• Genetic and Biochemical Response to Obesity
• American Heart Walk

The following article was published in the April 2007 edition of Beyond Change.

Genetic and Biochemical Responses to Obesity
By SHERYL WILLIAMS

Americans are gaining weight at an astonishing pace. Obesity is swiftly becoming an epidemic in this country. According to findings based on a national survey conducted in 2003-2004 and reported in the April 5 issue of The Journal of the American Medical Association, seven out of ten U.S. adults are overweight or obese.¹ This trend is magnified in our children. According to www.actionforhealthykids.org, 19 million children between the ages of six and 19 are overweight. The incidence of childhood obesity has doubled for children and tripled for adolescents.² It is estimated that 80 percent of overweight children become obese adults.³ Development of co-morbid conditions such as Type 2 Diabetes, heart disease, sleep apnea, osteoarthritis, high blood pressure, elevated cholesterol, and depression; once mostly prevalent in overweight adults, are now being seen at alarmingly increasing rates in children.

Obesity has reached prevalent proportions and health care costs associated with weight-related illnesses have skyrocketed. A sedentary life combined with access to an abundance of energy-dense food has lead to an increase in this chronic disease with national health care costs reaching $70 billion per year.⁴ It is interesting to note health care dollars are consumed with the treatment of weight-related diseases and not primarily focused toward research and prevention. The best, most effective intervention for the treatment of obesity is prevention.

The definition of obesity as used in this paper reflects a medical diagnosis generally indicated by an individual’s body mass index (BMI), a height to weight ratio. Adults are classified as overweight when their BMI is between 25-30, and classified as obese when it is above 30. The term obesity is not used as a means for judgment or as a physical observation. The World Health Organization, the American Medical Association, the National Institute of Health, the American Dietetic Association, and the Internal Revenue Service identify obesity as a disease. Obesity develops from a complex interaction between genetic and environmental factors and therefore is a multifactorial chronic disease.⁵ It is this genetic component and related biochemical physiological responses to this complex multifactorial chronic disease that is to be the focus of this paper.

Evidence for a strong genetic contribution of human obesity comes from a variety of sources. Twin and familial aggregation studies suggest that genetic factors account for 60 to 80 percent of the predisposition to obesity.⁶ Biological relatives are apt to resemble each other in numerous ways, including body weight. Individuals with a family history of obesity may be predisposed to gain weight. Family history is used to identify at risk individuals, especially children, for integrated prevention efforts. The risk of obesity is doubled if a child has a parent who is overweight, tripled if the parent is moderately obese and five times greater if the parent is severely obese.^a,b,e The number of genes, markers, and chromosomal regions associated with obesity phenotypes is currently well over 400.^7,a In fact, the 2000 human obesity gene map includes genes on every chromosome except the Y chromosome.⁸

Approximately 30 years ago, two genes believed to be a factor in the development of obesity were discovered. They were called the ob and the β3-adrenoreceptor genes. The β3-adrenoreceptor gene, located primarily in adipose tissue, is thought to regulate the resting metabolic rate (RMR) and fat oxidation. It is speculated that persons with a mutation of this gene may have an increased ability to gain weight by increasing the body’s efficiency to store fat. Fat stores are regulated over long periods of time. Overweight and obesity can come about from only a minute positive energy intake imbalance over an extended period of time.

With regard to the ob gene however, mice lacking the ob gene developed severe obesity.⁹ This gene in mice is considered to be identical in its correlation to humans. Leptin was later discovered as the protein coded for by the ob gene that acted as a satiety factor. Leptin receptors in the hypothalamus augment the negative feedback mechanism signaling to the brain the feeling of fullness (satiety) resulting in a reduction in energy (food) intake. The critical differentiation between the experimental leptin-deficient mouse and the obese individual is the absence of leptin in letpin-deficient mice versus high levels of leptin in obese patients. This yielded the conclusion that morbidly obese patients (BMI > 40) are leptin-resistant rather than leptin-deficient.

