New Obesity Targets: Molecular-Genetic and Transgenic Approaches

Several lines of evidence point to genetic factors as important determinants of obesity. First, the prevalence of obesity varies dramatically between different racial and ethnic groups; it is substantially higher in certain native American (e.g. Pima Indians) or South Pacific (e.g. Nauruans) populations (TURNER et al. 1993). Secondly, some studies have shown that twins reared apart are concordant for body mass index (BMI) (BOUCHARD et al. 1990), and thirdly, several rare syndromes of extreme obesity are inherited as either dominant or recessive single-gene disorders (BOUCHARD and PERUSSE 1993). These include the Prader-Willi (BUTLER 1990) and Bardet-Biedl (BEALES et al. 1997) syndromes, and recently described single cases of congenital leptin deficiency (MONTAGUE et al. 1997). In addition, a single patient with a mutation in prohormone convertase 1 (presumably leading to impaired central processing of regulatory peptides that control appetite or energy expenditure) has been described (JACKSON et al. 1997). Overall, about two thirds of the contribution to body mass index (BMI) seems to be genetically determined (BOUCHARD and PERUSSE 1993; STUNKARD et al. 1986). Although increased nutrient intake is a prominent cause of obesity, there is emerging evidence that suggests that energy expenditure per se is, at least in part, genetically determined (BOUCHARD et al. 1990). Moreover, clinically significant increases in adiposity may often occur when individuals with what was once a favored “thrifty genotype” (reduced satiety, more efficient fuel storage) are exposed to a sedentary lifestyle accompanied by increased food availability and advancing age (TURNER et al. 1993; WENDORF and GOLDFINE 1991). The prevalence of obesity in the United States is currently about 30%, representing a health care problem of enormous proportions (KUCZMARSKI et al. 1994). Even though accumulating data is providing insights into the control of BMI, our ability to therapeutically intervene in BMI disorders is limited since prolonged weight loss with current therapy cannot easily be accomplished (SAFER 1991; LEIBEL et al. 1995). This chapter will review genetic strategies (and recent attempts) to identify new targets for treatment of obesity. We will delineate developing models which attempt to explain the mode of action of several new targets.