John PH Wilding
DM, FRCP


Inherited Causes
 Single-gene defects causing obesity are rare in humans. Examples include
rare mutations in the gene encoding leptin or its receptor. Affected individuals
suffer uncontrollable hunger and develop severe obesity at a young age;
unlike similar syndromes in rodents, there is no evidence that these children
have a defect in thermogenesis. Other syndromes have been described
involving defects in downstream signals of leptin, notably in the POMC gene
and the melanocortin-4 receptor.
 Severe obesity is a feature of several inherited syndromes. The
most common is Prader-Willi syndrome. These children typically fail to thrive in
the first 2 years of life but then develop a voracious appetite, leading to
severe obesity and often causing complications such as type 2 diabetes and
obstructive sleep apnoea. Other features of the syndrome include learning
difficulties, short stature, small hands and feet, and almond-shaped eyes. The
syndrome is usually associated with a mutation in a paternally imprinted gene
on chromosome 15, but the biological explanation for the increased appetite
and obesity is not known.
 Such inherited syndromes account for only a very small proportion of the
20% of the population who are obese (though single-gene defects, notably
melanocortin-4 receptor mutations, may account for up to 1/20 cases of
severe early-onset childhood obesity). There is evidence from family and twin
studies that body weight and the tendency to develop obesity are at least
partly inherited. Early studies suggested that the inherited contribution is
about 60 to 70%, but that was clearly an overestimate.
 These studies were largely conducted at a time when the prevalence of
obesity in adults was low and the effect of shared environment could not be
readily quantified.
 Environmental Causes
 The recent rapid increase in mean population weight and obesity can be
caused only by adverse environmental influences that disturb the homeostatic
mechanisms described above. There are several reasons why this is thought
to have occurred, and all are likely to be important. In general, the subtle
hypothalamic regulator of appetite is readily overcome by social pressure and
food marketing.
 High-energy Diets
 In westernized countries, profound changes in diet have occurred over the
past 30 to 40 years, particularly involving increased consumption of energy-
dense foods and soft drinks that are high in fat and/or sugar. Experimental
studies show that such foods, particularly those high in fat, produce a less
powerful satiety response than meals that are high in complex carbohydrates,
leading to the phenomenon of passive overconsumption. Less regular eating
patterns, shorter meals and increased snacking may also contribute, though
the contribution of these changing dietary patterns remains uncertain.
Estimates of food consumption are greatly confounded by under-reporting by
obese subjects.
 Physical Inactivity
 Coincident with these changes in energy intake, there has been a marked
decline in physical activity. In the UK, the average individual now walks about
25 miles(40㎞) less per week than he did in 1950, and use of labour-saving
devices, greater car use and sedentary leisure-time pursuitse.g. television,
computer games) have been implicated.
 Although some surveys show little change in energy intake over this time,
current reported intake is inappropriately low, and actual consumption
inappropriately high for the reduced level of physical activity that is considered
normal in the modern world.
 Other Causes
 Previously undiagnosed endocrine disease is almost never the cause of
obesity. Hypothyroidism is rare as a cause, and thyroxine replacement seldom
produces dramatic weight loss. Hyperphagia and weight gain are sometimes
seen in thyrotoxicosis.
 Cushing`s syndrome is a rare cause of obesity, but it is important to consider
this possibility when assessing obese patients. Adults with growth hormone
deficiency exhibit increased body fat and reduced lean body mass, which can
be corrected with growth hormone replacement. Obesity is often a feature of
polycystic ovary syndrome, but the primary cause of this remains unknown.
 Hypothalamic Obesity
 It is exceedingly rare for previously unrecognized hypothalamic disease to
present as obesity. Tumours in the hypothalamic region(notably
craniopharyngiomas and pituitary macroadenomas with suprasellar extension)
often damage the ventromedial hypothalamic regions that regulate energy
intake and expenditure.
 Similar lesions may also occur following trauma or surgery. Such patients
often exhibit marked hyperphagia, but also have autonomic imbalance leading
to hyperinsulinaemia, which can exacerbate weight gain by promoting fat
deposition.
 Physical activity may be reduced as a result of somnolence or associated
visual loss. Endocrine disturbances (particularly growth hormone deficiency
and hypogonadism) may contribute to an unfavourable body-fat distribution,
increasing metabolic risk in this group.
 Drugs
 Many drugs(notably centrally acting drugs such as anticonvulsants, and
neuroleptic agents) promote weight gain. The mechanisms depend on the
agent concerned and are not well understood, but may involve both central
effects on appetite(as is thought to be the case with neuroleptics) and
peripheral metabolic effects(as with oral hypoglycaemic drugs and protease
inhibitors). Patients taking such drugs must be informed of this side effect and
of dietary measures to prevent it. In some cases, alternatives are available
that do not promote weight gain.
 Obesity in Childhood
 Overweight and obesity are becoming more common in children. The
aetiological factors are as described above - namely, increased consumption of
high-energy foods and decreasing physical activity. There is increasing
evidence that obese children are likely to become obese adults, and that such
individuals are at high risk of developing complications such as type 2
diabetes, which is now becoming a problem in teenage children.

About the Author
Dr Wilding is Reader in Medicine at the University of Liverpool and Honorary
Consultant Physician at University Hospital Aintree, Liverpool, United Kingdom.

■ 기사 요지 
 본지 자매지 `MEDICAL PROGRESS` 4월호에 게재된 글로 최근 성인·소아를 막론하고 만
성질환의 원인으로 대두되고 있는 비만의 병인론을 다루고 있다.
 비만의 선천적 요인인 단일유전자 결함이 있는데, 비만 관련 호르몬인 렙틴(laptin) 또는
그 수용체와 관계된 유전자의 돌연변이는 아주 드물게 나타난다.
 이같은 유전자변이가 일어나면 통제할 수 없는 식욕으로 젊은 시기부터 심각한 비만을 겪게
된다. 환경적 요인으로는 식습관의 변화와 운동량의 부족 서구적 생활방식이 가장 큰 원인이
다.
 이외에 다른 요인으로는 극히 드물지만 갑상선중독증(thyrotoxicosis)이나 쿠싱증후군
(Cushing`s syndrome) 등 내분비질환, 시상하부 기능부전(hypothalamic dysfunction)
으로 인한 시상하부 비만, 약물복용으로 인한 비만 등이 있다.
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