Obesity, Mood and Well-Being

Obesity, Mood and Well-Being

In studies of the general population, early studies showed few consistent patterns with
respect to psychosocial distress and obesity, partly due to small samples and varying
assessment tools. The relationship between BMI, smoking status, and depressive
symptoms was studied in a large US national sample, using validated instruments.
The investigators found that the relationship between obesity and depression varied
by sex. Among women, but not men, greater BMI was weakly associated with elevated
reports of depressive symptoms. This relationship remained significant after
controlling for age, years of education, and smoking status, indicating that relative
body weight is weakly related to psychological distress among women but not men. Another US study sought to test the relationships between relative body weight
and clinical depression, suicidal thoughts and suicide attempts in an adult US general
population sample comprising over 40,000 people. Outcome measures were past year
major depression, suicidal thoughts and suicide attempts. Among women, increased
BMI was associated with both major depression and suicide ideation. Among men,
lower BMI was associated with major depression, suicide attempts and suicidal
thoughts. There were no racial differences. Studies of clinical populations have used psychometric instruments for assessment of mental health and psychological functioning in obese individuals and compared them with healthy reference populations. In a much-cited Swedish study ,
severely obese men and women reported distinctly poorer current health and less
positive mood states than the reference subjects, a situation that was worse in women
than in men. Anxiety and/or depression on a level indicating psychiatric morbidity
were more often seen in the obese, again more often in women. The obese subjects
rated their mental well-being worse than chronically ill or injured patients, for example
patients with rheumatoid arthritis, cancer survivors with no recurrence and
spinal-cord injured persons several years after injury. These symptoms improved
with subsequent weight loss from bariatric surgical treatment, providing further support
for the idea that obesity was driving the psychological impairment. In contrast to the widely accepted view that much of the observed psychopathology
associated with obesity is secondary to the obesity itself, one line of research suggests
that psychosocial stress induces central obesity and the metabolic syndrome. Originally suggested by Björntorp and colleagues, subsequent research has been
hampered by largely cross-sectional designs and lack of prospective data. However, a
recent study found that the effect of job strain on subsequent weight change was
dependent on baseline BMI in men but not in women . In the leanest quintile
(BMI 22) at baseline, high job strain and low job control were associated with
weight loss, whereas among those in the highest BMI quintile ( 27), these stress
indicators were associated with subsequent weight gain. No corresponding interaction
between baseline BMI and weight change was seen among women. Furthermore,
the metabolic syndrome, with abdominal obesity as an important determinant, was
recently demonstrated to be closely related to cumulative exposure to work stressors
over 14 years, independent of other relevant risk factors. Employees with chronic
work stress (three or more exposures) were more than twice as likely to have the syndrome
compared to those without work stress. Altered adrenocortical function
induced by stress might influence hepatic lipoprotein metabolism and insulin sensitivity
at target organs, providing a partial explanation for the social inequalities in
obesity and obesity-related disorders. However, given the recent development with
decreasing socioeconomic differences in obesity seen in the US this is obviously a
complex issue.
Other than the conventional view of obesity as a condition carrying both medical
and psychosocial disabilities to the individual, obesity may also been viewed as a sociological
problem deriving from current cultural norms of beauty, normality and socially
acceptable behaviour. In other cultural contexts, where food was less plentiful, obesity
was often considered beautiful. On the other hand, a negative attitude towards obesity,
with stigmatisation of obese individuals, is not entirely a recent phenomenon, with
ascetism and self-denial idealised in many Western societies throughout the centuries.
One of the views driving the stigma of obesity is the notion that it is self-inflicted, with
the cardinal sins of sloth and gluttony emanating from low morals and poor character.
Despite increasing knowledge about the importance of heritability in obesity, and the
societal changes behind the obesity epidemic, these attitudes still prevail.
The growing stigma attached to all degrees of overweight reflects a society with a
contemporary ideal of extreme leanness. There is a belief that this attitude is setting
the stage for an epidemic of dieting and eating disorders.
One of the repeating themes emerging from research on psychosocial aspects of
obesity is the necessity for a gender perspective. Medically, due to the greater likelihood
of central adiposity in men, obesity may be said to confer a greater risk among
males. However, there is much evidence suggesting that the psychological and social
consequences of obesity are far worse for women. Even so, it should be noted that
increased prevalence of body dissatisfaction is occurring in both men and women.
Is there an association between obesity and depression? In Western society, being
overweight has been associated with increased risk for low self-esteem and depression.
It has, however, not been quite clear whether obesity increases the risk of
depression, or if depression increases the risk of obesity, or if there is a reciprocal relation
such that the obese are at increased risk of depression and the depressed are at
increased risk of obesity. Roberts et al. summarised 11 studies studying this association
using cross-sectional or prevalence study designs, with seven of these finding
some evidence of greater risk of depression among the obese. But while seven of these
studies found support for the proposition that the obese are at a greater risk for
depression, evidence was not uniformly robust, and the temporal relation between
obesity and depression was unclear. In their own study of 2,123 adults age 50 and
older, participants reported their height, weight and depressive symptoms during
interviews in 1994 and 1999. Subjects who were obese in 1994 had twice the risk of
becoming depressed in 1999 than subjects who were not obese in 1994. They did not
find any support for depression predicting subsequent obesity, after adjusting for
baseline obesity, or limiting the analyses to the non-obese at baseline. Accordingly, to
date, there is little conclusive evidence that obesity is caused by depression, whereas
obese people do seem more prone to develop future depression.

