Add as bookmark

Genetics and Obesity

by Dr Peter Kay(more info)

listed in dna gene expression, originally published in issue 243 - January 2018

Obesity is one of the world’s most important health issues because it leads to development of insulin resistance and increased susceptibility to many serious medical conditions, such as type 2 diabetes, hypertension, cardiovascular disease, stroke and other disorders. Because of the pathological and economic significance of obesity, many studies have been undertaken with a view to understanding underlying mechanisms of pathological weight gain.  As a consequence, it has become clear that there are a large number of different genes and their genetic re-arrangements that give rise to obesity. Therefore, it is unlikely that a simple ‘one-size-fits-all’ pharmacological or other intervention will be applicable to resolution of obesity. This mini-review describes some of the wide range of genetic influences that have been found thus far that contribute to pathological excess weight gain.

Peter Kay 243 - Genetics and Obesity

What is Obesity?

The most common way of defining obesity is by reference to the body mass index (BMI). BMI is calculated by dividing a person’s weight in kilograms by the square of the person's height in meters. Adults with a BMI between 25 and 30 are considered to be simply overweight. Those with a BMI equal to or greater than 30 are considered to be obese. In children, because the BMI calculation cannot be reliably applied, those who are above the 95th percentile with respect to body weight at a particular age are considered obese.

Many years ago, it was thought that ways to help those who suffer from obesity would evolve from a better understanding of the mechanisms that underpin this condition and that identification of the predisposing gene, such as found in many monogenic pathological conditions such as cystic fibrosis, or small number of genes would help in this regard. As it turned out, this was not the case.

Is there a Genetic Basis to Obesity?

Whether or not there was a genetic basis to development of obesity was the subject of intense investigation for many years. Distinction between genetically controlled factors and others such as environment, customs and behaviour for example has been a major obstacle in characterisation of genetic factors that contribute to development of obesity.

Initially, the most compelling evidence that there is a genetic basis to development of obesity came from twin studies. For example, concordance for development of obesity between monozygotic (genetically identical) twins was found to be in the order of 80% whilst in dizygotic (genetically non-identical) twins the concordance rate was found to be around 40%. These findings confirmed that there is a clear genetic component to development of obesity.[1]

In recent years, the heritability of obesity has been confirmed by other types of genetic studies such as segregation analyses in families, candidate gene approaches and the use of genome wide association studies.

How Many Susceptibility Genes are There?

Over the years, there have been many hundreds of studies undertaken to identify obesity susceptibility genes. There have been at least 100 candidate genes identified thus far. They include genes that encode leptin (LEP), leptin receptor (LEPR), melanocortin four receptor (MC4R), adiponectin (ADIPOQ), corticotrophin-releasing hormone1 (CRHR1), prohormone convertase1 (PC1), pro-opiomelanocortin (POMC), resistin (RETN) and the gene that encodes the fat mass and obesity-associated protein (FTO). They are mostly involved in the control of biological processes involving food intake. The very fact that over 100 genes have been implicated in development of obesity clearly illustrates that there are numerous biological and psychological pathways involved in pathological weight gain.[1]

The Problem

Various gene mutants have been found that can promote obesity in a given environment by increasing the desire to overeat and the tendency to be sedentary.  Other factors include a diminished ability to utilize dietary fats as fuel and an increased capacity to store fat. This mini-review outlines some of the many genes that have been found that affect susceptibility to development of obesity. To understand the complexity of resolving the genetic basis of obesity it has become clear thus far that the strongest obesity-associated mutant variants in the FTO and MC4R genes only account for less than 2% of the variance in adult BMI. The combined results of all obesity genome wide gene association studies thus far account for only a very small fraction of the heritability of BMI, even though over 100 obesity associated genes have been identified to date.

Monogenic Causes of Obesity

It has been found that some forms of obesity are monogenic, that is, they are caused by alteration in the workings of a single gene such as FTO, POMC, PC1, and MC4R as well as LEP and LEPR. Identification of monogenic obesity is relatively easy by family studies for example.

As indicated, there have been many different genes identified that cause monogenic obesity. Two consistently identified monogenic causes of obesity include FTO, which encodes the fat mass and obesity-associated protein[2] one of the first genetic causes of obesity identified, and MC4R. MC4R plays an important role in regulating leptin's effects on control of desire for food intake and body weight.[3] The pathogenetic roles of FTO and MC4R are discussed further below because mutations in these genes are some of the most consistent findings in obese subjects.

