid levels may affect repolarization(4).  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(4).  A QTc of more than 0.42 seconds was associated with increased mortality in “healthy” obese patients(4).  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%(3).  Physical activity attenuates the risks of obesity on coronary health and also increases myocardial oxygen supply, improving myocardial contraction and electrical stability(3).  Various studies have shown that obesity is an independent predictor of coronary artery disease and this is also linked to BMI(4) 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(4).
 
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(4). Adipose tissue is considered as an active endocrine organ(3).  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(3). 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(5).  Monoctye chemoattractant protein-1 appears to be involved in the exaggerated responses to ischaemic stroke in obese mice.


== Non-alcoholic liver disease and obesity ==
== Non-alcoholic liver disease and obesity ==
 
[[Nonalcoholic fatty liver disease]] is an accumulation of fat (mainly [[triglyceride]]s) in the hepatocytes that exceeds 5% of the liver weight, a condition known as ''[[steatosis]].''  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.<ref name=angulo2002>Angulo P (2002) Nonalcoholic fatty liver disease ''New Eng J Med'' 346:1221-3</ref> The ratio of aspartate aminotransferase to alanine aminotransferase is usually less than 1, but as fibrosis in the liver advances, this ratio increases. NAFLD affects 10 -24% of the world’s population, and 58-74% of obese persons, including 2.6% of children and 23-53% of obese children.<ref name=Angulo2007>Angulo P (2007) Obesity and nonalcoholic fatty liver disease, ''Nutr Rev'' 65:s57-s63</ref>.
 
'''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:'''
'''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)
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.<ref name=stranges2004>Stranges S ''et al.''(2004) Body fat distribution, relative weight, and liver enzyme levels: a population based study ''Hepatology'' 39:754-63</ref>
 
'''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:'''
'''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.  
[[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 the oxidation of long fatty acid chains and dicarboxilic acids, leading to microvesicular steatosis and steatohepatitis. Loss of function of acyl-coenzyme A oxidase also causes sustained hyperactivation of [[peroxisome proliferator activated receptor-α]] (PPAR- α), leading to upregulation of PPAR-α regulated genes <ref name=Fan1998>Fan C''et 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</ref>. Studies suggest that PPAR-α is responsible for promoting the synthesis of [[uncoupling protein]] 2 in the liver <ref name=Chavin1999>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</ref>. Increased levels of fatty acids in the liver provide a source of oxidative stress, which is thought to be responsible for the progression from steatosis to steatohepatitis and finally to cirrhosis.  
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


'''The role of the keratin cytosleleton'''
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 filament]]s in the [[cytoplasm]]. In NAFLD, the keratin cytoskeleton in hepatocytes is disrupted, <ref name=Zatoukal2003>Zatloukal K (2003) The keratin cytoskeleton in liver diseases ''J Pathol'' 204:367-76</ref> apparently due to [[oxidative stress]].<ref name=Zatoukal2003 />


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


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:''' [[Oestrogen]]s are synthesized by aromatization of circulating [[testosterone]]s, catalysed by the enzyme [[aromatase]]. This occurs at many sites throughout the body, including in adipose tissue <ref name=Purohit2002>Purohit A, Reed MJ (2002) Regulation of oestrogen synthesis in postmenopausal women. ''Steroids'' 67:979-83</ref> <ref name=Bianchini2002>Bianchini F ''et al.'' (2002) Overweight, obesity, and cancer risk. ''Lancet Oncol'' 3:565-74</ref>. An increase in adipose tissue mass results in a greater capacity for aromatization, and an increase in oestrogen levels <ref name=Bates1982>Bates GW, Whitworth N (1982) Effects of obesity on sex steroid metabolism. ''J Chronic Dis'' 35:893</ref>.
 
'''Oestrogens:''' Oestrogens are synthesized by aromatization of circulating testosterones, catalysed by the enzyme aromatase (12.)  This process occurs at many sites throughout the body including adipose tissue (9, 10). Therefore, an increase in adipose tissue mass, results in a greater capacity for aromatization, and an increase in oestrogen levels (11.)
 
In premenopausal, non-pregnant women, the principal site of aromatization is the ovaries (12) 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 (12.)


