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Chapter 1 the OBESE {Ob/Ob) MOUSE and the DISCOVERY of LEPTIN

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Chapter 1 the OBESE {Ob/Ob) MOUSE and the DISCOVERY of LEPTIN Chapter 1 THE OBESE {ob/ob) MOUSE AND THE DISCOVERY OF LEPTIN V. Daniel Castracane and Michael C. Henson 'Texas Tech University School of Medicine, Lubbock, TX and ^Department of Biological Sciences, Purdue University Calumet, Hammond, IN Abstract: Early theories describing appetite regulation and energy expenditure suggested the lipostatic theory, which hypothesized that some peripheral signal, probably from adipose tissue, would feedback to central satiety centers to modulate food intake and body weight. However, the experimental techniques needed to validate this hypothesis were lacking at that time. Subsequently, two strains of obese mutants, the ob/ob mouse and later the db/db mouse, were discovered 50 and 40 years ago, respectively, and proved invaluable to studying the regulation of food intake, energy expenditure, and obesity. Prior to the development of today's more sophisticated techniques for studying biological and biochemical processes, the use of parabiosis, the surgical attachment of two animals with a shared blood supply, provided valuable insights into the obesity. Information gained from studies of these strains of mice, especially in parabiotic studies with normal counterparts, provided evidence for a humoral factor involved in appetite regulation and initiated the search for its identity. Friedman et al discovered leptin in 1994, and demonstrated that this hormone, the product of the obese (ob) gene, was produced in white adipose tissue and served as the peripheral signal to the central nervous system of nutritional status. After leptin's discovery, the obese mouse model continued to play an invaluable role in the validation of leptin as the missing factor in the ob/ob mouse and served as a principal model to delineate the many facets of leptin physiology. Key words: obesity, ob/ob mouse, db/db mouse, genetics, mice, leptin "Corpulence is not only a disease itself, but a harbinger of others." Hippocrates 2 Chapter 1 1. INTRODUCTION The multiple health risks of obesity have been recognized for centuries, but the last few decades have seen an explosion in its incidence, most particularly in developed countries such as the United States and those in Western Europe. Perhaps the most important findings related to obesity in the last decade are linked to our greater understanding of appetite regulation and energy expenditure that began with the discovery and characterization of leptin in 1994', followed by the identification of other associated endocrine factors. The breakthrough which led to this discovery was the finding of a genetic mutation in the mouse that resulted in obesity.^ This obese mouse (ob/ob) provided insights into obesity that led to expectations that some unknown humoral substance was related to the development of obesity in this model. This chapter will describe the initial contributions of the ob/ob mouse (and other mouse models) that led to the discovery of leptin and the invaluable role of this model in proving that the newly discovered adipokine was indeed responsible for controlling adiposity in mice. 2. THE OBESE (ob/ob) MOUSE The obese mouse was a fortuitous observation in the summer of 1949 at the Jackson Laboratories in Bar Harbor. Obese mice were first distinguished from littermates at 4-6 weeks of age. Thereafter, they continued to increase in weight and generally weighed four times more than wild type littermates. In the original report, no effect on lifespan through 12 months had been observed. The obese animals were sterile and offspring of heterozygote matings demonstrated the 3:1 ratio characteristic of a recessive gene. The gene responsible was designated ob (2) (now Lep). In subsequent reports, the ob/ob mouse was reported to come from a noninbred stock where the mutant presented with massive obesity and marked hyperglycemia and was originally considered to be a model of diabetes. The syndrome is inherited as a single autosomal recessive gene located on chromosome 6. The original mutation was transferred to a standard inbred strain (C57BL/6J) by a series of cross-intercross matings. This resultant BL/6 obese mouse was characterized by obesity, hyperphagia, transient hyperglycemia, and elevated plasma insulin concentrations (10-50 times normal) that were associated with a huge increase in the number and size of the beta cells of the pancreas. Mutants of both sexes are infertile.^ When the obese mutation is expressed on a different genetic background. The obese (ob/ob) mouse and the discovery ofleptin 3 markedly different diabetic syndromes can result, emphasizing the role of other genetic interactions with the obese mutation.'* 3. THE DIABETIC {db/db) MOUSE Another mutant strain of obese mouse called diabetes (db/db) was discovered, also at the Jackson Laboratory, in 1966.