Diabetes in New York: Topics in Obesity

Zachary T. Bloomgarden, MD


December 20, 2002

In This Article

Obesity: Genes vs Environment

Note: This is the first in an occasional series of articles by Zachary T. Bloomgarden, MD, discussing diabetes conferences, presentations, and meetings in the New York metropolitan area.

A debate[1] on the relative contributions of genes and the environment to the development of obesity was conducted at the Metropolitan Diabetes Society between Jeffrey S. Flier, MD, Beth Israel Deaconess Medical Center, and Eleftheria Maratos-Flier, MD, Joslin Diabetes Center, both in Boston, Massachusetts.

Dr. Jeffrey Flier stated that genes are the dominant factor and suggested that this approach will lead to new treatment approaches. Genes, he pointed out, control 50% to 90% of the variation in body weight and fat content in human populations, according to information from twin and adoption studies. For example, Dr. Flier stated that monozygotic twins have a 74% correlation in body weight, dizygotic twins have a 32% correlation, and spouses have a 12% correlation.

A number of approaches have been taken to finding "obesity genes." Transgenic overexpression and gene deletion models have shown the effects of excess and deficient specific genes. Spontaneous mouse mutations such as the "ob" and "db" strains were crucial in the discovery of leptin and have led to studies of "candidate genes" in humans with obesity. Genome linkage studies in human populations have been less successful. The genes involved in monogenic obesity, such as those for leptin and its receptor, have all been found to play roles in energy homeostasis. Leptin is an adipocyte product that responds acutely to changes in energy balance and responds chronically to changes in adipocyte mass. In the brain, leptin increases the activity of cocaine and amphetamine-regulated transcript (CART)/propiomelanocortin (POMC) neurons, while decreasing that of Agouti-related peptide (AGRP)/neuropeptide Y (NPY) neurons. POMC in turn increases melanocyte-stimulating hormone (MSH) levels, acting on the melanocortin-4 (MC-4) receptor. Mutations in most of these steps have been identified in humans with severe obesity. In animals, deletion of the MC-4 receptor increases weight, and similar phenotypes in humans with abnormal MC-4 genes appear in approximately 5% of persons with severe obesity.

Genes that protect against obesity may be as relevant as those that predispose to obesity. However, they may be more difficult to find and may be evident only under conditions of environmental stress, as, for example, in the animal model of NPY deficiency, which protects against obesity when added to leptin deficiency.

At least 95% of human obesity is polygenic. Studies of intracellular cortisol metabolism by 11-beta hydroxysteroid dehydrogenase (HSD) suggest that this gene may play an important role. Cortisol is inactivated by HSD2 to cortisone, which in turn is reconverted to cortisol by HSD1. HSD1 is expressed to a greater extent in visceral than in subcutaneous fat, suggesting that visceral obesity may represent a syndrome of "Cushing's disease of the abdomen." HSD1 transgenic mice have increased visceral fat and increased adipose tissue cortisol with normal serum cortisol levels. They display hyperphagia, diabetes, insulin resistance, and hypertension, suggesting an "intracrine" (as apposed to a "paracrine" or "endocrine") pathway to the insulin resistance syndrome.

Interestingly, studies of effects of the thiazolidinediones show that what Dr. Flier termed "the single most dramatically affected gene" is a decrease in the activity of HSD1. Studies of the genetics of HSD1 expression may reveal important aspects of the predisposition to obesity and to the insulin resistance syndrome.

Dr. Maratos-Flier reviewed evidence of the environmental causes of obesity. We recognize the epidemic of obesity in the United States and other western societies. This epidemic appears to be due to what she termed "changes in the food environment" that have occurred over the past 30 years. From 1962 to 1994, among persons over age 20 in the United States, the prevalence of body mass index (BMI) < 25 kg/m2 decreased from 50% to 40%, while the prevalence of BMI > 30 increased from 10% in 1964 to 14% in 1990 to 18% in 2000. Dr. Maratos-Flier asserted that this change "cannot possibly be genetic." Patterns are similar among men and women, and among blacks, whites, and Hispanics. Education is associated with decreased body weight and increased amounts of physical activity, particularly among women, suggesting cultural factors. In the United States, leisure time activity is often sedentary, even among the young. For a 150-pound person, walking 3.5 miles in an hour on a 10° grade surface, walking 2.5 miles in an hour on a level surface, and sitting typically produce energy expenditures of 440, 211, and 91 kcal/hour, respectively. As Dr. Maratos-Flier stated, sustained activity and "the cumulative effect of a lot of small things" are needed to prevent obesity.

Another environmental influence is food choice. The message that we must reduce fat intake to prevent obesity may be mistaken, since it has not prevented the increase in carbohydrate (CHO) intake that appears to be responsible for most of the excess in dietary calories. Dr. Maratos-Flier stated that the emphasis on CHO "is what is making people fat." Average calorie intake increased 15% between 1980 and 1995, with little increase in fat, a 15% increase in protein, but a massive increase in CHO -- from 300 to 500 g/day. Foods with a high glycemic index increase hunger sensation 5 hours after meals and are associated with greater overall food intake. An important concept is that the current "food pyramid" positions high-carbohydrate foods as the most desirable, and this should be changed to emphasize vegetables. An interesting suggestion from the audience was that variations in glycemic response to high glycemic index foods may be in part genetic and may play a role in the development of obesity.

It should be noted that there is controversy surrounding the concept that CHO is responsible for obesity and, hence, that low-CHO, high-fat diets are preferable. See the editorial, "Confusion! High Fat, Low Fat--Which Is It?," posted on Medscape Today (originally published in Journal of Clinical Hypertension)[2] for a contrary position on the importance of this environmental factor.

Dr. Jeffrey Flier agreed that the recent increase in obesity reflects environment, but suggested that although phenotypic expression is environmental, susceptibility is genetic. He asked whether body weight increases similarly in persons of low and high genetic susceptibility with increasing environmental weight-promoting influence, or whether the latter group shows particular increase. We currently have little insight into the interaction of genetic susceptibility and the environment, despite the great importance of this potential determinant. The contribution of different nutritional and exercise components to promote or prevent weight gain may be of crucial importance. Furthermore, there may be unidentified environmental influences, such as toxins or viral infection. Identification of susceptibility genes may help in environmental modification, and newly discovered pathways may lead to more specific pharmacologic approaches.


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