Genetics of obesity

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Begin your article with a brief overview of the scope of the article. Include the article name Genetics of Obesity Remember you are writing an encyclopedia article; it is meant to be readable by a wide audience, and so you will need to explain some things clearly, without using unneccessary jargon.

Overview

Obesity is the condition of excessive fat accummulation typically defined as a BMI of 30 or more. It presents as a major risk factor for premature mortality and is attributable to a number of chronic diseases: cardiovascular, metabolic and cancerous . With the onset of the obesity epidemic, an increasing number of institutions are researching into the causes of this current trend. While the environmental influences (including the ease of access to high energy palatable foods and sedentary lifestyle) cannot be neglected, there is much focus on genomics to explain inter-individual variation in susceptibility to adiposity (2).

Leptin pathway

Although several genes have been identified, they are limited to monogenic causes. Many of these are mutations of proteins in the “leptin pathway” which has an important role in energy balance. Each of those represented in the diagram has been shown to cause obesity, most often through twin studies.

In the case of all (except for MC4R) the quantity of mutations remains insignificant in the average population. However these findings do suggest there can be more common multifactorial influences on susceptibility to adiposity which are likely to be involved in similar pathways (7).

Population genetics

Pima Indians

The Pima Indian population represents a useful model for demonstrating the potential impact of genetic factors in influencing obesity. The Pima once resided in the deserts of Mexico where resources were scarce, however some migrated and communities now exist in Arizona, USA. Those who settled in the US were presented with a relative abundance of nourishment and exhibit extremely high levels of obesity and type 2 diabetes, whereas other communities of Pima do not. It has been proposed that genetic factors have protected this population in the past and allowed them to withstand conditions of deprivation, though if exposed to greater levels of food intake they are more susceptible to developing obesity as a result. This is known as the 'thrifty gene hypothesis'. [8]

Thrifty gene hypothesis

The thrifty gene hypothesis was first put forward by Neel in 1962 It states that, in history, a genotype that stores energy more efficiently in times of food abundance would have been advantageous to our ancestors to survive times of food shortage. It is widely accepted that this genotype has been naturally selected through years of food shortage but in modern day society has become a source health problems. These days food is almost always easily available so those showing the thrifty phenotype are in constant food storage mode preparing their bodies for a period of food shortage that never comes. This is suggested to be causing the widespread prevalence of obesity and type 2 diabetes in the developed world.

More recently this hypothesis has been challenged. Most noteably, JR Speakman highlighted some problems of the thrifty gene hypothesis in a review for the International Society of Diabetes Vascular Disease. He suggested that not enough significant famines have occurred in human populations and that mortality levels during these famines would not have been sufficient to lead to the levels of natural genotype selection that the thrifty gene hypothesis implies. Mortality patterns also do not fit with the hypothesis because deaths were often not due to starvation but due to disease, so the thrifty phenotype would not have been particularly advantageous and those age groups incurring the highest mortality rates would have been the very young and very old, and not those of reproductive age so gene selection for future generations would be unaffected. Whether the thrifty geneotype explains some of modern day obesity remains unclear as records of famine and mortality rates in history are not always well kept.

Polynesian Populations

Polynesia is a subregion of Oceania, encompassing more than 1000 islands over the central and southern Pacific Ocean. Polynesians share language, culture, beliefs and other features of society. The populations are interesting for study because of the relatively conserved gene pool, the concept of modernisation, and the migration of Polynesians to other countries. Polynesian populations exhibit high rates of type 2 diabetes and obesity, as shown in Samoans by McGarvey. However, increased rates of other obesity-associated problems such as metabolic syndrome and dyslipidaemia are not observed. Finally, a study in several Oceanic populations did not support Neel's thrifty gene hypothesis: population frequencies of common FTO polymorphisms displayed no significant association with BMI.

Monozygotic Twin Studies

Twin studies are useful for reliable investigation of the gene-environment interactions of obesity as they can yield more powerful data (1). Using twins in a study by Bouchard et al (2) can show whether the already known inter-individual effects of changes in energy balance or dietary interventions are due to genetic factors. For example, exposing monozygotic twins to positive energy balance/overfeeding lets us investigate whether differing sensitivities in individuals gaining fat when exposed to positive energy balance is dependent on genotype or not. Variables in phenotype measured in the study included; body weight, body composition, fat distribution, abdominal visceral fat and resting metabolic rate. The findings after overfeeding/exercise in the twins conveyed clear intrapair resemblance and variation between different twin pairs. This suggested the differences in susceptibility of overeating must be controlled mainly by genetic factors (which are thought to be inherited), though the exact genes involved in sensitivity of energy balance are currently not known. (2)

Using monozygotic twin studies also allows measurement of the relationship between dietary factors and body fat independent of genetic factors. (3) Both diet and genetic influences are thought to influence body fat. Using monozygotic twin studies it is possible to investigate the effect of diet on body fat independent of genotype. This therefore lets us analyse the extent genetics are involved in influencing body fat as no relationship between dietary fat and body fat was found in middle-aged women in a study conducted by Samaras et al (4), indicating that diet in determining total body fat may have been overestimated in the past and genetic factors are perhaps therefore more influential.(4)

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