The Journal of Nutrition Vol. 127 No. 9 September 1997, pp. 1871S-1873S
Copyright ©1997 by the American Society for Nutritional Sciences

Overview¹

George L. Wolff

National Center for Toxicological Research, Food and Drug Administration, U.S. Department of Health and Human Services, Jefferson, Arkansas 72079 and Departments of Biochemistry/Molecular Biology and Pharmacology/Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 

FOOTNOTES

This symposium, an educational activity of the Office of Continuing Medical Education, University of Arkansas for Medical Sciences College of Medicine, was organized for the purpose of providing physicians and basic researchers an overview of the present understanding of the genetic bases of obesity. It was also intended to counterbalance the media's preoccupation with the thesis that cloning of single "obesity" genes promises an eventual cure for the disease "obesity." Although there is no question that the cloning of these genes and identification of their function is of great importance for unraveling the complexity of processes underlying human "obesity," the Symposium Organizing Committee (George L. Wolff, chairman, Alan D. Elbein, Philip A. Kern, Richard P. Woychik and Terence T. Yen) sought to emphasize the complexity of the problem by including diverse examples of genes that, directly or indirectly, induce "obesity" defined as excess lipid deposition in the adipose tissue. Here, it is considered to be an easily detectable and visible symptom of a complex network of dysregulated metabolic and physiologic processes that affect the normal functioning of the whole organism. In short, obesity per se is more a signal of serious trouble than a "disease" to be prevented or cured.

The papers in this Supplement are based on the lectures presented by their authors on March 4, 1997, at the Excelsior Hotel in Little Rock, Arkansas.

In the keynote address, Jules Hirsch reviewed the pathophysiology of human obesity. Fundamentally, obesity results from dysregulation of the balance between the relative magnitudes of food intake and energy expenditure. Psychologic/behavioral factors are important because they influence these parameters. When body weight is altered by 10% in obese or nonobese subjects, there are startlingly reproducible changes in the expenditure of energy. When body fat mass is increased 10% above "usual" weight, there is an unanticipated persistent increase in energy expenditure of roughly 10 kcal/(kg·d) of fat free mass. When body fat declines and is maintained at a new lower level, e.g., 10% below usual body weight, a similar decrease in energy expenditure occurs and persists. These changes lead to an approximate alteration of 15% in total energy expenditure and may be significant in the maintenance of usual body weight whether the individual is obese or nonobese.

Richard E. Keesey and Matt D. Hirvonen reviewed the evidence that, at the regulated or set-point body weight, the intake and expenditure of energy are in balance. If weight rises above the set-point, food intake declines and whole-body metabolism is elevated. Below the set-point, increased intake occurs in conjunction with sharp declines in energy expenditure. These coordinate behavioral and metabolic adjustments serve to resist displacement from and facilitate a return to the regulated body weight. Obese individuals also display these behavioral and metabolic adjustments to weight perturbations and thus resist being displaced from their ordinarily elevated body weights. Experimental studies of two forms of obesity in animals support a view of obesity as a condition of body energy regulation at an elevated set-point. The set-point for body weight is apparently adjustable, changing during the lifespan as a result of naturally occurring, but still unspecified, physiologic changes. The set-point can be adjusted by direct manipulation of specific hypothalamic sites. Lesions of the lateral hypothalamus, for example, cause a reduction in the level at which laboratory animals chronically regulate body weight. It thus appears that hypothalamic mechanisms play a key role in determining an individual's body weight set-point.

The review by William H. Dietz emphasized three critical periods for the development of obesity in children, namely, fetal development, the period of adiposity rebound between 5 and 7 y of age and adolescence. Important factors during the prenatal period may include development of the function of the hypothalamic-pituitary-adrenal axis and/or the responsiveness of adipocytes and/or the hypothalamus to signals that regulate satiety and/or systems responsible for fat oxidation. Adiposity rebound, a second critical period, may represent the time when behaviors entrained in early childhood begin to influence food intake or activity. During adolescence, the third critical period for development of pediatric obesity, increases in body fat in girls and the redistribution of body fat from peripheral to visceral sites suggest that a variety of metabolic processes may be affected. Whether childhood obesity is associated with an altered distribution of body fat in adulthood or whether the age of onset of obesity influences the risk of subsequent co-morbidity remain challenges for future research.

