Weight and Physical Health - The Genetics Of Body Weight And Obesity

Genetics, the study of single genes and their effects, explains how and why such traits as hair color and blood types run in families. In the early twenty-first century the scientific community agrees that body shape and body weight also are regulated traits, that genes govern much of this regulation, and that altering genetically predetermined set points for body weight is often difficult. "Genomics," a discipline that emerged during the 1980s, is the study of more than single genes; it considers the functions and interactions of all the genes in the genome. In terms of understanding genetics as a risk factor for obesity, genomics has broader applicability than does genetics because it is likely that humans carry dozens of genes that are directly related to body size, and most obesity is multifactorial—resulting from the complex interactions of multiple genes and environmental factors.

Since genomics is a relatively new discipline, many questions are still unanswered about how genes influence the ability to balance energy input and energy expenditure, and why individuals vary in their abilities to perform this critical body function. Table 2.5 summarizes what is known and what remains to be learned about variations in body weight, energy metabolism, and inherited obesity syndromes.

Single Mutant Genes Cause Obesity

While the majority of obesity in humans is not due to mutations (alterations or changes) in single genes, there are obesity syndromes caused by variations in single genes, and these account for approximately 5 percent of all obesity. In rare cases of severe obesity that begin during childhood, a single gene has a major effect in determining the occurrence of obesity, with environmental TABLE 2.2
Life expectancy at birth, at 65 years of age, and at 75 years of age, according to race and sex, selected years 1900–2001
[Data are based on death certificates]

	All races			White			Black or African American1
Specified age and year	Both sexes	Male	Female	Both sexes	Male	Female	Both sexes	Male	Female
At 75 years	Remaining life expectancy in years
1980	10.4	8.8	11.5	10.4	8.8	11.5	9.7	8.3	10.7
1985	10.6	9.0	11.7	10.6	9.0	11.7	10.1	8.7	11.1
1990	10.9	9.4	12.0	11.0	9.4	12.0	10.2	8.6	11.2
1991	11.1	9.5	12.1	11.1	9.5	12.1	10.2	8.7	11.2
1992	11.2	9.6	12.2	11.2	9.6	12.2	10.4	8.9	11.4
1993	10.9	9.5	11.9	11.0	9.5	12.0	10.2	8.7	11.1
1994	11.0	9.6	12.0	11.1	9.6	12.0	10.3	8.9	11.2
1995	11.0	9.7	11.9	11.1	9.7	12.0	10.2	8.8	11.1
1996	11.1	9.8	12.0	11.1	9.8	12.0	10.3	9.0	11.2
1997	11.2	9.9	12.1	11.2	9.9	12.1	10.7	9.3	11.5
1998	11.3	10.0	12.2	11.3	10.0	12.2	10.5	9.2	11.3
1999	11.2	10.0	12.1	11.2	10.0	12.1	10.4	9.2	11.1
20004	11.4	10.1	12.3	11.4	10.1	12.3	10.7	9.2	11.6
20015	11.5	10.2	12.4	11.5	10.2	12.3	10.8	9.3	11.7
1Data shown for 1900–60 are for the nonwhite population.
2Death registration area only. The death registration area increased from 10 states and the District of Columbia in 1900 to the coterminous United States in 1933.
3Includes deaths of persons who were not residents of the 50 states and the District of Columbia.
4Life expectancies (LEs) for 2000 were revised and may differ from those shown previously. LEs for 2000 were computed using population counts from Census 2000 and replace LEs for 2000 using 1990-based postcensal estimates.
5Life expectancies for 2001 were computed using 2000-based postcensal estimates. Notes: Populations used for computing life expectancy and other life table values for 1991–99 are postcensal estimates of U.S. resident population, based on the 1990 census.
SOURCE: "Table 27. Life expectancy at birth, at 65 years of age, and at 75 years of age, according to race and sex: United States, selected years 1900–2001," in Health, United States, 2003, Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, MD, 2003 [Online] http://www.cdc.gov/nchs/hus.htm [accessed January 2, 2004]

factors playing a lesser role. The mutations occur in genes that encode proteins related to the regulation of food intake. One example is mutations of the leptin gene (on chromosome 7) and its receptor. The circulating hormone leptin (leptos means thin) sends the brain a satiety signal to decrease appetite. Obese mice of the ob/ob strain produce no leptin and tend to overeat; when given leptin, the mice stop eating and lose weight. Unfortunately, experiments have failed to replicate these findings in humans. Blood concentrations of leptin are usually elevated in obese humans, suggesting that they may be insensitive or resistant to leptin, rather than leptin deficient. The majority of obese individuals appear to have normal genetic sequences for leptin and its receptor, although humans with a demonstrable genetic leptin deficiency suffer from extreme obesity.