^ This mutation occurred in an inbred mouse strain (C57BL/Ks) and is characterized by a metabolic disturbance resembling diabetes mellitus. The diabetic mutant is phenotypically similar to the obese mutant but demonstrates symptoms at an earlier age and has a shortened life span. Blood sugar concentrations were 200 mg/dl or greater by 8 weeks of age and reached or exceeded 300 mg/dl by 10 weeks of age. Both diabetes (db) and obese (ob) genes are inherited as autosomal recessives with complete penetrance. Diabetic homozygotes are fat, hyperglycemic, and nonfertile, and heterozygotes cannot be visually distinguished from normals. Attempts to control weight by food restriction, as has been successful with the obese mouse, failed in the db/db mouse. The db/db mouse did not survive on reduced food intake. ^ The db mutation is located on chromosome 4. Homozygous mutants are infertile, obese, hyperphagic, and consistently develop severe diabetes with marked hyperglycemia. Increased plasma insulin concentrations are observed as early as 10 days of age. The concentration of plasma insulin peaks at 6-10 times normal by 2-3 months, then drops precipitously to near normal levels. During the time of elevated insulin, there is a hyperplasia and hypertrophy of the beta cells of the Islets of Langerhans. The decline in plasma insulin is concomitant with islet atrophy and rising blood glucose, which remains above 400 mg/dl until death at 5-8 months.^ 4. PARABIOSIS It is important to remember that in 1950 many of the experimental techniques so readily available today had not yet been developed. One of the available techniques that was important in determining the nature of this new obese mutant was parabiosis. Parabiosis is the union of two living organisms, which may occur spontaneously as in the example of conjoined twins or, most often as used in experimental research, following a surgical procedure in laboratory animals such as the mouse or rat.^' ^ This technique allows animals with different physiologies or genetics to be conjoined and to 4 Chapter 1 share their blood supplies. Any humoral (endocrine) substances would readily communicate from one parabiont to the other. This technique was most useful in establishing the fact that a humoral substance was involved in the regulation of satiety and adiposity.^ Early studies demonstrated the existence of a satiety center within the hypothalamus and that hypothalamic lesions would result in obesity.''" Hervey parabiosed a pair of rats, one being normal and the other bearing hypothalamic lesions that resulted in obesity. This union resulted in severe weight loss and the suppression of appetite in the normal partner. We now appreciate that the increased adipose tissue of the hypothalamic lesioned rat produced excess leptin and affected the normal partner, but not the lesioned rat, since the satiety center had been destroyed.^ In a series of important studies, Coleman used the parabiotic technique to great advantage to define the nature of the genetic obese mouse models which had become recognized at his institution. When a normal mouse is parabiosed with an ob/ob obese mouse, the obese animal gains weight at a slower rate and approaches the normal body weight, demonstrating that some factor from the normal control mouse crosses to the obese mouse to induce satiety. These results demonstrate that the obese mouse has a deficiency of a satiety factor, but also does not produce any substance which adversely affects the normal partner. The ob/ob mouse exhibits an improvement in plasma insulin and blood glucose concentration. In sharp contrast, when the db/db obese mouse was parabiosed with a normal mouse, the normal mouse rapidly lost weight, became hypoglycemic and died of apparent starvation within 50 days of surgery.^' ^'" The db/db mouse in this parabiosis pair was resistant to the endogenous factor produced by the normal partner. Later studies would confirm that leptin was produced in the normal mouse and decreased many aspects of obesity in the ob/ob partner. In the db/db mouse, the mutation caused a loss of the leptin receptor and therefore was resistant to any leptin effect. Moreover, this mutant produced excess leptin (due to increased adipose tissue), which suppressed appetite severely in the normal partner and resulted in death. Parabiotic studies using rat models have also been valuable in identifying the humoral nature of appetite regulation. As an example, parabiosis of normal pairs of rats, in which one member of the pair was tube fed twice its normal amount, would result in obesity, but the partner had a slight decrease in food consumption from that seen in individuals in normal parabiotic pairs. These studies indicated that some humoral factor from the obese partner would cross the parabiotic union to suppress food intake in the normal partner.'^ The obese (ob/ob) mouse and the discovery ofleptin 5. EARLY THEORIES OF APPETITE REGULATION Early hypotheses of the feedback regulation of satiety have been reviewed by Hervey.'^ Three hypotheses were presented to identify the substance responsible for this closed loop regulatory system for energy balance. The first was that the maintenance of body temperature indicated the state of energy balance.
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