Family studies on obesity that have typed candidate genes and microsatellite markers were reviewed by Claude Bouchard. These studies measured the body mass index , but some also included a more extensive panel of phenotypes including body composition, fat distribution, resting metabolic rate, relative substrate oxidation rate and others. In the Pima Indian sibling study, the strongest evidence for linkage with body fat was with markers on chromosomes 11q, 6p and 3p. Evidence for linkage with markers on chromosome 7q was obtained in all family studies except the Pima Indians. The Quebec Family Study suggests that there are linkages between body fat, as assessed from hydrodensitometry, and markers on chromosome 1p32-p22. In addition, significant linkages have also been obtained between body fat and markers spanning the region from the ADA locus to the MC3-R locus on chromosome 20q. The human homolog of the mouse agouti locus (agouti signalling protein ASIP)² is located in the same region of chromosome 20q; however, although ASIP is normally expressed in human adipose tissue, no effect of this locus on human obesity has been reported.

Steven C. Elbein reviewed data that suggest a strong genetic component to noninsulin-dependent diabetes mellitus (NIDDM, Type 2 diabetes) susceptibility. These included high concordance between identical twins, familial aggregation and risk of NIDDM in siblings and offspring of NIDDM probands. Obesity is synergistic with positive family history in the risk for NIDDM. Mutations in three genes, which regulate insulin secretion, appear to cause an early onset, autosomal dominant disease known as maturity onset diabetes of the young (MODY). Late onset NIDDM has been linked to unknown genes on chromosome 2q in Hispanic siblings and to a locus at or near MODY3 in a subset of Finnish families with low insulin secretion. Although obesity segregates as an autosomal recessive trait in these families, no known human homolog of the mouse obesity genes is linked to NIDDM or obesity. There is evidence for recessive inheritance of a susceptibility locus near apolipoprotein A₂ on chromosome 1, and possible evidence for an independently segregating locus controlling fasting glucose on chromosome 9. Elbein emphasized that defining the genetics of NIDDM and of obesity among human individuals at risk for NIDDM is complicated by probable heterogeneity and epistasis and makes achievement of this goal a real challenge.

The view that obesity is a pleiotropic effect of the specific molecular actions of gene mutations and is secondary to the dysregulation of any of numerous metabolic pathways directly or indirectly involved in energy metabolism was espoused by George L. Wolff. He defined pleiotropic effects of a gene as those due to the utilization of the peptide or protein specified by the gene in more than one tissue or cell type or in a variety of cellular processes. To illustrate this thesis, the morphologic, physiologic and molecular characteristics of two diverse "obese" mouse mutants, viable yellow A^vy and obese hyperglycemic Lep^ob, were compared.

The underlying molecular and physiologic bases of the pleiotropic effects, among them obesity, of dominant "yellow" mutations at the mouse agouti locus were reviewed by Richard P. Woychik and his colleagues. Continuous ectopic expression of these mutations induces a pleiotropic syndrome characterized by obesity, mild hyperphagia, decreased thermogenesis, insulin resistance, impaired glucose tolerance, hyperglycemia in males, increased body growth, increased susceptibility to cancer and yellow hair.

When the wild-type agouti gene was joined with a constitutively active promoter and transfected to a nonmutant mouse, the transgenic mice developed yellow fur and became obese, hyperinsulinemic and hyperglycemic. Thus the ectopic expression of agouti is responsible for the obesity. Treatment of transgenic mice, in which the agouti gene was coupled to an adipocyte-specific transcriptional promoter, with daily injections of insulin caused a significant increase in weight gain, even over a very short period of time. This suggests that agouti expression in adipose tissue, combined with exogenously induced or endogenous hyperinsulinemia, promotes obesity in the dominant "yellow" mutant mice. Because humans normally express the agouti signalling protein gene (ASIP) in adipose tissue, the human agouti gene possibly may be functional in adipose tissue lipid metabolism.

