HINI

Molecular Genetics of Obesity:
Observations of a Rapidly Expanding Field
William J. Klish, M.D.
Professor of Pediatrics, Baylor College of Medicine
Head, Pediatric Gastroenterology and Nutrition
Texas Children's Hospital, Houston, Texas, U.S.A.

The prevalence of obesity is increasing throughout North America at an alarming rate. Indeed, it has reached what might be considered epidemic proportions. The 1990 National Health and Nutrition Survey (NHANES III) revealed that approximately 34% of the adult population in the United States was obese. What was impressive and somewhat frightening was that in 1980 only 25% of adults in the U.S. were obese. Approximately one quarter of children and adolescents 6 - 17 years of age are overweight or obese and this prevalence is increasing. There are undoubtedly many factors that are influencing this phenomenon. Not only is food plentiful in North America but it is getting increasingly convenient. Physical activity is declining due to the proliferation of work saving devices available at home and school as well as the work place. Over the past five years our knowledge of the molecular physiology of obesity has rapidly expanded. It provides us with a better understanding of why people become obese and may ultimately help in the control of obesity. This article will briefly review some of what is known in this field. It by no means, will be all inclusive. The field of molecular genetics of obesity is expanding at such a rapid rate that some of the observations will be outdated by the time this article reaches publication.

We have known for many years that fat parents make fat children even if the children are not raised in the same household as the parents. If both parents are obese, two-thirds of their children are obese. If only one parent is obese and the other normal, one half of their children develop obesity. If both parents are of normal weight, only 9% of their children become obese. Twin studies have shown that about one-third of fraternal twins have a weight difference as adults that is greater than 6 kilograms. The same is true of non-twin siblings. However, in identical twins there is almost no difference in the weight as adults whether they were raised in the same family or separated at birth.

In 1994, the first rodent gene for obesity, the ob gene was identified and the familial nature of obesity began to make sense. Since homology exists between rodent genes and human genes, it became possible to search for the human obesity genes. The product of the ob gene is a 16 kilodalton protein which was named leptin from the Greek word for thin. The ob gene appears to be functional only in the adipocyte and is activated by the deposition of fat into the cell. As the fat content increases leptin synthesis is stimulated and this substance is secreted into the bloodstream and circulated to the hypothalamus where it helps regulate the satiety center. In the mouse, the leptin concentration in the serum parallels the fat content of the body. The higher the fat, the higher the leptin blood level which down-regulates the hypothalamus and decreases appetite thereby regulating weight. Mice with a defect in this gene cannot produce leptin effectively and have an uncontrolled appetite that results in morbid obesity. When this gene was first described a wave of excitement passed through the scientific community because it was felt if the cause of obesity was this simple it would be easy to produce a leptin pill that could be used to control appetite and ultimately weight. Unfortunately, it was soon discovered that the leptin levels in obese humans are high rather than low implying human obesity was much more complicated than that of the ob mouse.

Since the discovery of the obese (ob) gene several other rodent genes have been described. They all have been given rather poetic names dictated by the characteristics of the mouse from which they were cloned and include fat (fat), tubby (tub), yellow agouti (ay) and diabetes (db) genes. The human locus of all of these genes has been identified and it is interesting to note that they all reside on different chromosomes namely 1, 4, 7, 11 and 20. Much is known about all of these genes.

As mentioned above, the ob gene produces leptin. Leptin not only reduces appetite but it also appears to increase the resting metabolic rate which in turn increases fat oxidation. This circulating protein appears to be a very potent regulator of body weight so when a gene mutation results in a decrease in leptin output morbid obesity occurs. It appears also that an isolated defect in the ob gene is rare in humans. However, case reports of this defect are beginning to appear. Unique to leptin deficiency in humans is that the obesity appears early in infancy and progresses throughout childhood.

The diabetes or db gene appears to regulate the leptin binding site in the hypothalamus. The name of this gene has recently been changed to ob- r or ob-receptor to reflect this function. How it relates to the diabetes in animals that have a defect in this gene has not been entirely worked out. Abnormalities in this gene may explain (at least partially) why many obese humans have high leptin levels.

The fat gene produces the enzyme carboxypeptidase E (CPE). The function of this intracellular enzyme is to cleave the side chain of prohormones producing their active form. In the case of the fat mouse, insulin is misprocessed resulting in elevated levels of proinsulin. How this causes obesity is not well understood but it is interesting to note that the obesity this gene causes is of late onset.