'''Androgens''':  The increased capacity for aromatization results in hypoandrogenism in males, as a higher proportion of circulating testosterone is converted to oestrogen (13.)  Other factors contributing to the decrease in circulating testoerone include insulin resistance and the suppression of the hypothalamic pituitary testicular axis (13.)
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 <ref name=Simpson2000>Simpson ER (2000) Role of aromatase in sex steroid action. ''J Mol Endocrinol'' 25:149-56</ref>.


In contrast, in obese premenopausal women, obesity is associated with an increase in free testosterone levels (14.)  This is thought to be partly mediated by the increased levels of insulin and IGF-1 associated with obesity (14, 15.)   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 dehydrogenase (14.) Therefore there is a positive association between adipose tissue mass and androgen concentration.
'''Androgens''':  The increased capacity for aromatization results in hypoandrogenism in males, as more circulating testosterone is converted to oestrogen <ref name=Hammoud>Hammoud AO ''et al.'' Obesity and male reproductive potential ''J Androl'' 27:619–25</ref>. Other factors contributing to the decrease in circulating testosterone include insulin resistance and the suppression of the hypothalamo-pituitary-testicular axis. In contrast, in obese premenopausal women, obesity is associated with an increase in free testosterone levels <ref name=Lukanova2004>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 Endocrinol'' 190:161-71</ref> This is thought to be partly mediated by the increased levels of insulin and IGF-1 associated with obesity.<ref name=Metwally2007>Metwally M ''et al.''(2007) The impact of obesity on female reproductive function ''Obesity Rev''' 8:515-23</ref> 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 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 (16l.)  This is thought to be associated with the rise in insulin levels associated with obesity, as insulin inhibits hepatic synthesis of SHBG (16.)  The decreased concentration of binding protein results in an increase in the free fraction of sex steroids (14.)
'''SHBG:''' Sex steroids are highly lipophilic and are carried in the circulation bound to [[sex hormone binding globulin]]s (SHBG.)  Obesity results in a decreased concentration of SHBG <ref name=Haslam2005>Haslam DW, James WP (2005) Obesity ''Lancet'' 366:1197-209</ref>. This is thought to be associated with the elevated 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 <ref name= Lukanova2004 />
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Fig 2:  Summary of the endocrine changes in obesity
'''Summary of the endocrine changes in obesity'''


==Obesity and Cancer==
==Obesity and Cancer==
 
It is estimated that 10% of all [[cancer]] deaths among non-smokers are related to obesity <ref name=Haslam2005>Haslam DW, James WP (2005) Obesity ''Lancet'' 366:1197-209</ref>. 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.  <ref name=Bianchini2002/><ref name=Lukanova2004 /> These observations led to the ''unopposed oestrogen hypothesis'', which suggests that mitotic activity of cells is increased in the presence of oestrogen, unopposed by progestogens. <ref name=Key1988>Key TJ, Pike MC (1988) The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk ''B J Cancer'' 57:205-12
It is estimated that 10% of all cancer deaths among non-smokers are related to obesity (17.) Many hypotheses have been proposed to explain this. It is hypothesised that alterations in endogenous hormone metabolism mediate the effects of obesity on cancer risk, due to sex steroid hormone regulation of cell proliferation, differentiation and apoptosis (10.)
</ref>. Increased mitotic activity leads to a higher prevalence of mutations, thus increasing the risk of cancer.
 
Many types of cancer are more prevalent in obese subjects, the most widely studied of which are breast and endometrial cancer.  These types of cancer are associated with an increase in oestrogen concentration, a decrease in plasma SHBG and an increase in androgen levels.  (10, 14)  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 (18.) Increased mitotic activity leads to a higher prevalence of mutations occurring, thus increasing the risk of developing cancer.


==Obesity and Infertility==
==Obesity and Infertility==


Obesity is thought to account for around 6% of primary infertility (17.)
Obesity is thought to account for around 6% of primary infertility <ref name=Haslam2005>Haslam DW, James WP (2005) Obesity ''Lancet'' 366:1197-209</ref>.
 
'''Women:'''Many studies have observed increased risk of anovulatory infertility in obese women (15.)  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 (11, 15).  Excess oestrogen also contributes to infertility by reducing gonadotrophin secretion through excess negative feedback (17, 13.)
 
One of the commonest reproductive disorders in women is PCOS, which affects 5-10% of women of reproductive age (19.)  This syndrome is characterized by anovulatory infertility, obesity, hirsutism, multiple ovarian cysts and insulin resistance (16.)  Despite their being a well established association between obesity and PCOS, it remains unknown which is the cause and which is the effect. (15, 19) 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 (13.)
 