As the study of genes lead to the study of leptin, the study of leptin has lead to the study of ghrelin. Ghrelin is a gastric hormone regulated by the hypothalamus by which production is increased by lack of food in the stomach. Leptin and Ghrelin are reportedly opposing metabolic counterparts, regulated reciprocally by alterations in energy balance.¹⁰ In people, ghrelin concentrations increase abruptly before and decrease rapidly after each meal. Ghrelin and leptin, are both satiety regulatory hormones. Current genetic and biochemical research leads to the perception that in morbidly obese patients, the signaling functions of both hormones are considered to be defective. Gastric bypass patients are less hungry post-operative because the portion of the stomach that signals ghrelin production no longer receives food and therefore it is expected to see low levels of ghrelin in these individuals¹¹.

Last year another gene was associated with obesity, as published by the genetics and genomics department at Boston University’s medical school. This new study ascertains that five percent or one in every ten people, including children, has a gene variant pattern (mutation) linked to obesity. At present, the report only suggests an “association” between the gene variant and obesity. The researchers of this study found that when two copies of a particular gene variant were present, people had a higher BMI and were more likely to be obese.¹²

There is no magic bullet to fight obesity. In an environment that sustains a readily available resource for a vast array of food, individuals will respond differently to this stimulus. Some individuals store fat more readily in an environment of excess, others lose less fat in an environment of famine. It has been suggested that obesity is so heterogeneous and polygenic that there will be no major genes; rather, 20 or more common gene variations may each contribute their part in the genetic burden of obesity.¹³ Seldom do people have a mutation in a single gene that causes severe obesity. However, research is providing valuable insight into the complex biological pathways that regulate the sensitive balance in relation to energy input and energy output. Obese individuals have similar genetic profiles that may open the doors to understanding the biological differences that predispose some individuals to gain weight. Continued research will be extremely beneficial in the treatment of obesity in these at risk individuals.

Moreover, while genes appear to enhance the vulnerability toward obesity, other determinants must be present for obesity to occur. It is important to recognize that the genetic expression of obesity and the biochemical regulations occur in an environment that increases the ability of the body to accumulate excessive food intake and more efficiently store fat. Environmental influences and technological advances include an overall decrease in physical activity while at the same time provides an increase in food availability, directly proportionate to the increase in consumption of more calorie dense, readily available and thus extremely easily obtainable foods. Our lifestyles have become increasingly more stressful while at the same time we have become increasingly more sedentary.

Just as the disease of obesity is multifactorial, so the discovery for a cure will have to be also. Just as there is no one, singular cause for the obesity epidemic, it is quite doubtful that there will be only one, singular gene or biochemical aspect that will ultimately bring an end to this epidemic. However, current research continues to substantiate that obesity is not simply a matter of willpower or lack thereof.

According to the National Institute of Health, diets for the purpose of sustained and significant weight loss have a 98 percent failure rate. We have become a nation of veteran dieters. If one diet actually achieved what it promised to do, wouldn’t we have found it by now? Honestly, it’s not in finding a diet that works because all of them work to some degree – one loses weight. However, the true test is in finding a diet that works for good.

With ever increasing food portion sizes, eating out more frequently, changes in the overall composition of the food we eat, our increase in overall daily calorie consumption, and the steadily decrease in physical activity; the fueling of the obesity epidemic will continue to blaze. For individuals who are genetically predisposed to weight gain, prevention is the best course of treatment. The management of obesity, though proven more difficult for some than others, is possible. Gastric bypass surgery is considered to be the most effective “tool” available for the management of this chronic disease. Genes are not destiny. Obesity is a complex problem related to a multitude of contributing factors including our environment, our biology, our actions, our attitudes, and our genes.

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References: 

¹ Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM, Prevalence of Overweight and Obesity in the United States, 1999-2004; JAMA. 2006;295:1549-1555.