Recently the tub gene has been shown to produce phosphodiesterase which seems to be involved in hypothalamic cellular apoptosis. This somehow plays a role in weight and appetite control.

The agouti gene has stimulated greatest interest recently. It produces a protein called the agouti signaling protein or melanocyte stimulating hormone. It is this hormone that gives the agouti mouse its yellow coat, however, it also stimulates a hypothalamic neurotransmitter called melanocortin. This substance cross talks with other hypothalamic neurotransmitters that affect appetite. Somehow this gene is activated during weight gain and ultimately suppresses appetite through this alternate pathway.

Many of the hypothalamic transmitters that control appetite have been described. Neuropeptide-Y has been considered to be the most important appetite stimulant. Glucagon-like peptide-1

Unique to leptin deficiency in humans is that the obesity appears early in infancy and progresses throughout childhood.

SUGGESTED READINGS

Bandini LG, Dietz WH. Myths about childhood obesity. Ped Annals 1992; 21:647-52.
Considine RV, Sinha MK, Leiman Ml, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New Engl J Med 334(5):292-295, 1996.
Dietz, WH, Robinson TN. Assessment and treatment of childhood obesity. Ped Rev 1993; 14:337-44.
Friedman JM. The alphabet of weight control. Nature 385:119-120, 1997.
Perusse L, Chagnon YC, Dionne FT, Bouchard C. The human obesity gene map: the 1996 update. Obesity Research 5(1):49-61, 1997 January.
Rohner-Jeanrenaud F, Jeanrenaud B. Obesity, leptin and the brain. New Engl J Med 334(5):334-325, 1996.
Schwartz MW, Seeley RJ. The new biology of body weight regulation. J of Dietetic Association 97:54-58, 1997 January.
Stephens TW. Life without neuropeptide Y. Nature 381:377- 378, 1996.
Troiano RP, Flegal, KM, Kuczmarski, RJ, Campbell SM, Johnson CL. Overweight Prevalence and Trends for Children and Adolescents. Arch Pediatric Adolesc Med/Vol 149:1085-1091, 1995.
Whitaker RC, Wright JA, Pepe MS, Seidel KD, Dietz WH. Predicting obesity in young adulthood from childhood and parental obesity. New Eng J Med 337(13):869-873, 1997 September.

(GLP-1) is believed to be an important appetite inhibitor. When injected into the ventricles of animals, these substances either stimulate or inhibit appetite, causing the animals to become either obese or lean. However, a knockout mouse which cannot make neuropeptide-Y was bred and this mouse maintained a normal body weight. This implies redundancy in the neurotransmitter system for appetite with other neuropeptides working in concert with neuropeptide-Y and GLP. Melanocortin is obviously an important substance as mentioned above but other substances such as corticotropin-releasing substance norepinephrin and serotonin also seem to have a role.

Since the prevalence of obesity is so high, defects in the genes described must be common. One can speculate that these mutations are common because they offered survival advantage. During the early history of man, food was not always available. During periods of food availability, individuals with these obesity mutations had an increased efficiency in fat disposition. These larger stores of fat allowed them to survive longer during periods of starvation. Therefore, these defects were selected for rather than against in the early phase of human history. Given this model of genetic predisposition to obesity, the influence of environmental factors on the ultimate phenotypic expression becomes especially important. By emphasizing healthy diet and exercise patterns from an early age, obesity need not be the inevitable outcome.

Dr. William J. Klish joined the INI / HINS Advisory Council earlier this year. His article, "Molecular Genetics of Obesity: Observations of a Rapidly Expanding Field", appears in this issue of In-Touch. Dr. Klish is Professor of Pediatrics at Baylor College of Medicine, Houston and also Chief of the Nutrition and Gastroenterology Service and Head of the Department of Medicine at Texas Children's Hospital. Dr. Klish completed his undergraduate work at Wisconsin State University at Eau Claire, and received his medical degree from the University of Wisconsin School of Medicine in 1967.

After one year of pediatric residency at Baylor College of Medicine in 1967, he served with the U.S. Naval Reserve Medical Corps at Camp Pendelton, California from 1968 to 1970. He completed his pediatric residency at Baylor College of Medicine from 1970 to 1972 and became Chief Resident in 1972.