Melanocortin 4 receptor (MC4R) deficiency is the most commonly occurring monogenic (single gene) form of obesity. Nearly 6 percent of persons with severe obesity commencing in childhood have this mutation. Inheriting one copy of certain variants of the gene causes obesity in some families. Researcher I. Sadaf Farooqi and his colleagues screened 500 subjects with severe, early-onset obesity for mutations in MC4R and conducted clinical studies of those with mutations. The investigators conducted body composition studies, measured subjects' resting metabolic rates (calories expended at rest), performed metabolic and endocrine testing, and assessed eating behaviors. In "Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene" (New England Journal of Medicine, vol. 348, no. 12, March 2003), the investigators reported that mutations in MC4R produced a distinct obesity syndrome that is inherited. They also concluded that these mutant receptors played a pivotal role in the control of eating behavior—that regulation of body weight in humans is sensitive to variations in the amount of functional MC4R.

Multiple Gene Variants Involved in Body Weight and Obesity

It has long been known that heredity affects health. Heritability studies, which seek to determine the proportion of variance of a particular trait that is attributable to genetic factors and the proportion that is attributable to environmental factors, indicate that genetic factors may account for as much as 75 percent of the variability in human body weight and approximately one-third of the variation in the overall body mass index (BMI; body weight in kilograms divided by the height in meters squared). Genetic factors affect the variations in resting metabolic rate, body fat distribution, and weight gain related to overfeeding, which explains in part why some individuals are more susceptible than others are to weight gain or weight loss. To ensure survival in times of scarce food supplies, the human body has TABLE 2.3
Leading causes of death and numbers of deaths, according to sex, race, and Hispanic origin, 1980 and 2001
[Data are based on death certificates]