^2-3 Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity Among US Children, Adolescents, and Adults, 1999-2002. JAMA. 2004;291:2847-2850

⁴ Wolf AM, Coldtiz GA, Current Estimates of the Economic Cost of Obesity in the United States, JAMA. 1999; 282: 1530-1538

⁵ National Institute of Health and National Heart, Lung and Blood Institute. Clinical Guidelines on the identification, Evaluation, and Treatment of Over-weight and Obesity in Adults – The Evidence Report. Obes Res. 1998: xi

⁶ Maes HH, Neale MC, Eaves IJ, Genetics and Environmental Factors in Relative Body Weight and Human Adiposity. Behav Genet. 1997; 27: 325-335

^7-8 Perusse L et al: The Human Obesity Gene Map: the 2000 update, Obes Res 9:135, 2001

⁹ Nijhuis J, Van Dielen FMH, Buurman WA, Greve JWM, Review Article-Leptin in Morbidly Obese Patients: No Role for Treatment of Morbid Obesity but Important in the Postoperative Immune Response. Obes Surg 2004: 14, 476-483

¹⁰ Fruhbeck G, Diez-Caballero A, Gil MJ, Montero I, Gomez-Ambrosi J, Salvador J, Cienfuegos J, The Decrease in Plasma Ghrelin Concentrations Following Bariatric Surgery Depends on the Functiona Integrity of the Fundus. Obes Surg 2004: 14, 6006-612

^11,iiNijhuis J, Van Dielen FMH, Buurman WA, Greve JWM, Ghrelin, Leptin and Insulin Levels after Restrictive Surgery: a 2-Year Follow-up Study, Obes Surg, 2004:14:783-787

¹² Herbert A, Obesity Epidemic Balloons to New Girth, News Release, Science, Harvard School of Public Health. April 14, 2006; Vol. 312: 279-283

¹³ Shuldiner AR, Sabra M: TRp64Arg β3-Adrenoceptor: When Does a Candidate Gene Become a Disease-Susceptibility Gene? Obes Res 9:806, 2001

Additional References:

Bray GA, Contemporary Diagnosis and Management of Obesity. Health Care Co: Newtown PA; 1998:35-67

iKoza RA, Mikonova , Hogan J, Rim JS, Mendoza T, Faulk C, Skaf J, Kozak L, Changes in Gene Expression Foreshadow Diet-Induced Obesity in Genetically Identical Mice. PloS Genetic. 2006:2: 769-780

Website References:

^aOffice of Genetics and Disease Prevention, Center for Genomics and Public Health, University of Washington, Public Health Perspectives:  What We Know, What We Don’t Know and What it Means

^bCDC Public Health Perspective

^cObesity Gene Map

^dCenter for Nutrigenomics at UC Davis

^eAmerican Dietetic Association

^fAction for Healthy Kids

American Heart Walk
By SHERYL WILLIAMS
September 20, 2003

The American Heart Association's American Heart Walk took place at Woodward Park. Teams and informational booths were sponsored by several local organizations.

Together with the American Heart Association, the First Annual "Walk from Obesity" formed a team in support of the American Society of Bariatric Surgeons.

A team of 51 walkers was assembled. Overall efforts throughout the morning were expected to serve over 1,500 participants and volunteers, raising upwards of $160,000 for the American Heart Association alone!

Both two-mile and four-mile walks began shortly after 8:00 a.m.

My nine-year-old son, Jacob, and I tackled the two-mile course. Before the walk began I made a deal with Jacob, if he went most of the way at a steady pace, I’d carry him over the finish line on my shoulders. Silly me, I should have defined the word "most".

At the half-way mark I was bombarded with, "Is this far enough yet, Mommy?"

During the last quarter mile, I kept my promise. As we crossed the finish line I made the comment to the water-boys, "Next year, he's carrying me!"

We must have looked a sight. We were filmed by the local news!

There was an obstacle course, antique fire truck rides, bounce house and face painting for the kids. In keeping with the theme of the festivities, most children were getting variations of hearts painted on their faces. Jacob chose the blue alien.

The morning was enhanced still further when we received our goodie bags! In addition to our really cool t-shirts, the goodie bags included a water bottle, a sun visor that matched our t-shirts, a talking pedometer, a Frisbee, sunscreen, note pads, pens, pencils, emery boards and candy.

We left this event around 10:30 a.m. We were so motivated; we headed off to the gym for more exercise!

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