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Stigmatisation in Obesity

Stigmatisation in Obesity

When considering psychological aspects of obesity, it is widely believed that most
psychological disturbances are more likely to be consequences, rather than causes, of
obesity. One of the most compelling illustrations was reported in the early 1990s,
based on 47 patients who were, on average, 66 kg overweight before surgery for morbid
obesity, who lost 45 kg or more subsequently and who successfully maintained
weight loss for at least 3 years. As a group, they perceived their previous morbid
obesity as having been extremely distressful. Most patients said that they would prefer
to be normal weight with a major handicap (deaf, dyslexic, diabetic, legally blind,
very bad acne, heart disease, one leg amputated) than to be morbidly obese. All
patients said they would rather be normal weight than a morbidly obese multi-millionaire.
Thus obesity, as perceived by obese individuals themselves, is an extremely
serious handicap, although not always perceived as such by others. A recent review
summarised that extreme obesity is associated with significant psychiatric morbidity
and impaired health-related quality of life that in many cases imposes a greater burden
of suffering than the physical complications of obesity.
A second issue is how the obese individuals are treated by others. Negative attitudes
are prevalent, and exacerbated by idealisation of thinness in many Western cultures.
There are numerous examples of obesity-related discrimination, including how
children perceive overweight and obese peers, among employers, students’ ideas
about suitable spouses. In a classic study on childhood stereotypes, young children
associated overweight in children with being lazy, dirty, stupid, cheats and liars. The perception of obesity as a self-inflicted condition creates little sympathy for
the obese. Studies of morbidly obese patients show that in many instances they feel
that they are treated disrespectfully by the medical profession because of their weight,
that people look critically at them and their shopping cart when they go shopping,
and that their spouses and children do not like them to accompany them to social
functions because of their weight. At the workplace, they often feel that they are
placed out of sight of the public and they may be passed over for promotion. When
the 47 patients studied by Rand and Macgregor were asked the same questions
after gastric bypass surgery which they had answered before the surgery, their
responses were dramatically different showing a much more positive view of their
own position. Therefore, these perceptions are reversible, following efficient treatment
of obesity. This demonstrates that the obese suffer not only from negative attitudes
but, in addition, also from frank discriminatory behaviour. Unsuccessful dieting may have negative psychological consequences, due to a sense
of distress, failure and self-blame assumed to accompany the visible consequences of
weight gain. The data supporting this are, however, mixed. In severely obese subjects,
the number of previous dieting attempts was associated with mood disturbance and
anxiety, and was a strong predictor of obesity-related psychosocial problems in women.
In contrast, an evaluation of young women before and after treatment at a weight clinic
did not detect any significant effect of one cycle of weight loss and regain on mood.

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Socioeconomic Status and Obesity

Socioeconomic Status and Obesity

Is it relevant, when discussing individual determinants of obesity, to consider the
common assumption that specific psychological and/or risk factor profiles are
causally related to obesity? The reverse question must also be asked: what is the evidence
that psychological and socioeconomic characteristics are not the consequences,
but rather the causes, of the obese state?
There has been a strong interest in studying the relation between socioeconomic status (SES) and obesity. Previous studies have shown that the association between
SES and obesity may vary by population, sex and age . H owever, a p erson’s body
weight status may also affect his/her education and occupational opportunities,
which subsequently affect his/her SES. A good understanding of the association
between obesity and SES has many important public health and policy implications,
particularly for the prevention and management of obesity. It is well known that obesity
is more prevalent in the lower socioeconomic classes and that this pattern is more
common among women than men. Even so, there is a varying relation of SES with
obesity between countries at different stages of development .
A landmark review of studies published prior to 1989 on SES and obesity proposed
that obesity in the developing world would be essentially a disease of the socioeconomic
elite . However, in a recent review from developing countries, the authors concluded from the studies they had
reviewed that obesity in the developing world is no longer a disease of groups with
higher SES. Additionally, the burden of obesity in each developing country tends to
shift towards the groups with lower SES as the country’s gross national product
increases. They also concluded that the shift of obesity in women with low SES apparently
occurs at an earlier stage of economic development than it does for men.
Socioeconomic gradients with respect to obesity, even in the Western world, are both
heterogeneous and in transition. For example, it has long been accepted that in the US
population, groups with low SES are at greater risk to be obese than people of high SES.
This perception, however, was challenged in a recent study . Based on nationally
representative data collected in the National Health and Nutrition Examination Surveys
from American adults since the 1970s, the findings indicated an overall trend of a weakening
association between SES and obesity, with differing patterns across ethnic groups.
In a study of children and young people grouped by race, sex, and age, different results
were observed in the association between overweight and SES. Between 1988–1994 and
1999–2002, the ratio in the prevalence of overweight in adolescent boys with a low or
high SES decreased from 2.5 to 1.1 and from 3.1 to 1.6 in girls (fig. 1) . Consistently
across almost all SES groups, the prevalence of overweight was much higher in blacks
than in whites, indicating highly complex patterns in the association of SES and overweight
. The authors speculated that television viewing might have been the primary
type of inactivity in poor adolescents during the early part of the period they were
studying, whereas computers and computer games became more widely accessible and
264 Rosengren · Lissner
affordable during the more recent part of the observation period, especially in high SES
groups. Accordingly, the energy intake and expenditure patterns of all adolescents
regardless of SES, particularly for white adolescent boys, became more similar, resulting
in smaller economic disparities of the proportion of overweight subjects. Similarly, data
from the US show that in the 70s there was as much as a 50% relative difference in obesity
prevalence among those with less than high school education, compared to people
with college education, but by 1999–2000, the difference had decreased to 14% .
Similar observations of a decreasing socioeconomic gradient in obesity were reported
in one Swedish study of young adults . These findings underline that individual
characteristics are probably not the main cause of the current obesity epidemic. In addition,
changing patterns of consumption and of physical activity directly affect socioeconomic
differences in a way that is not always predictable.
The other side of the obesity-SES association is whether obesity can be shown to be a
risk factor for subsequent changes in SES. Among the first studies indicating that obesity
might affect social mobility was based on a Swedish population-based sample of
women examined in the late 1960s showing that the shift toward higher socioeconomic
level since childhood was more common in normal-weight than in overweight women
. However, this study did not establish which subjects were already overweight
as children. One US study, which classified adolescents and young adults as being
overweight or normal at baseline, found that the overweight group, 7 years later, were
less often married, had lower income and had completed fewer years of education.
These prospective findings were independent of initial SES, suggesting that obesity created
a situation of downward social mobility, and, in addition, more often occurring in
women than in men. Thus, in addition to the physical health consequences of obesity,
obese people, particularly obese women, suffer from social stigmatization, prejudice,
and discrimination . In a Swedish longitudinal study, no social difference in overweight
was observed at age 16 years but at 30 years educational level was associated with
overweight, reflecting the cumulative influence of multiple adverse circumstances experienced
from adolescence to young adulthood .
Potential mechanisms for an effect of obesity on subsequent social status have
been proposed, the most obvious being related to the stigmatisation experienced by
the obese. Leanness is often equated with beauty, success, fitness and self-control.
Obesity, on the other hand, is considered as undesirable as leanness is desirable, for
reasons that are more often related to cosmetic concerns than to actual or potential
medical complications. Specific examples for discrimination may be seen in the areas
of marital, employment and educational opportunities. If obesity has both social
causes and effects, a self-perpetuating cycle may be created that reinforces the relationship
between low SES and obesity.