Many studies have reported a negative association between spermatogenesis and increasing BMI (13.)  The mechanism mediating this association is yet to be identified.  However, it has been suggested that hypoandrogenism in obese males may result in a reduced concentration of testosterone within the testes (13.) The observed hyperestrogenism may also contribute to infertility as it causes inappropriate suppression of the hypothalamic-pituitary-gonadal axis, resulting in reduced spermatogenesis.  Obesity has also been associated with erectile dysfunction (13.)
 
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 <ref> 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 </ref>. 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.
[[User:Rachael White|Rachael White]] 15:09, 23 October 2009 (UTC)
 
 
You can also cite published work accessible online.
<ref>"Part 2," Appetite and obesity. 2006. Retrieved July 21, 2009 from [http://www.appetiteandobesity.org/part2.html http://www.appetiteandobesity.org/part2.html]</ref>
 
 
You can also cite published work from books.
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==References==
 
1.  Boon NA, Colledge NR, Walker BR.  Davidson's Principles and Practice of Medicine. 2006.  p 111
 
2.  Kopelman P.G.  Obesity as a medical problem. Nature 2000; 404:635-642.
 
3.  Gaal L.F.V. et al.  Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444:875-879.
 
4.  Mathew B. et al. Obesity: effects on cardiovascular disease and its diagnosis. J Am Board Fam Me 2008; 21:562-568.
 
5.  Terao S. et al.  Inflammatory and injury responses to ischemic stroke in obese mice. Stroke; 2008. 39:943-950
 
6. Paul Angulo, Obesity and Nonalcoholic fatty Liver Disease, Nutrition reviews, vol 65, 6, 2007, s57-s63
 
7. Paul Angulo, Nonalcoholic fatty liver disease, New England Journal of Medicine, vol346, 16, 2002, 1221-1231
 
8. 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
 
9.  Purohit A, Reed MJ.  Regulation of oestrogen synthesis in postmenopausal women.  Steroids 2002:  67; 979-983
 
10. Bianchini F, Kaaka R, Vainio H.  Overweight, obesity, and cancer risk.  The Lancet Oncology 2002; 3: 565-574
 
11,  Bates GW, Whitworth N.  Effects of obesity on sex steroid metabolism. Journal Chronic Diseases 1982; 35: 893
 
12. Simpson ER.  Role of aromatase in sex steroid action.  Journal of Molecular Endocrinology (2000);25: 149-156
 
13. Hammoud AO, Gibson M, Peterson CM et al.  Obesity and Male Reproductive Potential.  Journal of Andrology:  27; 619 – 625


14. Lukanova A, Lundin E et al.  Body mass index, circulating levels of sex steroid hormones, IGF-1 and IGF-binding protein-3: a cross-sectional study in healthy women. European Journal of Enodcrinology 2004; 190: 161-171
'''Women:''' Obese women are at increased risk of anovulatory infertility<ref name=Metwally2007/>. This is thought to be due to hyperandrogenism in which high androgen levels increase apoptosis of the [[granulosa cell]]s, as well as damaging the [[endometrium]] and developing [[oocyte]]s.  Excess oestrogen also contributes to infertility by reducing [[gonadotrophin]] secretion through excess negative feedback <ref name=Hammoud/>. One of the commonest reproductive disorders in women is PCOS, which affects 5-10% of women of reproductive age <ref name=Strauss1999>Strauss JF, Dunaif A (1999) Molecular mysteries of polycystic ovary syndrome ''Mol Endocrinol'' 13;800-5</ref>. This syndrome is characterized by anovulatory infertility, obesity, [[hirsutism]], multiple [[ovarian cyst]]s 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.  