Rudolph L. Leibel emphasized that obesity is an example of many of the diseases in which relevant genes mediate susceptibility to disease in a specific environmental context, rather than the inevitable expression of the phenotype regardless of environment. Individuals with otherwise potent genetic predisposition to obesity will be lean in an environment of food deprivation/high demand for physical activity. Individuals not genetically predisposed to obesity may become obese in an environment that includes tasty, calorically dense foods and/or few inducements to physical activity. Thus the "environment" remains a critical factor in any effort to elucidate the genetic bases for susceptibility to obesity and in determining what genes will be identified. Because "obesity" genes may affect energy intake, energy expenditure, and/or the partitioning of calories between lean tissues and fat, the ability to define the gross metabolic basis for the obesity is very important in determining which genes are relevant to the phenotype. The attainment of an obese state may actually rectify the metabolic imbalances predisposing to obesity. Several recessive and dominant genes that induce obesity in laboratory animals have been cloned. They encode molecules that appear to interact in physiologic systems that influence body fat stores. Human homologs of these genes have been identified; however, none have yet been associated with human obesity.

Janis S. Fisler discussed quantitative trait locus (QTL) mapping, a general technique to map Mendelian factors influencing complex traits such as obesity. QTL mapping involves crossing two strains differing in the trait to produce F₂ or back-cross progeny that are individually phenotyped, genotyped and statistically associated with the markers and the phenotype. This technique has been used recently to map genes for many traits, including body weight, growth, obesity, atherosclerosis and ethanol sensitivity in the mouse, as well as blood pressure, diabetes and arthritis in the rat. Once a trait has been located in a chromosomal subregion, identifying the underlying gene remains a significant problem. With the generation of dense marker and transcript maps, however, the positional candidate strategy, which relies on a combination of mapping to a chromosomal subregion followed by a survey of the interval to see if attractive candidates reside there, becomes very practical. This approach has been used to identify genes involved in obesity and lipoprotein metabolism. It can be generalized to humans as well by using linkage studies of human families.

Philip A. Kern proposed that the metabolic interplay of lipoprotein lipase (LPL) and tumor necrosis factor-. (TNF) is a homeostatic mechanism that would provide a survival adaptation during times of ample food to prevent obesity. Human fat cells rely on lipoprotein lipase-mediated plasma triglyceride hydrolysis for lipid. Adipose tissue LPL is hyperresponsive to feeding and is elevated in obesity. LPL is elevated further after weight loss as well as in very obese patients. This is consistent with the maintenance of lipid stores during fasting and the fast replenishment of lipid stores during refeeding. Muscle LPL catabolizes plasma triglycerides to make free fatty acids available for energy and is regulated inversely to adipose LPL. The increase in adipose LPL during weight loss may be accompanied by a decrease in muscle LPL and thus further partition dietary lipid into adipose tissue. An increased adipose/muscle LPL ratio may be a survival adaptation in a hunter-gatherer lifestyle. Metabolic efficiency was likely advantageous during evolutionary periods characterized by high levels of physical activity and prolonged episodes of fasting and refeeding. TNF is produced at higher than normal levels by adipose tissue of obese rodents and humans, as well as by muscle cells in insulin-resistant subjects. Injection of insulin-resistant rodents with anti-TNF binding protein improved insulin action. Uncoupling of obesity and insulin resistance with decreased adipose TNF expression was observed in aP2 knockout mice. TNF inhibits LPL expression, resulting in an inverse relationship between adipose tissue TNF and LPL expression in humans and rendering the organism less obese and more insulin resistant.

The Symposium covered a range of topics, each representing an important aspect of the problem of obesity. The Organizing Committee is grateful to the participants for their contributions and The Journal of Nutrition for its willingness to make these reviews available to a wider audience.

FOOTNOTES

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