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The Sociology of Obesity

The Sociology of Obesity

The current obesity epidemic is largely driven by environmental factors, including nutritional transition
towards refined and fatty foods with the growing production of energy-dense food at relatively low cost,
increased access to motor vehicles, mechanisation of work and sedentary lifestyles. These influences in
modern society are modified by individual characteristics. Ultimately, energy intake in excess of caloric
expenditure causes obesity, but why this occurs in some but not all individuals is not known. Obesity is
more prevalent in the lower socioeconomic classes but even so, there is a varying relation of socioeconomic
status with obesity between countries at different stages of development and, even in the
Western world, socioeconomic gradients with respect to obesity are both heterogeneous and in transition.
Potential mechanisms for an effect of obesity on subsequent social status have been proposed, the
most obvious being related to the stigmatisation experienced by the obese. Obesity seems to be
causally related to mood disturbances, whereas there is no conclusive evidence that the reverse is true.
When considering psychological aspects of obesity, depressive symptoms are more likely to be consequences,
rather than causes of obesity.

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adiponectin obesity

adiponectin obesity

Adiponectin was discovered independently by several laboratories, hence its various
names: Acrp30 (adipocyte complement-related protein of 30kDa), apM1 (adipose
most abundant gene transcript 1), adipoQ and GBP28 (gelatin-binding protein of
28kDa) . Adiponectin is composed of an N terminal sequence, hypervariable
domain, 15 collagenous repeats and a C terminal domain. A trimeric form of
adiponectin is secreted by adipocytes and gives rise to higher order complexes, i.e.
dimers of trimers (hexamers, low molecular weight, LMW) and six trimers (18-mers,
high molecular weight, HMW) through noncovalent bonding. HMW adiponectin is thought to be the bioactive form in plasma. In contrast, trimeric and hexameric
adiponectin is predominant in the cerebrospinal fluid. Adiponectin also undergoes
posttranslational modifications including glycosylation . Although there is
structural similarity between the globular (head) of adiponectin and TNF- , these
adipokines do not appear to be functionally related.
In contrast to other polypeptide hormones, adiponectin circulates at very high
concentrations ( g/ml), raising the possibility that a smaller cleaved product mediates
its action on various tissues. Total and HMW adiponectin are more abundant
in females, partly due to suppression of adiponectin by androgens in males.
Adiponectin is inversely related to adiposity, in contrast to leptin and most
adipokines. Thus, adiponectin is markedly reduced in obesity and rises with prolonged
fasting and severe weight reduction. Adiponectin, particularly HMW, is
increased by thiazolidinediones (TZDs) and mediates the insulin sensitizing effect of
this class of antidiabetic drugs. A role for adiponectin in glucose homeostasis
is further exemplified by hepatic insulin resistance in rodents and humans lacking
adiponectin. In contrast, adiponectin treatment enhances insulin sensitivity,
primarily by suppressing glucose production. Adiponectin produced in
bacteria has been shown to decrease glucose, stimulate fatty acid oxidation and
reduce body weight and fat; however, these are likely to be pharmacological effects
since bacterially derived adiponectin is incapable of forming high order complexes. Administration of full length or globular adiponectin via systemic or intracerebroventricular
injection induces thermogenesis, fatty acid oxidation and weight
loss in mice. These actions are abrogated in agouti mice (Ay/a), indicating a crucial
role for melanocortin signaling in the central action of adiponectin.
Hypoadiponectinemia is related to insulin resistance, inflammation, dyslipidemia
and cardiovascular risk among various populations. Lack of adiponectin promotes
atherosclerosis in rodents. Adiponectin reverses this by inhibiting monocyte
190 Ahima · Osei adhesion, macrophage transformation, proliferation and migration of smooth muscle
cells in blood vessels. Studies have implicated activation of AMPK and inhibition of
nuclear factor B (NF- B) and vascular adhesion molecules as putative mechanisms
underlying the effects of adiponectin on the vascular system. Adiponectin also
exerts a protective action in myocardial remodeling in response to acute ischemiareperfusion. Adiponectin-deficient mice had increased myocardial apoptosis
and infarct size than wild-type. Importantly, adiponectin treatment diminished
infarct size, apoptosis and TNF- production in both knockout and wild-type mice.
These actions appear to be mediated through activation of AMPK, induction of
cyclooxygenase-2-dependent synthesis of prostaglandin E2.
Adiponectin receptors (AdipoR1 and AdipoR2) contain seven transmembrane
domains, but are structurally and functionally distinct from G-protein-coupled receptors. AdipoR1 is abundant in muscle and binds with high affinity to globular
adiponectin and low affinity to the full-length protein, whereas AdipoR2 is enriched in
liver and has intermediate affinity for globular and full-length adiponectin. Both
receptors mediate the phosphorylation and activation of AMPK. Although studies
have failed to demonstrate a blood-brain transport of adiponectin, both AdipoR1
and AdipoR2 are distributed widely in the brain. Injection of adiponectin into
the 4th ventricle depolarized AdipoR1 and AdipoR2-positive neurons in the area
postrema, suggesting a potential mechanism for its central adiponectin action.
In a recent study, adenovirus-mediated expression of AdipoR1 and AdipoR2 activated
AMPK and peroxisome proliferator-activated receptor (PPAR)- in the liver of
lepr null mice, reduced gluconeogenesis and increased fatty acid oxidation.
Targeted disruption of AdipoR1 prevented adiponectin-induced AMPK activation,
whereas disruption of AdipoR2 decreased PPAR- activity. Disruption of both
AdipoR1 and AdipoR2 abolished adiponectin binding and induced steatosis, inflammation,
oxidative stress, insulin resistance and glucose intolerance. Together, these
results support a role of AdipoR1 and AdipoR2 as major mediators of adiponectin
action on glucose and lipid metabolism.