Many studies have also confirmed that different genetic forms of the LEP and LEPR genes are also well recognised monogenic causes of obesity. They are also discussed in detail because they play a critical role of controlling food intake.

Polygenic Causes of Obesity

Comprehensive genetic studies using genome wide association studies have revealed that there are many different forms of polygenic obesity.[4, 5] Because of the complex nature and number of different genes involved in polygenic obesity, much more work is required to understand the ways in which multiple genes may interact to cause obesity.

Genes Controlling Sedentary Behaviour

It is well known that obesity is also associated with lack of exercise. It has now been identified that  exercise and responses to exercise are under genetic control.[6] Some of the genes identified thus far include EDNRB, MC4R, UCP1, FABP2, CASR and SLC9A9. Thus future studies will aim to understand the genetic interactions between genes that control exercise outcome and food intake for example.

Genes Controlling Fat Storage and Adipolysis

Apart from having an excessive urge to eat and lack of willingness to exercise, it is clear that genetically controlled variation in the rate in which fat is metabolised, lipolysis, could affect weight gain. Thus far scientists have shown that different genetic forms of the PLIN and ADRB3 genes affect the way in which fat deposits are metabolised.[7] These findings demonstrate further the interactive complexity of  the genetic factors that underpin the development of obesity.[7]

Satiety and Obesity

There are a number of neural pathways within the brain that play a key role in the control of food intake. Thus far, one of the best characterised mechanisms is the hypothalamic leptin–melanocortin signalling pathway including leptin, its receptor and other components. This pathway plays a critical role in appetitive behaviour. Most forms of obesity are caused by genetic disruptions of this pathway.

What is the Leptin - Melanocortin Pathway?

The leptin-melanocortin pathway involves signalling in the brain that involves many components including the hormone leptin, its receptor and the melanocortin receptors, in particular melanocortin 4 receptor. As indicated, these are encoded by the genes LEP, LEPR and MC4R respectively. Therefore it is not surprising that obesity is associated with mutant forms of these genes.

About Leptin

Leptin plays a critical role in obesity because it has been shown that homozygosity for a rare genetic LEP mutant which results in leptin deficiency causes a severe type of obesity even in the very young.

The hormone leptin is produced by fat cells or adipose tissue. Therefore, obese subjects generally have increased amounts of leptin in their blood.

Interestingly, it was always thought that the binding of leptin to its receptor in the hypothalamus triggers a series of chemical signals that produce a feeling of fullness, suppressing the feeling of hunger. It is now recognized that leptin is not really a signal to suppress hunger but a signal to let the brain know how much fat or adipose tissue we bear. Low fat levels and thus low leptin levels tell the brain to emit a signal to eat more. This system has evolved as an important survival system. It follows, therefore that qualitative or quantitative defects driven by the LEP gene will lead to instruction to eat more. Other than the very rare leptin deficiency mutant LEP gene, there are only very few other allelic forms of the LEP gene.

So, given that obesity is associated with increased levels of leptin, what causes the urge to over-eat in obese subjects?  It is partly due to quantitative or qualitative defects in the leptin receptor caused by mutant forms of LEPR.

About the Leptin Receptor

The LEPR gene provides instructions for synthesizing the leptin receptor. The leptin receptor is found on the surface of cells in many organs and tissues of the body, including a part of the brain called the hypothalamus. As indicated, the hypothalamus controls hunger as well as other functions such as sleep, moods, and body temperature. It also regulates the release of many hormones that have functions throughout the body. Even in the presence of sufficient amounts of leptin, appetite supressing messages cannot be released from the brain (hypothalamus) if leptin cannot bind to its receptor.

LEPR Mutants and Obesity

To determine the prevalence of pathogenic LEPR mutations in severely obese patients, Farooqi and colleagues[8] sequenced the LEPR gene in 300 patients with hyperphagia (increased urge to eat) and severe early-onset obesity. Eight (3%) of the 300 patients had nonsense or missense LEPR mutations, including 7 homozygotes and 1 compound heterozygote. All missense mutations resulted in impaired receptor signalling. These findings have been supported by many other studies. Thus, it is now understood that a the excessive eating habits of only a small number of obese subjects is due to homozygosity or compound heterozygosity of genetic  mutations within the LEP and LEPR genes. Fortunately, obesity can be resolved in those who suffer from leptin deficiency by replacement therapy in much the same way in which type 1 diabetic patients can be treated with insulin.