	1980		20011
Sex, race, Hispanic origin, and rank order	Cause of death	Deaths	Cause of death	Deaths
All persons
…	All causes	1,989,841	All causes	2,416,425
1	Diseases of heart	761,085	Diseases of heart	700,142
2	Malignant neoplasms	416,509	Malignant neoplasms	553,768
3	Cerebrovascular diseases	170,225	Cerebrovascular diseases	163,538
4	Unintentional injuries	105,718	Chronic lower respiratory diseases	123,013
5	Chronic obstructive pulmonary diseases	56,050	Unintentional injuries	101,537
6	Pneumonia and influenza	54,619	Diabetes mellitus	71,372
7	Diabetes mellitus	34,851	Influenza and pneumonia	62,034
8	Chronic liver disease and cirrhosis	30,583	Alzheimer's disease	53,852
9	Atherosclerosis	29,449	Nephritis, nephrotic syndrome, and nephrosis	39,480
10	Suicide	26,869	Septicemia	32,238
Male
…	All causes	1,075,078	All causes	1,183,421
1	Diseases of heart	405,661	Diseases of heart	339,095
2	Malignant neoplasms	225,948	Malignant neoplasms	287,075
3	Unintentional injuries	74,180	Unintentional injuries	66,060
4	Cerebrovascular diseases	69,973	Cerebrovascular diseases	63,177
5	Chronic obstructive pulmonary diseases	38,625	Chronic ower l respiratory diseases	59,697
6	Pneumonia and influenza	27,574	Diabetes mellitus	32,841
7	Suicide	20,505	Influenza and pneumonia	27,342
8	Chronic liver disease and cirrhosis	19,768	Suicide	24,672
9	Homicide	18,779	Nephritis, nephrotic syndrome, and nephrosis	18,852
10	Diabetes mellitus	14,325	Chronic liver disease and cirrhosis	17,393
Female
…	All causes	914,763	All causes	1,233,004
1	Diseases of heart	355,424	Diseases of heart	361,047
2	Malignant neoplasms	190,561	Malignant neoplasms	266,693
3	Cerebrovascular diseases	100,252	Cerebrovascular diseases	100,361
4	Unintentional injuries	31,538	Chronic lower respiratory diseases	63,316
5	Pneumonia and influenza	27,045	Diabetes mellitus	38,531
6	Diabetes mellitus	20,526	Alzheimer's disease	38,090
7	Atherosclerosis	17,848	Unintentional injuries	35,477
8	Chronic obstructive pulmonary diseases	17,425	Influenza and pneumonia	34,692
9	Chronic liver disease and cirrhosis	10,815	Nephritis, nephrotic syndrome, and nephrosis	20,628
10	Certain conditions originating in the perinatal period	9,815	Septicemia	17,931
White
…	All causes	1,738,607	All causes	2,079,691
1	Diseases of heart	683,347	Diseases of heart	610,638
2	Malignant neoplasms	368,162	Malignant neoplasms	479,651
3	Cerebrovascular diseases	148,734	Cerebrovascular diseases	140,465
4	Unintentional injuries	90,122	Chronic lower respiratory diseases	113,819
5	Chronic obstructive pulmonary diseases	52,375	Unintentional injuries	85,964
6	Pneumonia and influenza	48,369	Diabetes mellitus	57,180
7	Diabetes mellitus	28,868	Influenza and pneumonia	54,774
8	Atherosclerosis	27,069	Alzheimer's disease	50,348
9	Chronic liver disease and cirrhosis	25,240	Nephritis, nephrotic syndrome, and nephrosis	31,345
10	Suicide	24,829	Suicide	27,710
Black or African American
…	All causes	233,135	All causes	287,709
1	Diseases of heart	72,956	Diseases of heart	77,674
2	Malignant neoplasms	45,037	Malignant neoplasms	62,170
3	Cerebrovascular diseases	20,135	Cerebrovascular diseases	19,002
4	Unintentional injuries	13,480	Unintentional injuries	12,462
5	Homicide	10,172	Diabetes mellitus	12,305
6	Certain conditions originating in the perinatal period	6,961	Homicide	8,226
7	Pneumonia and influenza	5,648	Human immunodeficiency virus (HIV) disease	7,844
8	Diabetes mellitus	5,544	Chronic lower respiratory diseases	7,589
9	Chronic liver disease and cirrhosis	4,790	Nephritis, nephrotic syndrome, and nephrosis	7,274
10	Nephritis, nephrotic syndrome, and nephrosis	3,416	Influenza and pneumonia	5,880

evolved to resist any loss of body fat. This biological drive to maintain weight is coordinated through central nervous system pathways, with the involvement of many neuropeptides. (Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones outside of the nervous system.) Evidence from twin, adoption, and TABLE 2.3
Leading causes of death and numbers of deaths, according to sex, race, and Hispanic origin, 1980 and 2001
[Data are based on death certificates]