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Leptin

Leptin

The discovery of leptin more than a decade ago was a major turning point in our understanding
of adipokines. Mice and humans homozygous for the leptin gene mutation
develop hyperphagia, severe early-onset obesity, insulin resistance preceding obesity,
excess lipid accumulation outside adipose tissue (steatosis), and neuroendocrine abnormalities,
notably, hypothalamic hypogonadism and tertiary hypothyroidism.
Moreover, there is evidence for immunosuppression in congenital leptin deficiency. Leptin is expressed and secreted mainly by adipocytes, but low levels are present in the gastric fundus, mammary gland, placenta, pituitary and skeletal muscle. Leptin has a relative molecular mass of 16kDa and circulates in free or bound forms. The latter represents leptin bound mainly to its soluble receptor and is thought
to be inactive. The concentration of leptin is higher in obese than lean individuals.
Leptin falls rapidly during fasting and increases gradually during feeding. Studies in
rodents and human indicate a link between these changes in leptin and insulin.
Higher leptin level in women is explained partly by increased production in subcutaneous
adipose tissue and stimulation by estrogens. On the other hand, leptin is suppressed
by androgens in males. Chronic glucocorticoid exposure, TNF- and IL-6
increase leptin, while adrenergic stimulation decreases leptin. Leptin exhibits a
diurnal rhythm, peaking at night in humans and in the morning in rodents.
A pulsatile leptin rhythm has also been recognized in humans, although the underlying
mechanisms and functional significance are unknown.
Five leptin receptor isoforms, LRa–LRe, are derived from alternate splicing of lepr
mRNA. LRa is the predominant ‘short leptin receptor’ which lacks the key
cytoplasmic domain required for signaling through the JAK/STAT (signal transduction
and activators of transcription) pathway. LRa is abundantly present in brain capillary
endothelium and peripheral tissues, and is thought to mediate leptin transport.

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Adipokines in Obesity

Adipokines in Obesity

Adipose tissue is the source of soluble mediators (adipokines), secreted mainly by adipocytes. Leptin acts
on the brain and peripheral organs to regulate energy homeostasis and the neuroendocrine axis.
Adiponectin regulates glucose and lipid metabolism by targeting the liver and skeletal muscle. Adiposederived
proinflammatory cytokines, vasoactive peptides, coagulation and complement factors, visfatin,
vaspin and retinol-binding protein signal through paracrine and hormonal mechanisms. Understanding
the biology of adipose tissue and the rapidly growing list of adipokines provides new insights into normal
physiological regulation, as well as the pathogenesis and treatment of obesity, diabetes and disorders
of lipid metabolism and cardiovascular system.

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The Obesity Epidemic

The Obesity Epidemic

Health care systems around the globe are beginning to recognise the risk that obesity
poses to human health and many programmes are now being put into place in an
effort to reduce the burden of obesity and its related diseases. Current definitions of
obesity are based on the ratio of bodyweight (in kg) and height squared (in m2) and
expressed as body mass index (BMI) with a normal BMI defined as 20–24.9, moderate
overweight between 25–29.9 and obesity as 30. In 2000, the World Health
74 Armitage · Poston · Taylor
Organisation released the following statement: ‘Obesity is a chronic disease, prevalent
in both developed and developing countries, and affecting children as well as adults.
Indeed it is now so common that it is replacing the more traditional public health
concerns, including under-nutrition and infectious disease as one of the most significant
contributors to ill health’ [1]. At the turn of the millennium and the time of publication
of the WHO report, the incidence of obesity in the United States was 30.5%
(compared with 22.9% in 1994) and 64.5% of the population were overweight (compared
with 55.9% in 1994) [2]. More recent statistics suggest that the incidence of
obesity and overweight is rising, not falling, in spite of the apparent efforts of governments
and health care agencies. This shift in body mass has occurred over the past
one to two generations and as such it is unlikely that genetic drift is the cause of the
current obesity epidemic. Rather, a change in lifestyle, compounded by epigenetic or
developmental programming of an obese phenotype are the likely causative factors.
Obesity statistics from the United States are most often quoted, perhaps because
they give the greatest impact; however, scientific studies conducted in other nations
emphasise the fact that obesity is a worldwide problem. A study of cause of death in
South Korea illustrates this fact. In 1938, cardiovascular disease accounted for
approximately 1% of deaths in South Korea whilst infectious diseases were the cause
of approximately 23% of deaths. By 1993, this trend had reversed; approximately 30%
of deaths were attributable to cardiovascular disease whereas only 3% of deaths were
caused by infection. Certainly such statistics are affected both by the vast improvements
in anti-microbial medication and sanitation in that 60-year period; however,
the fact remains that obesity-related illness is the next public health hurdle.
Obesity may not, in itself, be a great risk to human health. Indeed, there are some
individuals who are overweight or obese but do not show any other signs of disease or
ill health. However, for the vast majority, increased body fat is associated with a range
of other, more serious conditions. These include increased blood pressure, insulin
resistance and diabetes mellitus, atherogenic plasma lipid profiles, and increased levels
of vascular inflammatory markers. Collectively, this spectrum of conditions is
termed the ‘metabolic syndrome’ and clinical diagnosis is based on the presence of 3
or more of the above signs. Endothelial dysfunction and leptin resistance are also
likely to contribute to the metabolic syndrome [3].
The rise of obesity is certainly due to the increased availability of food, and the
preponderance of energy dense (high fat and simple carbohydrate) foods that are regularly
consumed in developing and developed societies. Moreover, the industrial era
has produced all manner of labour saving devices that has ultimately seen a reduction
in the physical activity quotient over time [4]. However, despite the obvious importance
of food intake and energy expenditure during adulthood, there is now evidence
that adult lifestyle may not be the only factor at play in determining obesity [5]. The
environment encountered during the in utero and early postnatal periods may also
act to ‘programme’ an individual to have a greater risk of developing obesity and the
metabolic syndrome.