Dr. Klish's practice focuses both on pediatric gastroenterology and pediatric clinical nutrition. He has received awards for excellence in teaching from both the Baylor College of Medicine and the University of Rochester. He has served as Chairman of the Committee of Nutrition, American Academy of Pediatrics and as a member of the National Digestive Diseases Advisory Board. He is a Past President of the North American Society for Pediatric Gastroenterology and Nutrition. After becoming its first Chairman, Dr. Klish served as a member of the Sub-Board of Pediatric Gastroenterology for the American Board of Pediatrics for six years. He serves as a consultant for many national issues related to pediatric gastroenterology and nutrition and has been on the Board of Directors of several foundations.

Dr. Klish has published more than 130 papers, 80 abstracts, and has been featured in many articles in the lay press.

Nutrition for Healthy Term Infants
New National Guidelines on Infant Nutrition from the Canadian Paediatric Society,
Dietitians of Canada and Health Canada

Donna Secker MSc, RD
Clinical Dietitian
The Hospital for Sick Children,
Toronto, Canada

Meeting the nutritional needs of infants is well recognized as essential for optimizing their growth and development. Health professionals of many disciplines are devoted to ensuring that infants get the best start to life through proper nutrition. To provide the best advice to parents and caregivers on how to feed their infants, health professionals seek answers from the results of scientific research as well as guidance from key national and international pediatric and / or nutrition organizations.

In Canada, the last national guidelines on infant feeding were released by Health and Welfare Canada and the Canadian Paediatric Society in 1986. Those guidelines were based upon a statement published by the Canadian Paediatric Society Nutrition Committee in 1979. In 1992, the Canadian Paediatric Society, the Canadian Dietetic Association (now known as Dietitians of Canada) and Health Canada agreed to collaborate on a new national statement on infant nutrition.

Released in April 1998, "Nutrition for Healthy Term Infants", summarizes the existing scientific literature on nutrition for infants from birth to 24 months, and presents principles and recommendations to help health care professionals promote optimal and evidence-based nutritional care for infants in North America. Collaboration between the three key stakeholder organizations involved in infant nutrition in Canada has produced a document which delivers unified messages for health care professionals to deliver to the public. Health professionals have already begun using the science of infant nutrition found in the Statement as a basis for direct counselling and education of parents and caregivers, establishment of appropriate protocols in hospitals, development of community programs and policy at the local and national level, and education of future health care professionals and policy makers.

A summary of the Statement's principles and recommendations is published here in its entirety. A copy of the complete Statement, including the reference list of 200 citations, is available for downloading from all three of the collaborating organization's web sites (www.cps.ca, www.dietitians.ca, www.hc-sc.gc.ca). For individuals without Internet access, a hard copy of the statement can be obtained from the respective organizations, e.g. Dietitians of Canada, 480 University Ave., Suite 604, Toronto, Ontario, Canada M5G 1V2.

Nutrition for Healthy Term Infants offers multidisciplinary health professionals the most current scientific tool for advising parents and positively influencing the nutritional environment provided to infants in North America.

Executive Summary

The Canadian Paediatric Society Nutrition Committee, Dietitians of Canada and Health Canada collaborated on the preparation of this statement on nutrition for healthy term infants from birth to 24 months of age. This statement is intended for the use of health care professionals. It provides information that is basic to communicating consistent messages about infant nutrition to parents and caregivers across Canada. It is not designed, however, to be an all-encompassing practical guide to infant feeding. The recommendations in this statement are based on available scientific evidence. However, many studies on infant nutrition are not based on randomized trials because they are neither possible nor ethical in many circumstances. In the absence of solid science, accepted practice and its rationale is presented. Throughout the document, we have attempted to clearly distinguish those recommendations based on science versus those based on common practice. A summary of the principles and recommendations found in the document is presented below.

Breastfeeding is the optimal method of feeding infants.