Mutations in Melanocortin 4 Receptor (MC4R) Gene

I have included reference to MC4R here because MC4R mutations are one of the most frequently found genetic variants in obese subjects, even though they are only found in around less than 2% of adult obese subjects.

The melanocortin 4 receptor, the fourth member of the melanocortin receptor family of 7-transmembrane G-protein linked receptors was first discovered over 20 years ago.  The MC4R gene is expressed in the brain.

It has been found that activation of melanocortin-4 receptor is critical for nicotinic-induced decreases in food intake by influencing the hypothalamic melanocortin system.

The MC4R gene product acts in part via the leptin system

The MC4R gene is highly polymorphic. Since discovery of MC4R well over100 mutations many of which are associated with early onset obesity have been found.[9] Some of the clinical features of MC4R mutation carriers are an increase in the urge to eat and a marked increase in bone mineral density.

There are many different types of MC4R mutations that give rise to development of obesity. These include missense, nonsense, frameshift mutations and deletions.  Different types of mutations affect severity of obesity and age of onset. For example, mutations that cause deficiency of the receptor on the cell surface are associated with earlier age of onset and greater severity of obesity.[10] By contrast, many of the missense mutations lead to a loss-of-function of the melanocortin 4 receptor even when normal amounts of the receptor are expressed on the surface of cells. Age of onset of obesity is greater in these people.[10]

Subjects with homozygous MC4R mutations show more severe obesity than their heterozygous relatives; thus, the mode of inheritance is co-dominant. Importantly, although the MC4R gene is highly polymorphic, only some of the mutant variants are pathogenic and give rise to defective melanocortin 4 receptor activity and thus obesity.[10]

In 2003, Farooki and colleagues[10] also concluded that mutations in the MC4R gene are the most common cause of obesity. Even so, as indicated above, MC4R mutations only account for about 2-3% of all cases of obesity. Thus, many different underlying mechanisms, controlled by many genes must be involved in development of obesity.

It has been also been shown that the frequency of pathogenic MC4R mutations varies between different racial groups.  Pathological MC4R mutations are more prevalent in obese subjects from European countries compared to Asian countries.

Genetic Variability of Melanocortin Receptor Accessory Protein 2

Melanocortin receptor accessory protein 2, encoded by the gene MRAP2, plays an important role in support of the neural activity of the melanocortin 4 receptor. Thus far, three mutant forms of MRAP2 have been reported. These mutants encode proteins which have altered amino acid sequences at various sites. The E24X variant is associated with severe obesity while a further two N88Y and R125C are associated with modest obesity.[11] It is important to stress that, although they are significant causes of obesity, MRAP2 genetic variants are rare.

The FTO Gene and Obesity

The FTO gene encodes the fat mass and obesity related protein. It was actually the first gene to be unequivocally associated with obesity.[12] Since its discovery many years ago, extensive studies have been unable to determine exactly how different genetic forms of FTO predispose to obesity.

The FTO gene expresses a 505 amino acid protein that shares sequence motifs with other enzymes that are involved in DNA methylation, a means of controlling gene expression suggesting that FTO may be involved in DNA demethylation, one of the epigenetic ways of increasing gene expression. However, from an obesity standpoint, it has been shown that genetic variants of FTO are involved in the control of various biological processes that influence fat mass, leptin levels and waist-to-hip ratio, as well as an increase in food intake and a reduction in satiety.

Interestingly, the inheritance of obesity associated FTO mutants has been shown to increase preference for intake of energy-dense foods, especially those with a higher fat content. Thus reference to dietary preferences may be used to identify particular obesity associated genetic mutants.

It has been difficult to determine the precise role of FTO in development of obesity because the results of research are showing that FTO has a wide ranging impact on many biological functions. For example, scientists have found evidence that FTO also plays a role in controlling the length of telomeres.[13] This is an important biological consideration because preservation of telomere length plays an important role in the ageing process as well as enabling the progression of cancer.

Understanding the relationship between FTO mutants and development of obesity is even more problematical because heterozygosity for dysfunctional FTO mutants has been shown to be associated with obesity, and paradoxically, leanness as well.[14]

Resolution of Obesity

There are a number of different approaches to resolution of obesity.