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Obesity and BBS

Obesity and BBS

Obesity is a cardinal aspect of the BBS phenotype, beginning in early childhood and
progressing with age; it is usually associated with the trunk and proximal limbs. A survey
of UK BBS patients identified 72% of adults as overweight (BMI 25) and 52%
defined as obese (BMI 30) . At present, the physiological and biochemical abnormalities
underlying obesity in BBS are poorly understood. A case-control study
showed no significant differences between resting metabolic rate between obese BBS
and controls suggesting no underlying defect in metabolism . Bbs-deficient mouse
models (Bbs4 and Bbs6) are initially runty at birth but display progressive weight gain
associated with increased food intake, culminating in obesity at 12 weeks

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Genetic Obesity Syndromes

Genetic Obesity Syndromes

There are numerous reports of multi-system genetic disorders with obesity. Many have a characteristic presentation
and several, an overlapping phenotype indicating the likelihood of a shared common underlying
mechanism or pathway. By understanding the genetic causes and functional perturbations of such syndromes
we stand to gain tremendous insight into obesogenic pathways. In this review we focus particularly
on Bardet-Biedl syndrome, whose molecular genetics and cell biology has been elucidated recently, and
Prader-Willi syndrome, the commonest obesity syndrome due to loss of imprinted genes on 15q11–13. We
also discuss highlights of other genetic obesity syndromes including Alstrom syndrome, Cohen syndrome,
Albright’s hereditary osteodystrophy (pseudohypoparathyroidism), Carpenter syndrome, MOMO syndrome,
Rubinstein-Taybi syndrome, cases with deletions of 6q16, 1p36, 2q37 and 9q34, maternal uniparental
disomy of chromosome 14, fragile X syndrome and Börjeson-Forssman-Lehman syndrome.

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Energy Homeostasis and Obesity

Energy Homeostasis and Obesity

The concept of the gut as an endocrine organ is hardly a new. The gut peptide secretin
was the first substance to be termed a hormone whilst the appetite inhibitory actions
of cholecystokinin (CCK) were first reported over 30 years ago. However, in
recent years, further scientific endeavour in this field has been motivated by the need
to develop new strategies to tackle the global pandemic of obesity.
The prevalence of obesity in adults has increased by over 75% worldwide since
1980. Given that obesity is causally associated with cardiovascular disease, type 2 diabetes,
hypertension, stroke, obstructive sleep apnoea and certain cancers, this has
translated into healthcare costs of over half a billion pounds every year in the UK
alone. Obesity is not only a problem in the developed world, but is set to overtake
infectious diseases as the most significant contributor to ill-health worldwide and has
been classified as an epidemic by the World Health Organization .
166 Wren

Public health initiatives have failed to reverse the rising incidence of obesity.
Medical and behavioural interventions, with the exception of bariatric surgery, have
limited success, as discussed in the treatment section of this volume. This chapter will
focus on the peptide hormone signals from the gut that communicate the status of
body energy stores to the brain and the brain centres on which they act. These regulatory
systems are not only of academic interest, but are likely to underpin any future
strategy to tackle obesity, by providing drug targets for the holy grail of safe sustainable
weight loss.

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Gut and Hormones and Obesity

Gut and Hormones and Obesity

Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised
and released from the gastrointestinal tract have been identified. While their roles in the regulation
of gastrointestinal function have been known for some time, it is now evident that many of these
hormones also physiologically regulate energy balance. Our understanding of how gut hormones
signal to the brain has advanced significantly in recent years. Several hormones, including peptide
YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as
satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger
signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent
research suggests that gut hormones can be manipulated to regulate energy balance in man
and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity
pandemic continues unabated, despite public health initiatives and current best therapy. Future
gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.

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Obesity in Old Age

Obesity in Old Age

Many older people in developed countries are overweight or obese. The prevalence is increasing as
more people reach old age already overweight. Obesity in old age is associated with increased morbidity
and a reduction in quality of life. The relative increase in mortality is less in older than young adults
and the body weight associated with maximal survival increases with advancing age. Although intentional
weight loss by overweight older people is probably safe and beneficial, caution should be exercised
in recommending weight loss to overweight older people on the basis of body weight alone.
Methods of achieving weight loss in older adults are the same as in younger adults. Weight loss diets
should be combined with an exercise program to preserve muscle mass, as dieting results in loss of muscle
as well as fat, and older people have reduced skeletal muscle mass in any case. Weight loss drugs
have not been extensively studied in older people, and there is the potential for drug side effects and
interactions. Weight loss surgery appears to be safe and effective, albeit slightly less so than in younger
adults, but little is known about the outcomes of such surgery in those over 65 years.