15. Metwally M, Li TC, Ledger L. The impact of obesity on female reproductive function. Obesity Reviews 2007; 8: 515-523
'''Men:''' "Hyperestrogenic hypogonadotropic hypogonadism" in obese men results in high oestrogen levels, low testosterone levels and subfertility. There is 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 hyperestrogenism may also cause inappropriate suppression of the hypothalamic-pituitary-gonadal axis, resulting in reduced [[spermatogenesis]]. Obesity has also been associated with [[erectile dysfunction]]. <ref name=Hammoud />


16.  Bray AG. Obesity and Reproduction. Human Reproduction 1997; 12: 26-32
==='''Psychosocial Consequences of Obesity'''===
The relationship between obesity and mental health has been the subject of debate over the past 30 years.  Early studies were consistent with the “jolly fat” hypothesis, suggesting that obesity confers a protective role against [[anxiety]] and depressive disorders, but more recent studies suggest that depression and obesity are linked. <ref name=Stunkard2003>Stunkard AJ ''et al.'' (2003) Depression and obesity ''Soc Biol Psychiat'' 54:330-7</ref> <ref name=Mather2009>Mather AA ''et al.'' (2009) Association of obesity with psychiatric disorders and suicidal behaviours in a nationally representative sample. ''J Psychosomatic Res''66:277-85</ref>. 


17. Haslam, D.W. and James, W.P  Obesity. Lancet 2995;  366:1197-1209.
'''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.<ref name= Rivenes2009>Rivenes, AC ''et al.''(2009) The relationship between abdominal fat, obesity, and common mental disorders: results from the HUNT Study ''J Psychosomatic Res'' 66:269-75</ref> <ref name=Simon>Simon GE ''et al.'' (2008) Association between obesity and depression in middle-aged women ''Gen Hosp Psychiat'' 30:32-9</ref> <ref name=Scott2008>Scott KM ''et al.''(2008) Obesity and mental disorders in the general population: results from the World Mental Health Surveys ''Int J Obes'' 32:192-200</ref> These newly discovered mediators give rise to new hypotheses, involving over-activity of the [[hypothalamic-pituitary-adrenocortical]] axis.


18. Key TJ, Pike MC.  The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. British Journal of Cancer 1988: 57; 205-12
'''Experimental evidence:''' A nationally representative Canadian study found positive relationships between obesity and an array of lifetime psychiatric disorders and past-year mood and anxiety disorders. These <ref name=Stunkard2003/> <ref name=Scott2008/> <ref name=Simon /><ref name=Carpenter2000>Carpenter KM ''et al.''(2000) Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study ''Am J Pub Health'' 90:251–7</ref><ref name=Onyike2003>Onyike CU ''et al.''(2003) Is obesity associated with major depression? Results from the third National Health and utrition examination survey. ''Am J Epidemiol'' 158:1139–47</ref>. Subgroup analyses revealed that obese women were more susceptible to specific mental disorders than men, including [[depression]], mania, [[panic attack]]s, panic disorder, [[social phobia]] and [[agoraphobia]].<ref name=Mather2009/> These findings, which are consistent with other research, thus reinforce the notion that obese women are more vulnerable to developing 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.<ref name=Dong2006>Dong C ''et al.''(2006) Extreme obesity is associated with suicide attempts: results from a family study ''Int J Obes'' 30:388-90</ref> 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 <ref name=Mather2009/><ref name=Kleiner2004>Kleiner KD ''et al.''(2004) Body mass index and alcohol use ''J Addict Dis'' 23:105-18</ref>
           
'''Contradictory evidence:''' Some studies fail to identify mental disorders as a psychosocial consequence of obesity <ref name=Hasler2004>Hasler G ''et al.''(2004) The associations between psychopathology and being overweight: A 20-year prospective study ''Psychol Med'' 34:1047–157</ref><ref name=Faith2002>Faith MS ''et al.'' (2002) Obesity-depression associations in the population. ''J Psychosom Res'' 53:935–942</ref>.  Similarly, whilst much research indicates sex differences between obesity and mental disorders, this is not a universal conclusion. In addition, some research only identifies associations amongst the severely obese, with a BMI of >35kg/m<small>2</small> <ref name=Scott2008/>. These variable conclusions may reflect methodological differences between studies.


19. Strauss JF, Dunaif A.  Molecular Mysteries of Polycystic Ovary Syndrome.  Molecular Endrocinology 1999: 13; 800-805
==References==  
{{reflist | 2}}[[Category:Suggestion Bot Tag]]

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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 below. 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 discussed in Diabesity.

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, and this 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. As a result, 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.