Summary of Principles and Recommendations

Breastfeeding
Breastfeeding is the optimal method of feeding infants. Breastfeeding may continue for up to 2 years of age and beyond.
Recommendation:

Encourage exclusive breastfeeding for at least the first 4 months of life.
Active public health, hospital, community and workplace support of breastfeeding will increase initiation rates and duration of breastfeeding.
Recommendations:
Provide antenatal and postnatal counselling about the principles and practice of breastfeeding.
Encourage frequent feeds during the early postnatal period.
Provide more community-based programs supporting breastfeeding families as the length of hospital stays decreases.
Encourage support in the community and workplace for flexible work schedules, part-time nursing and the use of expressed breast milk. Breastfeeding is rarely contraindicated. Neither smoking nor environmental contaminants are necessarily contraindications to breastfeeding. Moderate, infrequent alcohol ingestion, the use of most prescription and over-the-counter drugs and many maternal infections do not preclude breastfeeding.
Recommendations:
Encourage women who smoke to stop or reduce smoking; however, even if smoking is continued, breastfeeding is still the best choice.
Limit intake of alcohol.
Whenever drugs are prescribed or infection detected, assess each case on an individual basis.
When the mother is known to be HIV antibody positive, alternatives to breastfeeding are indicated.
Vitamin D deficiency is a health concern in Canada. Infant formulas and milks are fortified with vitamin D. Breastfed infants should also receive extra vitamin D in the form of a supplement.
Recommendation:
Provide a vitamin D supplement to all breastfed infants starting at birth and until the diet provides a source of vitamin D.
Alternate Milks
If an infant is not breastfed, or is partially breastfed, commercial formulas are the most acceptable alternative to breast milk until 9 to 12 months of age.
Recommendations:
Use cow's milk-based, iron-fortified formulas until 9 to 12 months of age.
Iron-fortified follow-up formulas are a preferred alternative to cow's milk from 6 months until 9 to 12 months of age.
Use soy-based formulas only for those infants who cannot take dairy-based products for health, cultural or religious reasons, such as a vegan lifestyle, or galactosemia.
Specialty formulas are indicated only for infants with detected or suspected pathology.
The use of nutritionally incomplete alternate milks as the sole source of nutrition for infants is inappropriate. Pasteurized whole cow's milk, however, is an important component of a mixed infant diet after 9 months of age. For infants unable to take cow's milk products, continue commercial soy formula until 2 years of age.
Recommendations:
Pasteurized whole cow's milk may be introduced at 9 to 12 months of age and continued throughout the second year of life.
Partly skimmed milk (1% and 2%) is not routinely recommended in the first 2 years.
Skim milk is inappropriate in the first 2 years.
Soy (except soy formula), rice or other vegetarian beverages, whether or not they are fortified, are inappropriate alternatives to breast milk, formula or pasteurized whole cow's milk in the first 2 years.
Other Fluids in Infant Feeding
Tap water, well water meeting established standards of safety and commercially bottled water, except mineral or carbonated water, are generally suitable for infants. Limit the use of "fruit juice" to avoid interfering with the intake of nutrient-containing foods and fluids. Herbal teas and other beverages are of no known benefit to an infant and may be harmful.
Recommendations:
Bring all water for feeding infants under 4 months of age to a rolling boil for at least 2 minutes to ensure that it is pathogen free.
Limit fruit juice to avoid interfering with the intake of breast milk or infant formula.
Do not use herbal teas or other beverages.
Transition to Solid Foods
Infants between 4 and 6 months of age are physiologically and developmentally ready for new foods, textures and modes of feeding. By 1 year of age, the ingestion of a variety of foods from the different food groups of Canada's Food Guide to Healthy Eating is desirable.
Recommendations:
Introduce complementary foods at 4 to 6 months to meet the infant's increasing nutritional requirements and developmental needs.
To prevent iron deficiency, iron-containing foods such as iron-fortified cereals are recommended as the first foods.
Safety Issues Around Feeding
Foods provided to infants must be free of pathogens, appropriate in size and texture, nutritionally sound and fed safely.
Recommendations:
To prevent infant botulism, do not use honey in the feeding of infants under 1 year of age.
To prevent salmonella poisoning, cook all eggs well and do not use products containing raw eggs.
Hard, small and round, smooth and sticky solid foods are not recommended because they may cause choking and aspiration.
Ensure that infants and toddlers are always supervised during feeding.
Avoid feeding an infant using a "propped" bottle.