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Causes of Obesity in Childhood

Causes of Obesity in Childhood

Endocrine and single gene disorders causing obesity in childhood are rare, accounting
for 1–2% of obese children seen in a tertiary care setting. Nevertheless, an understanding
of these disorders is required to recognise rare but treatable causes of
childhood obesity. A thorough description of these conditions is beyond the scope of
this review and can be found elsewhere.
The majority of cases, however, arise from a simple interaction between host factors
that enhance susceptibility and environmental factors which increase food intake and
decrease energy expenditure. Factors causing the imbalance in energy intake and
energy expenditure are numerous, simply reflecting the components of the obesogenic
environment in which we live. Factors important in excessive energy intake include the
consumption of energy-dense foods, increased portion sizes, between-meal snacking
and regular intake of sugar-sweetened beverages and fruit juices. Decreased energy
expenditure is often due to the coupling of increased sedentary activities, such as TV and
computer games, alongside decreased physical activity. There are also very significant parental and socioeconomic [1, 17] contributions to obesity risk as demonstrated by
a recent study which showed that while 89% of parents of overweight 5- to 6-year-olds
were unaware that their child was overweight, 71% were not concerned, with less educated
parents being less likely to take action . Ethnicity also significantly impacts
upon obesity risk and the development of co-morbidities. For example, data from several
countries show that black children have a higher prevalence of obesity than white children while obese children from certain ethnic groups (e.g. South Asia) appear to
exhibit higher rates of complications like T2DM for a given level of obesity .
Addressing these complex demographic and lifestyle interactions remains central to the
development of effective prevention and treatment programs for childhood obesity.

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The Definition of Childhood Obesity

The Definition of Childhood Obesity

 Childhood adiposity can be measured in numerous ways although body mass index (BMI) remains the most commonly used. Whilst BMI is a relatively simple tool with which to assess body mass, it is a relatively poor predictor of actual body composition in both adults and children. Due to its ease of determination however, along with a good correlation with body fat, it has remained the accepted method to define obesity in children based on current expert opinion [5]. Another important measure is waist circumference which has been validated as a surrogate marker of visceral adiposity in children [6]. In adults, a BMI 25 and 30 corresponds to ‘overweight’, whereas a BMI 30 identifies those with obesity. These cut-off points correspond to an increased risk of cardiovascular disease and diabetes in adults. In children, however, BMI changes with normal longitudinal growth, as shown in figure 1. Therefore, it is inappropriate to simply express raw BMI in children, without adjusting for age and sex. Instead, BMI standard deviation scores or z-scores (BMI SDS – representing increases or decreases around the 50th centile for age and sex) are used to determine which children are relatively ‘overweight’ or ‘obese’. For national statistics, BMI levels of 95th, 97th, or 98th percentile have been used to identify the ‘fattest’ children within different populations. These limits have high specificity and moderate sensitivity, and allow temporal changes within countries to be assessed. For across-country comparisons, international cut-off points must be used and these have been based on the extrapolation of adult cut-off points back into childhood [7]. The international cut-off points tend to greatly underestimate obesity prevalence when used for determining prevalence rates within a specific country [8]. However, BMI SDS may not be the best tool with which to assess longitudinal changes in adiposity in children enrolled into weight management programs, as the within-child variability over time depends upon the child’s levels of adiposity. Under these circumstances, age-adjusted BMI (calculated by subtracting the sexand age-specific median BMI) may be a better tool [9]. However, the normative data necessary to make these calculations are currently unavailable so most workers continue to use BMI SDS when reporting their results.

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The Prevalence of Childhood Obesity

The Prevalence of Childhood Obesity

There has been a dramatic rise in the number of children who fulfil the criteria necessary
for the diagnosis of obesity . Data from the CDC in the USA
(http://www.cdc.gov) demonstrate an increase in the prevalence of children aged 6–19
years old who were considered to be overweight ( 95th percentile) from 4–5% in
1963–1970 to 15% in 1999–2000. Using similar criteria in the majority of cases, the
International Obesity Task Force have inspected the p revalence of obesity in children
aged around 10 years old from data derived from 21 European countries between 1992
and 2001 and found levels to vary between 10 and 36%. Data from the Health
Survey for England in 2002 indicated that 8.5% of all 6-year-olds and 15% of all 15-
year-olds satisfied the criteria for obesity, and similar data from 2003 found that the
prevalence of obesity in children aged 2–10 had increased from 9.9 to 13.7% from 1995
(www.dh.gov.uk). In the non-Westernised world, there is also evidence that obesity in
general is increasing, especially amongst urban populations . For example, China
(a country previously defined as one of the world’s leanest populations) has witnessed
a dramatic recent rise in childhood overweight and obesity prevalence.

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Childhood Obesity

Childhood Obesity

Most countries throughout the world, excepting certain areas of Sub-Saharan Africa have witnessed a continued increase in the prevalence of obesity over the last two decades [1]. This carries major public health implications as there is little doubt that obese children are at increased risk of developing long-term morbidity and eventual mortality secondary to increasing adiposity. Despite this, there remain very few effective prevention or treatment strategies with which to halt this escalating epidemic. Understanding the factors that regulate adiposity in childhood, and the development of co-morbidities, would allow us to focus prevention and treatment strategies to those most at risk.