	1980		20011
Sex, race, Hispanic origin, and rank order	Cause of death	Deaths	Cause of death	Deaths
American Indian or Alaska Native
…	All causes	6,923	All causes	11,977
1	Diseases of heart	1,494	Diseases of heart	2,402
2	Unintentional injuries	1,290	Malignant neoplasms	2,155
3	Malignant neoplasms	770	Unintentional injuries	1,361
4	Chronic liver disease and cirrhosis	410	Diabetes mellitus	644
5	Cerebrovascular diseases	322	Cerebrovascular diseases	574
6	Pneumonia and influenza	257	Chronic liver disease and cirrhosis	533
7	Homicide	217	Chronic lower respiratory diseases	427
8	Diabetes mellitus	210	Suicide	321
9	Certain conditions originating in the perinatal period	199	Influenza and pneumonia	318
10	Suicide	181	Nephritis, nephrotic syndrome, and nephrosis	236
Asian or Pacific Islander
…	All causes	11,071	All causes	37,048
1	Diseases of heart	3,265	Malignant neoplasms	9,792
2	Malignant neoplasms	2,522	Diseases of heart	9,428
3	Cerebrovascular diseases	1,028	Cerebrovascular diseases	3,497
4	Unintentional injuries	810	Unintentional injuries	1,750
5	Pneumonia and influenza	342	Diabetes mellitus	1,243
6	Suicide	249	Chronic lower respiratory diseases	1,178
7	Certain conditions originating in the perinatal period	246	Influenza and pneumonia	1,171
8	Diabetes mellitus	227	Suicide	634
9	Homicide	211	Nephritis, nephrotic syndrome, and nephrosis	625
10	Chronic obstructive pulmonary diseases	207	Certain conditions originating in the perinatal period	543
Hispanic or Latino
…	—	—	All causes	113,413
1	—	—	Diseases of heart	27,090
2	—	—	Malignant neoplasms	22,371
3	—	—	Unintentional injuries	9,523
4	—	—	Cerebrovascular diseases	6,416
5	—	—	Diabetes mellitus	5,663
6	—	—	Homicide	3,331
7	—	—	Chronic liver disease and cirrhosis	3,301
8	—	—	Chronic lower respiratory diseases	2,832
9	—	—	Influenza and pneumonia	2,722
10	—	—	Certain conditions originating in the perinatal period	2,227
White male
…	All causes	933,878	All causes	1,011,218
1	Diseases of heart	364,679	Diseases of heart	295,5561
2	Malignant neoplasms	198,188	Malignant neoplasms	248,146
3	Unintentional injuries	62,963	Unintentional injuries	55,493
4	Cerebrovascular diseases	60,095	Chronic lower respiratory diseases	54,561
5	Chronic obstructive pulmonary diseases	35,977	Cerebrovascular diseases	53,428
6	Pneumonia and influenza	23,810	Diabetes mellitus	26,917
7	Suicide	18,901	Influenza and pneumonia	23,744
8	Chronic liver disease and cirrhosis	16,407	Suicide	22,328
9	Diabetes mellitus	12,125	Nephritis, nephrotic syndrome, and nephrosis	15,241
10	Atherosclerosis	10,543	Chronic liver disease and cirrhosis	15,048
Black or African American male
…	All causes	130,138	All causes	145,908
1	Diseases of heart	37,877	Diseases of heart	37,016
2	Malignant neoplasms	25,861	Malignant neoplasms	32,679
3	Unintentional injuries	9,701	Unintentional injuries	8,537
4	Cerebrovascular diseases	9,194	Cerebrovascular diseases	7,907
5	Homicide	8,274	Homicide	6,780
6	Certain conditions originating in the perinatal period	3,869	Human immunodeficiency virus (HIV) disease	5,328
7	Pneumonia and influenza	3,386	Diabetes mellitus	5,049
8	Chronic liver disease and cirrhosis	3,020	Chronic lower respiratory diseases	4,187
9	Chronic obstructive pulmonary diseases	2,429	Nephritis, nephrotic syndrome, and nephrosis	3,186
10	Diabetes mellitus	2,010	Influenza and pneumonia	2,813

TABLE 2.3
Leading causes of death and numbers of deaths, according to sex, race, and Hispanic origin, 1980 and 2001
[Data are based on death certificates]