Firstly, weight loss may be brought about by reducing food intake by amplification of signals that inhibit food intake or by blocking signals that promote excessive eating. Secondly, by blocking nutrient absorption in the intestine. Thirdly, by increasing energy expenditure, increasing exercise and fourthly, by manipulating fat metabolism, reducing fat synthesis and increasing lipolysis. Other than attending to these interventions via a broad spectrum counselling process, various pharmacological approaches have become available based partly on the knowledge of genes and their mutants that have been found.

A series of pharmacological agents have been proposed for use in treating obesity.[15] Many of these drugs re-arrange parts of the neural network that control appetite suppression. In the studies reported [15] it is of great importance to recognise that the placebo effect plays an important role in weight reduction. These findings support the significance of inclusion of the counselling process in the treatment of obesity.

Many drugs have been proposed to treat obesity by targeting MC4R and its associated pathway by suppressing the excessive urge to eat. However, such approaches have suffered from unwanted side-effects such as increased blood pressure.[16] Recently, a new MC4R agonist, setmelanotide has been developed which does respond to obesity. Fortunately, this drug does not have the same unwanted side-effects as others that target the MC4R gene and associated pathway.

It is important to understand that, because there are many different genes involved in development of obesity, any form of genetically focused intervention will only be applicable in only a small fraction of patients that suffer from obesity.

References

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717174/control
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906751/
  3. https://www.gbhealthwatch.com/GND-Obesity-MC4R.php
  4. http://www.sciencedirect.com/science/article/pii/S1110863011000607#b00
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717174/
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183352/
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566022/
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670197/
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596802/
  10. http://www.nejm.org/doi/full/10.1056/NEJMoa022050#t=article
  11. http://www.cell.com/cell-metabolism/fulltext/S1550-4131(13)00342-2
  12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906751/
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580219/
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797938/
  15. http://www.oxfordahsn.org/wp-content/uploads/2015/11/Michael_Theodorakis_15_11_10.pdf
  16. https://link.springer.com/article/10.1007%2Fs00125-016-4187-x

Comments:

  1. No Article Comments available

Post Your Comments:

About Dr Peter Kay

Dr Peter Kay PhD specialized in blood group serology and haematology in the UK. In 1974, he moved to Australia and became involved in tissue transplantation serology and autoimmunity. He later became a member of the Dept. of Pathology at the University of Western Australia, specializing in Immunopathology. In the late 1980s he was awarded his PhD, subject matter, Immunogenetics. In 1989, he founded the first Molecular Pathology laboratory in Western Australia in the Faculty of Dentistry and Medicine at the University of Western Australia, and remained as Head until he retired from Academia in 2001. He has published over 80 peer reviewed articles to do with immunopathology and cancer in prestigious international scientific journals. Dr Peter Kay PhD may be contacted on Tel: 01772 691443;  peterhkay@gmail.com

  • College of Ayurveda UK

    Diploma in Āyurvedic Medicine, 4-year self-paced distant learning program in Āyurvedic medicine.

    ayurvedacollege.org

  • mycology research MRL

    MRL markets mushroom products food grade US & Netherlands GMP standards. Health Professional Videos

    www.mycologyresearch.com

  • health & fitness books

    Massage, sports injury, holistic, healthcare and specialists books written by leaders in their field

    www.lotuspublishing.co.uk

  • Seaweed as Superfood

    Comprehensive nutrient balance found in no other natural food but seaweed: colon health, weight loss

    seagreens.shop

  • FLEXXICORE EXERCISErs

    The FLEXXICORE exercise revolution: transform your fitness regime with 2 exhilarating exercisers

    www.FlexxiCore.com

  • nutrition and cancer

    by Sandra Goodman PhD The latest scientific research regarding Nutrition and Cancer. Full details at

    www.drsgoodman.com

  • Liposomal Nutrients

    Optimum system for nutrient delivery to cells - fully bioavailable vitamins absorbed and metabolised

    abundanceandhealth.co.uk

  • June Sayer Homeopathy

    Training Academy Homeopathy Nutrition Reiki, Distant Learning. Diet, Health Screening, Detox, Stress

    www.homeopathinessex.co.uk

  • Water for Health

    Specialist online health store focused on hydration, body pH balance and quality nutrition.

    www.water-for-health.co.uk

top of the page