Slide1.jpg

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. 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 decreases CHD risk by 8%. Physical activity increases myocardial oxygen supply, improving myocardial contraction and electrical stability. [3] Obesity is an independent predictor of coronary artery disease, and this is also linked to BMI; 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 was related to the amount of abdominal fat and BMI.[4]

The risk of strokeincreases 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 haemorrhagic stroke by 6%. The underlying mechanisms linking increased BMI to increased stroke risk are not clear but it is thought that they could involve the prothrombotic and proinflammatory state in obesity. Adipose tissue is as an active endocrine organ: release of adipokines (including leptin and adiponectin), proinflammatory cytokines (IL-6 and CRP) and hypofibrinolytic factors (PAI-1) might, together, lead to increased oxidative stress and endothelial dysfunction, promoting atherosclerosis which then leads to stroke.[3] Terao et al. (2008) investigated the effect of inflammatory and injury reposonse to ischaemic stroke in obese mice; when the middle cerebral artery was occluded and reperfused, the inflammatory and injury responses were worse in genetically obese mice (ob/ob) than in wild-type mice[5]. 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. 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. NAFLD affects 10 -24% of the world’s population, and 58-74% of obese persons, including 2.6% of children and 23-53% of obese children.[7].

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.[8]

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 the oxidation of long fatty acid chains and dicarboxilic acids, leading to microvesicular steatosis and steatohepatitis. Loss of function of acyl-coenzyme A oxidase also causes sustained hyperactivation of peroxisome proliferator activated receptor-α (PPAR- α), leading to upregulation of PPAR-α regulated genes [9]. Studies suggest that PPAR-α is responsible for promoting the synthesis of uncoupling protein 2 in the liver [10]. Increased levels of fatty acids in the liver provide a source of oxidative stress, which is thought to be responsible for the progression from steatosis to steatohepatitis and finally to cirrhosis.

The role of the keratin cytosleleton 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, [11] apparently due to oxidative stress.[11]

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 in adipose tissue [12] [13]. An increase in adipose tissue mass results in a greater capacity for aromatization, and an increase in oestrogen levels [14].

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 [15].

Androgens: The increased capacity for aromatization results in hypoandrogenism in males, as more circulating testosterone is converted to oestrogen [16]. Other factors contributing to the decrease in circulating testosterone include insulin resistance and the suppression of the hypothalamo-pituitary-testicular axis. In contrast, in obese premenopausal women, obesity is associated with an increase in free testosterone levels [17] This is thought to be partly mediated by the increased levels of insulin and IGF-1 associated with obesity.[18] 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 sex hormone binding globulins (SHBG.) Obesity results in a decreased concentration of SHBG [19]. This is thought to be associated with the elevated 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 [17]

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

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 [19]. 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. [13][17] These observations led to the unopposed oestrogen hypothesis, which suggests that mitotic activity of cells is increased in the presence of oestrogen, unopposed by progestogens. [20]. 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 [19].

Women: Obese women are at increased risk of anovulatory infertility[18]. 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 [16]. One of the commonest reproductive disorders in women is PCOS, which affects 5-10% of women of reproductive age [21]. 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.

Men: "Hyperestrogenic hypogonadotropic hypogonadism" in obese men results in high oestrogen levels, low testosterone levels and subfertility. There is 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 hyperestrogenism may also cause inappropriate suppression of the hypothalamic-pituitary-gonadal axis, resulting in reduced spermatogenesis. Obesity has also been associated with erectile dysfunction. [16]

Psychosocial Consequences of Obesity

The relationship between obesity and mental health has been the subject of debate over the past 30 years. Early studies were consistent with the “jolly fat” hypothesis, suggesting that obesity confers a protective role against anxiety and depressive disorders, but more recent studies suggest that depression and obesity are linked. [22] [23].

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] [25] [26] These newly discovered mediators give rise to new hypotheses, involving over-activity of the hypothalamic-pituitary-adrenocortical axis.

Experimental evidence: A nationally representative Canadian study found positive relationships between obesity and an array of lifetime psychiatric disorders and past-year mood and anxiety disorders. These [22] [26] [25][27][28]. Subgroup analyses revealed that obese women were more susceptible to specific mental disorders than men, including depression, mania, panic attacks, panic disorder, social phobia and agoraphobia.[23] These findings, which are consistent with other research, thus reinforce the notion that obese women are more vulnerable to developing 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.[29] 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 [23][30]

Contradictory evidence: Some studies fail to identify mental disorders as a psychosocial consequence of obesity [31][32]. Similarly, whilst much research indicates sex differences between obesity and mental disorders, this is not a universal conclusion. In addition, some research only identifies associations amongst the severely obese, with a BMI of >35kg/m2 [26]. These variable conclusions may reflect methodological differences between studies.