	1980		20011
Sex, race, Hispanic origin, and rank order	Cause of death	Deaths	Cause of death	Deaths
American Indian Alaska Native male
…	All causes	4,193	All causes	6,466
1	Unintentional injuries	946	Diseases of heart	1,358
2	Diseases of heart	917	Malignant neoplasms	1,103
3	Malignant neoplasms	408	Unintentional injuries	908
4	Chronic liver disease and cirrhosis	239	Chronic liver disease and cirrhosis	309
5	Cerebrovascular diseases	163	Diabetes mellitus	276
6	Homicide	162	Suicide	259
7	Pneumonia and influenza	148	Cerebrovascular diseases	217
8	Suicide	147	Chronic lower respiratory diseases	200
9	Certain conditions originating in the perinatal period	107	Influenza and pneumonia	160
10	Diabetes mellitus	86	Homicide	146
Asian or Pacific Islander male
…	All causes	6,809	All causes	19,829
1	Diseases of heart	2,174	Diseases of heart	5,165
2	Malignant neoplasms	1,485	Malignant neoplasms	5,147
3	Unintentional injuries	556	Cerebrovascular diseases	1,625
4	Cerebrovascular diseases	521	Unintentional injuries	1,122
5	Pneumonia and influenza	227	Chronic lower respiratory diseases	749
6	Suicide	159	Influenza and pneumonia	625
7	Chronic obstructive pulmonary diseases	158	Diabetes mellitus	599
8	Homicide	151	Suicide	458
9	Certain conditions originating in the perinatal period	128	Homicide	375
10	Diabetes mellitus	103	Nephritis, nephrotic syndrome, and nephrosis	320
Hispanic or Latino male
…			All causes	63,317
1	—	—	Diseases of heart	14,195
2	—	—	Malignant neoplasms	11,825
3	—	—	Unintentional injuries	7,157
4	—	—	Cerebrovascular diseases	2,982
5	—	—	Homicide	2,756
6	—	—	Diabetes mellitus	2,590
7	—	—	Chronic liver disease and cirrhosis	2,410
8	—	—	Suicide	1,576
9	—	—	Chronic lower respiratory diseases	1,482
10	—	—	Human immunodeficiency virus (HIV) disease	1,437
White female
…	All causes	804,729	All causes	1,068,473
1	Diseases of heart	318,668	Diseases of heart	315,082
2	Malignant neoplasms	169,974	Malignant neoplasms	231,505
3	Cerebrovascular diseases	88,639	Cerebrovascular diseases	87,037
4	Unintentional injuries	27,159	Chronic lower respiratory diseases	59,258
5	Pneumonia and influenza	24,559	Alzheimer's disease	35,634
6	Diabetes mellitus	16,743	Influenza and pneumonia	31,030
7	Atherosclerosis	16,526	Unintentional injuries	30,471
8	Chronic obstructive pulmonary diseases	16,398	Diabetes mellitus	30,263
9	Chronic liver disease and cirrhosis	8,833	Nephritis, nephrotic syndrome, and nephrosis	16,104
10	Certain conditions originating in the perinatal period	6,512	Septicemia	14,435
Black or African American female
…	All causes	102,997	All causes	141,801
1	Diseases of heart	35,079	Diseases of heart	40,658
2	Malignant neoplasms	19,176	Malignant neoplasms	29,491
3	Cerebrovascular diseases	10,941	Cerebrovascular diseases	11,095
4	Unintentional injuries	3,779	Diabetes mellitus	7,256
5	Diabetes mellitus	3,534	Nephritis, nephrotic syndrome, and nephrosis	4,088
6	Certain conditions originating in the perinatal period	3,092	Unintentional injuries	3,925
7	Pneumonia and influenza	2,262	Chronic lower respiratory diseases	3,402
8	Homicide	1,898	Septicemia	3,245
9	Chronic liver disease and cirrhosis	1,770	Influenza and pneumonia	2,958
10	Nephritis, nephrotic syndrome, and nephrosis	1,722	Human immunodeficiency virus (HIV) disease	2,516

TABLE 2.3
Leading causes of death and numbers of deaths, according to sex, race, and Hispanic origin, 1980 and 2001
[Data are based on death certificates]