Nutrition in the Second Year
Healthy eating is important in the second year to: (a) provide the energy and nutrients needed to grow and develop; (b) develop a sense of taste and an acceptance and enjoyment of different foods; and (c) instill attitudes and practices which may form the basis for lifelong health-promoting eating patterns.
Recommendation:
Small, frequent, nutritious and energy-dense feedings of a variety of foods from the different food groups are important to meet the nutrient and energy needs during the second year.
Other Issues in Infant Nutrition
(i) Food allergies
Whenever possible, allergies to food should be prevented.
Recommendations
Encourage exclusive breastfeeding for at least 4 months to decrease the risk of allergy in infants with a positive family history. Treatment of proven food allergies involves avoidance of foods known to cause symptoms.
Recommendation:
When food choices are restricted, ensure that dietary intake continues to meet nutrient and energy needs.
(ii) Colic
Dietary manipulations have had limited success in the treatment of colic.
Recommendation:
Ensure that any dietary modification or pharmalogical interventions are safe.
Iron deficiency is preventable through appropriate feeding choices.
(iii) Constipation
In infancy, true constipation is infrequent.
Recommendation:
Parents need to be educated about the wide variation in normal bowel function in infants and toddlers to avoid overtreatment of normal variants.
(iv) Dietary fat
Dietary fat is an important source of energy and the only source of essential fatty acids.
Recommendation:
Dietary fat restriction during the first 2 years is not recommended because it may compromise the intake of energy and essential fatty acids and adversely affect growth and development.
(v) Dental caries
Prevalence of dental caries is lower where infants and children have access to fluoridated water and where long-term exposure of teeth to nutrient-containing liquids is avoided. Excessive fluoride intake can cause dental fluorosis.
Recommendations:
Fluoride supplementation is not recommended for infants less than 6 months of age.
For infants between the ages of 6 months to 2 years who are living in areas where the household water supply contains less than 0.3 ppm (�g/L) fluoride, daily supplementation with 0.25 mg fluoride is recommended. Where the principal drinking water source contains 0.3 ppm (�g/L) fluoride, supplementation is not recommended.
Avoid excessive intake of fluoride.
Avoid the use of a bottle during sleep time or as a pacifier. Avoid nocturnal and long-term use of baby bottles containing liquids other than water.
Do not dip pacifiers or nipples in sugar or honey.
(vi) Gastroenteritis
Manage mild to moderate dehydration associated with gastroenteritis with oral rehydration therapy (ORT). Prevent malnutrition.
Recommendations:
Manage mild to moderate dehydration with an oral electrolyte solution and early refeeding.
For infants who are breastfed, continue breastfeeding while supplementing fluid intake with an oral electrolyte solution.
(vii) Diabetes
The exact role of early infant nutrition as a possible etiologic factor for infants genetically at risk for diabetes has not been proven.
Recommendation:
There is no justification at this time to recommend changes to infant feeding practices for the purpose of preventing diabetes.
(viii) Iron deficiency anemia
Iron deficiency is preventable through appropriate feeding choices.
Recommendations:
Continue exclusive breastfeeding for at least 4 months.
Introduce complementary foods containing iron at 4 to 6 months of age.
Choose iron-containing formulas for infants who are not breastfed or for infants receiving formula as well as breast milk.
Delay the introduction of whole cow's milk until 9 to 12 months of age.
Continue to offer iron-fortified foods beyond 1 year of age to provide sufficient iron.
Where informed parents choose not to adhere to these recommendations, screen for anemia at 6 to 8 months of age and provide medicinal iron drops if necessary.
(ix) Vegetarian diets
Nutritional needs can be met by most well-planned vegetarian diets. For vegetarian diets that are limited in variety and nutritional quality, professional advice regarding supplements is appropriate.
Recommendations:
For vegan infants who are not breastfed, promote commercial soy-based infant formula during the first 2 years of life.
After dietary assessment, recommend nutrient supplements for vegan diets which are found to be nutritionally incomplete.

Dietary fat restriction during the first 2 years is not recommended.

Opinions expressed In-Touch are those of the authors and do not necessarily reflect the views of the INI, HINS or the H.J. Heinz Company.
Material from In-Touch may be reproduced without written permission provided the source is acknowledged. Correspondence is welcome. Please write to Dr. D.L. Yeung, Director, Corporate Nutrition, H.J. Heinz Company, PO Box 57, Pittsburgh PA, 15230-0057 or H.J. Company of Canada Ltd, 21st Floor, 5700 Yonge Street, North York, ON M2M 4K6.
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