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Obesity and Cancer

Obesity and Cancer
THE TERM cancer refers to all malignant neoplasms or new cell growth. he molecular basis of cancer begins with nonlethal genetic damage to an individual cell. he processes through which a normal cell undergoes neoplastic transformation, deviates from its normal growth pattern, and progresses to a malignant phenotype have been separated into four phases. hey are: (1) change in the deoxyribonucleic acid (DNA) pattern or its expression in the target cell; (2) growth of the transformed cell; (3) invasion into adjacent structures; and (4) metastases and relocation to distant tissues. Cell division in the normal cell is remarkably accurate, and have multiple redundant systems that monitor cell integrity and detect DNA damage. Tumor suppressor gene products can arrest cell division until damage is repaired. Carcinogens exert damage by binding directly to the DNA or by modifying host detoxiication enzyme systems that convert procarcinogens to more polar metabolites. Sometimes a metabolite becomes an “ultimate carcinogen” capable of damaging DNA. Several cancers develop because the host has inherited mutations (germ-line mutations) that increase DNA susceptibility to damage. If acquired or inherited, mutations limit the ability of the cell to detect and correct DNA damage, or if proliferative signals from mediators and mutant oncogenes stimulate cell growth in spite of growth controls, the damaged cell will divide and produce daughter cells that contain “heritable” defecta that can be transmitted to all cell progeny. Further proliferative signals to cells with heritable DNA defects have potential to generate further mutations in the growing clone. Fortunately, genes that code for proteins make up only a small portion of the total genome. he eiciency of DNA repair, combined with the small number of scattered targets throughout the genome explain how organisms can survive “in a sea of carcinogens” without developing the disease. Heritable damage at a functional DNA locus is termed initiation. his damage modiies the behavior of the cell in one of two ways. It enhances the ability of the cell to (1) reproduce without consideration of normal cell restraints and (2) invade other tissues and travel to distant sites reserved for other cell types. Promoters are agents that, while not carcinogenic themselves, facilitate the growth of initiated cells by globally stimulating proliferation in the tissue or organ. In normal cells, the efects of growth promoters, hormones and other promoters are reversible. he life cycle of a cell proceeds through an orderly progression from birth to death, leaving no progeny. If the promoting inluence is removed from normal tissue, proliferation stops, cells progress through their life cycle and die, thus hyperplasia can regress. In contrast, the progeny of transformed (initiated) cells stimulated to undergo unrestrained proliferation do not die but accumulate until clinically detected as a tumor. As the transformed cell proliferates in deiance of DNA repair and normal cell cycle controls, it accumulates additional DNA damage that further augments its aggressive behavior. A transformed clone overgrows its neighbors, takes up essential nutrients, and prospers at the expense of the organism. Several physiological changes are characteristic of the mutant clone: (1) self-suiciency in growth signals, (2) insensitivity to growth inhibitory signals, (3) evasion of apoptosis, (4) defects in DNA repair, (5) limitless replicative potential, (6) sustained ability to stimulate ingrowth of new blood vessels (angiogenesis), and (7) ability to evade immune defenses and rejection. As the mutant clone expands, it acquires subpopulations with additional phenotypic attributes including altered hormonal responsiveness and reduced susceptibility to antineoplastic drugs (termed progression). hus, despite its origin as a single initiated cell, considerable genetic and phenotypic heterogeneity is observed in a tumor while it is still small and clinically undetectable. Ominously, some transformed cells acquire the ability to invade and metastasize at an early, undetectable stage.

RISK DUE TO CARCINOGENS, PROMOTERS, AND ANTICARCINOGENS IN FOOD

Environmental carcinogens, including chemicals, radiation and viruses, have potential to damage DNA and transform cells leading to cancer in animals. While some of the most potent carcinogens are produced in the extraction and incomplete combustion of fossil fuels, or are synthetic products created by industry, an enormous number of potentially carcinogenic chemicals are produced naturally by plants as defense against predators, as by-products of food processing, and by microorganism consumed in food. Because obesity results from storage of food ingested in excess of requirements, the obese subject may be at greater risk for cancer secondary to ingestion of a greater quantity of carcinogens in the food supply. At the same time, social, psychological, and biological factors that inluence food intake can result in consumption of foods that contain high levels of carcinogens. Some of the more common carcinogens in food include nitrostable amines and nitrates used to preserve food. Sodium nitrite is used to preserve bacon and processed meats such as ham and salami and is converted by gut bacteria to N-nitroso-compounds, carcinogenic in all species studied. Alatoxin produced by the fungus Aspergillus flavus grows on improperly stored grains, nuts, and legumes and has been implicated as a hepatocarcinogen. Additionally, food preparation methods that expose food to high heat for a long time is known to alter protein structure and create carcinogenic heterocyclic amines, lipid peroxides and other mutagens. Meat also contains heme iron and other components implicated in production of endogenous N-nitroso compounds and in increased risk for several cancers including prostate, colon, and rectum. Dietary fat is also implicated in cancer risk. In 1982, the National Academy of Sciences reviewed studies relating tumor growth to diet in experimental animals and large population studies demonstrating increased rates of breast, colon, prostate, and endometrial cancers correlated with per capita animal fat consumption. Based on this evidence, guidelines recommending reduction of fat intake to 30 percent of daily calorie intake were developed. Since then, a large body of experimental evidence has revealed that the relationship of dietary fat to cancer is more complex than originally thought. he inluences of total fat intake and total energy intake have not been irmly distinguished in animal models or in human studies, nor have the carcinogenic efects of red meat been separated from the effects of meat fat. Additionally, individual dietary fatty acids, even within a fatty acid type, may have diferent efects on carcinogenesis, tumor growth, and metastasis. Dietary fatty acids modulate cancer risk and metastasis through their role as substrate for local synthesis of eicosanoid metabolites such as prostaglandins and leukotrienes. hese hormones modulate processes such as tumor-endothelial cell adhesion, proteolytic enzyme activity, and other biological cascades that facilitate tumor growth and spread. While the mechanisms through which a speciic dietary fatty acid type modulates risk have not been fully elucidated, the eiciency of membrane fatty acid conversion to eicosanoids may be involved. Fatty acids of the omega-6 type, derived from grains, produce eicosanoids implicated in cancer risk. In contrast, fatty acids of the omega-3 type, derived from green plants and cold-water ish, replace omega-6 fatty acids in the cell membrane. Eicosanoids produced from diferent fatty acids have diferent structure and may account for the observed diference in cancer risk. Other dietary components also inluence risk. Over 250 epidemiologic studies conducted in numerous countries with diverse diets support the association between fruit and vegetable consumption and reduced risk. In addition to fruits and vegetables, other whole foods including whole grains, legumes, tea, cofee, and chocolate contain a myriad of components including carotenoids, vitamins C, E, and K, dietary iber, lavanoids, indoles, procyanidins, isoprenoids, and other bioactive components. Phytochemicals as well as substances in animal products are under intensive investigation for their ability to reduce DNA damage, modulate cell cycle activity, modify detoxifying enzymes that convert procarcinogens to ultimate carcinogens, mimic estrogens and other hormones by binding their receptors, and other activities that inhibit the initiation, promotion, and progression of cancer.