	1980		20011
Sex, race, Hispanic origin, and rank order	Cause of death	Deaths	Cause of death	Deaths
American Indian or Alaska Native female
…	All causes	2,730	All causes	5,511
1	Diseases of heart	577	Malignant neoplasms	1,052
2	Malignant neoplasms	362	Diseases of heart	1,044
3	Unintentional injuries	344	Unintentional injuries	453
4	Chronic liver disease and cirrhosis	171	Diabetes mellitus	368
5	Cerebrovascular diseases	159	Cerebrovascular diseases	357
6	Diabetes mellitus	124	Chronic lower respiratory diseases	227
7	Pneumonia and influenza	109	Chronic liver disease and cirrhosis	224
8	Certain conditions originating in the perinatal period	92	Influenza and pneumonia	158
9	Nephritis, nephrotic syndrome, and nephrosis	56	Nephritis, nephrotic syndrome, and nephrosis	131
10	Homicide	55	Septicemia	72
Asian or Pacific Islander female
…	All causes	4,262	All causes	17,219
1	Diseases of heart	1,091	Malignant neoplasms	4,645
2	Malignant neoplasms	1,037	Diseases of heart	4,263
3	Cerebrovascular diseases	507	Cerebrovascular diseases	1,872
4	Unintentional injuries	254	Diabetes mellitus	644
5	Diabetes mellitus	124	Unintentional injuries	628
6	Certain conditions originating in the perinatal period	118	Influenza and pneumonia	546
7	Pneumonia and influenza	115	Chronic lower respiratory diseases	429
8	Congenital anomalies	104	Nephritis, nephrotic syndrome, and nephrosis	305
9	Suicide	90	Essential (primary) hypertension and hypertensive renal disease	234
10	Homicide	60	Alzheimer's disease	188
Hispanic or Latino female
…	—	—	All causes	50,096
1	—	—	Diseases of heart	12,895
2	—	—	Malignant neoplasms	10,546
3	—	—	Cerebrovascular diseases	3,434
4	—	—	Diabetes mellitus	3,073
5	—	—	Unintentional injuries	2,366
6	—	—	Influenza and pneumonia	1,413
7	—	—	Chronic lower respiratory diseases	1,350
8	—	—	Nephritis, nephrotic syndrome, and nephrosis	965
9	—	—	Certain conditions originating in the perinatal period	959
10	—	—	Chronic liver disease and cirrhosis	891
… Category not applicable.
—Data not available.
1Figures for homicide and suicide include September 11, 2001–related deaths for which death certificates were filed as of October 24, 2002.
SOURCE: "Table 31. Leading causes of death and numbers of deaths, according to sex, race, and Hispanic origin: United States, 1980 and 2001," in Health, United States, 2003, Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, MD, 2003 [Online] http://www.cdc.gov/nchs/hus.htm [accessed January 2, 2004]

family studies reveals that biological relatives exhibit similarities in maintenance of body weight. First-degree relatives of moderately obese persons are at three to four times the risk of obesity relative to the general population. First-degree relatives of severely obese persons are at five times greater risk. Genetic predisposition to obesity does not mean that developing the condition is inevitable; however, research indicates that inherited genetic variation is an important risk factor for obesity.

Genetic factors have been implicated in the development of such eating disorders as anorexia and bulimia and appear to be involved in the extent to which diet and exercise are effective strategies for weight reduction. Further, genetic variations among individuals may promote different food preferences and eating patterns that interact with environmental conditions to maintain healthy body weight or promote obesity.

These genetic risk factors tend to be familial but are not inherited in a simple manner; they may reflect many genetic variations, and each variation may contribute a small amount of risk and may interact with environmental elements to produce obesity. By 2004 more than 300 genes, markers, and chromosomal regions had been associated or linked with human obesity. In addition to offering direction for future efforts to prevent and treat obesity, mounting genetic evidence offers a compelling argument that obesity is not a personal failing, and that in the majority TABLE 2.4
Overweight and obesity health consequences

Overweight and obese individuals (BMI of 25 and above) are at increased risk for physical ailments such as:

• High blood pressure, hypertension

• High blood cholesterol, dyslipidemia

• Type 2 (non-insulin dependent) diabetes

• Insulin resistance, glucose intolerance

• Hyperinsulinemia

• Coronary heart disease

• Angina pectoris

• Congestive heart failure

• Stroke

• Gallstones

• Cholescystitis and cholelithiasis

• Gout

• Osteoarthritis

• Obstructive sleep apnea and respiratory problems

• Some types of cancer (such as endometrial, breast, prostate, and colon)

• Complications of pregnancy

• Poor female reproductive health (such as menstrual irregularities, infertility, irregular ovulation)

• Bladder control problems (such as stress incontinence)

• Uric acid nephrolithiasis

• Psychological disorders (such as depression, eating disorders, distorted body image, and low self esteem).

SOURCE: "Overweight and Obesity Health Consequences," Overweight and Obesity, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Nutrition and Physical Activity, Control and Prevention, Atlanta, GA, 2003 [Online] http://www.cdc.gov/nccdphp/dnpa/obesity/consequences.htm [accessed January 2, 2004]

of cases, obesity involves multiple genetic and environmental components that affect endocrine, metabolic, and regulatory mechanisms.