References

  1. ↑ Boon NA et al. (2006) Davidson's Principles and Practice of Medicine p 111
  2. ↑ Kopelman PG (2000) Obesity as a medical problem Nature 404:635-42 PMID 10766250
  3. ↑ 3.0 3.1 3.2 Gaal LFV et al.(2006) Mechanisms linking obesity with cardiovascular disease Nature 444:875-9
  4. ↑ 4.0 4.1 Mathew B et al. {2008) Obesity: effects on cardiovascular disease and its diagnosis J Am Board Fam Med 21:562-8 PMID 18988724
  5. ↑ Terao S et al. (2008) Inflammatory and injury responses to ischemic stroke in obese mice Stroke 39:943-50
  6. ↑ Angulo P (2002) Nonalcoholic fatty liver disease New Eng J Med 346:1221-3
  7. ↑ Angulo P (2007) Obesity and nonalcoholic fatty liver disease, Nutr Rev 65:s57-s63
  8. ↑ Stranges S et al.(2004) Body fat distribution, relative weight, and liver enzyme levels: a population based study Hepatology 39:754-63
  9. ↑ 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
  10. ↑ 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
  11. ↑ 11.0 11.1 Zatloukal K (2003) The keratin cytoskeleton in liver diseases J Pathol 204:367-76
  12. ↑ Purohit A, Reed MJ (2002) Regulation of oestrogen synthesis in postmenopausal women. Steroids 67:979-83
  13. ↑ 13.0 13.1 Bianchini F et al. (2002) Overweight, obesity, and cancer risk. Lancet Oncol 3:565-74
  14. ↑ Bates GW, Whitworth N (1982) Effects of obesity on sex steroid metabolism. J Chronic Dis 35:893
  15. ↑ Simpson ER (2000) Role of aromatase in sex steroid action. J Mol Endocrinol 25:149-56
  16. ↑ 16.0 16.1 16.2 Hammoud AO et al. Obesity and male reproductive potential J Androl 27:619–25
  17. ↑ 17.0 17.1 17.2 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 Endocrinol 190:161-71
  18. ↑ 18.0 18.1 Metwally M et al.(2007) The impact of obesity on female reproductive function Obesity Rev' 8:515-23
  19. ↑ 19.0 19.1 19.2 Haslam DW, James WP (2005) Obesity Lancet 366:1197-209
  20. ↑ Key TJ, Pike MC (1988) The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk B J Cancer 57:205-12
  21. ↑ Strauss JF, Dunaif A (1999) Molecular mysteries of polycystic ovary syndrome Mol Endocrinol 13;800-5
  22. ↑ 22.0 22.1 Stunkard AJ et al. (2003) Depression and obesity Soc Biol Psychiat 54:330-7
  23. ↑ 23.0 23.1 23.2 Mather AA et al. (2009) Association of obesity with psychiatric disorders and suicidal behaviours in a nationally representative sample. J Psychosomatic Res66:277-85
  24. ↑ Rivenes, AC et al.(2009) The relationship between abdominal fat, obesity, and common mental disorders: results from the HUNT Study J Psychosomatic Res 66:269-75
  25. ↑ 25.0 25.1 Simon GE et al. (2008) Association between obesity and depression in middle-aged women Gen Hosp Psychiat 30:32-9
  26. ↑ 26.0 26.1 26.2 Scott KM et al.(2008) Obesity and mental disorders in the general population: results from the World Mental Health Surveys Int J Obes 32:192-200
  27. ↑ Carpenter KM et al.(2000) Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study Am J Pub Health 90:251–7
  28. ↑ Onyike CU et al.(2003) Is obesity associated with major depression? Results from the third National Health and utrition examination survey. Am J Epidemiol 158:1139–47
  29. ↑ Dong C et al.(2006) Extreme obesity is associated with suicide attempts: results from a family study Int J Obes 30:388-90
  30. ↑ Kleiner KD et al.(2004) Body mass index and alcohol use J Addict Dis 23:105-18
  31. ↑ Hasler G et al.(2004) The associations between psychopathology and being overweight: A 20-year prospective study Psychol Med 34:1047–157
  32. ↑ Faith MS et al. (2002) Obesity-depression associations in the population. J Psychosom Res 53:935–942
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