RISK FROM CHRONIC POSITIVE ENERGY BALANCE

 he possibility that chronic caloric overload increased risk for cancer has been investigated for over 50 years. Experiments with overfed animal models demonstrated increased numbers of cancers, while chronically restricted animals lived longer and were cancer free. Epidemiological studies that measured body size and height subsequently revealed that growth exerts a modest inluence on risk for all cancers, especially for hormone-dependent breast, uterine, and prostate cancer. Possible mechanisms for this increased risk include growth promoters and stimulatory hormones such as sex hormones, glucocorticoids, and insulin, as well as inlammatory mediators associated with obesity. Obesity has been generally associated with insulin resistance and elevated plasma insulin levels. Experimental and epidemiologic studies support the hypothesis that the growth promoting efects of insulin increase risk for colon carcinogenesis. Insulin may directly activate its own receptor, or the receptors for insulin-like growth factor (IGF) expressed on normal colorectal cells and on cancer cells. Since insulin is only weakly mitogenic, its action is likely to be indirect, mediated through the growth-promoting efect of nonesteriied fatty acids released from adipose tissue, which potentiate insulin resistance. Alternatively, elevated insulin levels may lead to increased concentrations of IGF and its binding proteins. hese peptides are involved in regulation of cell growth and proliferation as well as cell transformation and death. hus, the interactions of insulin, IGF, and IGF-binding proteins provide a mechanism linking excess energy intake with processes underlying the development and spread of cancer. Obesity and chronic hyperinsulinemia are also associated with changes in total and bioavailable plasma sex steroid levels in both pre- and postmenopausal women. Increased bioavailability of sex steroids, especially estrogens, may result from several interactions with insulin and IGF. Increase in insulin and bioactive IGF concentrations in the obese organism inhibit the hepatic synthesis of sex-hormone–binding globulin (SHBG). Insulin and IGF can also enhance the synthesis of androgens by the gonads and adrenal glands. Finally, androgens undergo increased conversion to estrogen metabolites by aromatization in adipose tissue. hus, in postmenopausal women, the body mass index (BMI) is positively related to plasma levels of estrogen metabolites as well as to levels of bioavailable estrone not bound to SHBG. he “unopposed estrogen” hypothesis proposes that mitogenic efects of estrogens, when insuiciently counterbalanced by progesterone can result in growth promotion in hormone dependent tissues. Recent investigations have revealed that estrogen can also act as a “complete” carcinogen, capable of inlicting DNA damage by oxidative mechanisms. Finally, adipose tissue accumulation is associated with the production of several proinlammatory factors including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein 1, inducible nitric oxide synthase, and transforming growth factor ß1. Macrophages enter adipose tissue where they scavenge large dying adipocytes and release reactive oxidative products and other mediators. While the link between chronic exposure to inlammatory mediators and cancer has not been clearly developed, inlammatory peptides induce rapid cell proliferation and produce DNA-damaging free radicals. Rapid cell division increases the likelihood of replication errors and inefective DNA repair at critical regulatory sites. In an inlammatory environment, key enzyme cascades are upregulated, resulting in synthesis of inlammatory eicosanoids and other mediators known to facilitate tumor growth, invasion, and metastases. One molecular basis for this relationship is through the nuclear factor kappa beta(NFKβ) pathway that regulates apoptosis, cell proliferation, and cell growth arrest and enhances growth of new blood vessels by inducing vascular endothelial growth factor expression. Clinical evidence for the link between chronic inlammation and cancer is seen in the development of hepatic cancer in chronic hepatitis and colon cancer in chronic colitis, and in the inverse association between long-term use of nonsteroidal antiinlammatory drugs (NSAID) and reduced risk of several cancers. In the endometrium, unopposed estrogens, as well as other established risk factors, induce an inlammatory efect. Insulin and estrogen exposure, in conjunction with inlammatory mediators, have been implicated in the development of endometrial cancer. A proinlammatory milieu can initiate and promote neoplastic transformation directly. It can also increase estrogen production, which may facilitate carcinogenesis by disrupting the estrogen-progestogen balance. In summary, increased body size (BMI) and obesity is associated with moderately increased risk for cancers of all types. he data are confounded by diiculties in measurement and the multifactorial nature of the risk factors. he food supply contains both carcinogens and anticarcinogens, thus the choices made by the obese subject may play a major role in actual risk. Accumulation of metabolically active adipocytes and associated macrophages have a signiicant impact on whole body homeostasis. Further, there is evidence that dietary and lifestyle patterns modify the inluence of adipose tissue on metabolic parameters. Mechanistic and clinical investigations are needed to guide recommendations.

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What is Obesity?

What is Obesity?
Though we all use the terms “fat” and “obese” casually in conversation, there is a medical definition of the condition and yes, obesity is considered a health “condition.”

“Obesity” specifically refers to an excessive amount of body fat. “Overweight” refers to an excessive amount of body weight that includes muscle, bone, fat, and water. As a rule, women have more body fat than men. Most health care professionals agree that men with more than 25 percent body fat and women with more than 30 percent body fat are obese. These numbers should not be confused with the body mass index (BMI), however, which is more commonly used by health care professionals to determine the effect of body weight on the risk for some diseases.

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