Genetic Susceptibility and Environmental Influences

Although genetics may largely predetermine adult body weight absent specific environmental triggers or influences, genetic destiny in terms of body weight may not necessarily be realized. For example, an individual with a strong genetic predisposition for obesity will not become obese in the absence of sufficient food (caloric) intake. Similarly, when persons genetically predisposed to normal body weight consume a largely high-fat diet, they may become overweight or obese because they may be more inclined to overeat. This is in part because the brain has difficulty conveying the satiety signal—the message to stop eating—when fatty foods are being consumed.

In addition to caloric intake and physical activity, both of which are able to modify body weight, environmental influences before birth also significantly influence adult health and body weight. Research has demonstrated that the pregnant mother's nutritional status affects the metabolism of her unborn child. Women who are severely malnourished during pregnancy stimulate the fetus to modify its metabolism to conserve and store energy, a survival practice that can promote overweight when the food supply is ample.

Societal and cultural norms also can cause such environmental influences as lifestyle and behavior to override TABLE 2.5
Obesity and genetics: What we know, what we don't know, and what it means

What we know:	What we don't know:
Biological relatives tend to resemble each other in many ways, including body weight. Individuals with a family history of obesity may be predisposed to gain weight, and interventions that prevent obesity are especially important.	Why are biological relatives more similar in body weight? What genes are associated with this observation? Are the same genetic associations seen in every family? How do these genes affect energy metabolism and regulation?
In an environment made constant for food intake and physical activity, individuals respond differently. Some people store more energy as fat in an environment of excess; others lose less fat in an environment of scarcity. The different responses are largely due to genetic variation between individuals.	Why are interventions based on diet and exercise more effective for some people than others? What are the biological differences between these high and low responders? How do we use these insights to tailor interventions to specific needs?
Fat stores are regulated over long periods of time by complex systems that involve input and feedback from fatty tissues, the brain, and endocrine glands like the pancreas and the thyroid. Overweight and obesity can result from only a very small positive energy input imbalance over a long period of time.	What elements of energy regulation feedback systems are different in individuals? How do these differences affect energy metabolism and regulation?
Rarely, people have mutations in single genes that result in severe obesity that starts in infancy. Studying these individuals is providing insight into the complex biological pathways that regulate the balance between energy input and energy expenditure.	Do additional obesity syndromes exist that are caused by mutations in single genes? If so, what are they? What are the natural history, management strategy, and outcome for affected individuals?
Obese individuals have genetic similarities that may shed light on the biological differences that predispose to gain weight. This knowledge may be useful in preventing or treating obesity in predisposed people.	How do genetic variations that are shared by obese people affect gene expression and function? How do genetic variation and environmental factors interact to produce obesity? What are the biological features associated with the tendency to gain weight? What environmental factors are helpful in countering these tendencies?
Pharmaceutical companies are using genetic approaches (pharmacogenomics) to develop new drug strategies to treat obesity.	Will pharmacologic approaches benefit most people affected with obesity? Will these drugs be accessible to most people?
The tendency to store energy in the form of fat is believed to result from thousands of years of evolution in an environment characterized by tenuous food supplies. In other words, those who could store energy in times of plenty were more likely to survive periods of famine and to pass this tendency to their offspring.	How can thousands of years of evolutionary pressure be countered? Can specific factors in the modern environment (other than the obvious) be identified and controlled to more effectively counter these tendencies?
SOURCE: "Obesity and genetics: What we know, what we don't know and what it means," Public Health Perspectives, Centers for Disease Control and Prevention, Genomics and Disease Prevention, Hyattsville, MD, 2003 [Online] http://www.cdc.gov/genomics/info/prespectives/files/obesknown.htm [accessed January 3, 2004]

FIGURE 2.2
National Health and Nutrition Examination Survey III: Age-adjusted prevalence of high blood cholesterol* according to body mass index (BMI)

genetic programming. For example, in the United States many young women with genetic predisposition to normal body weight or even overweight sharply limit their caloric intake and exercise vigorously in order to achieve "model thin" bodies. Similarly, in cultures where overweight is perceived as an indication of prosperity and is admired and coveted, people may override genetic tendencies to be normal weight by increasing caloric intake in an effort to achieve the culturally established ideal.