A complex system of many dynamically interdependent metabolic and physiologic intra- and extracellular processes adapts and adjusts mammals, including Homo sapiens, to ever-changing conditions in the internal milieu and the external environment. These processes have a basis in the interactions of thousands of peptides, each specified by one or more genes. They are integrated via a network of signal transduction pathways (Wilks and Oates 1996). These continuous adaptations are mediated by the responses of patterns of transcription-inducing or -inhibiting genes and of genes that modify translation of messenger RNAs (mRNA) to peptides. These patterns were established during evolution and enable the organism to function under a wide variety of external and internal conditions. Mutations at any of these gene loci may disrupt or prevent orderly adaptive metabolic or physiologic change and can thus result in diseases of regulation, such as obesity.

Although specific mutations may determine the likelihood that an individual will become obese, the individual's genetic background (genome) influences the degree of obesity, i.e., how fat the individual is likely to become. This is illustrated by the difference in the proportions of body fat (13.9 ± 2.3 vs. 5.7 ± 0.6%) in nonmutant lean mice of the C57BL/6J and VY/WfL strains (Yen et al. 1976). Maternal effects on the degree of obesity were demonstrated by the results of reciprocal matings that indicated that these differences correlated with the strain genomes of the mothers (Wolff and Pitot 1973). Obese yellow A^y/a male mice of one inbred strain were 26% heavier at 3 mo of age than their lean black a/a siblings, and obese yellow male mice of a different strain were 45% heavier than their black siblings. Similar effects on body weights of obese yellow and lean non-yellow mice from F₁ hybrids of reciprocal matings between two different inbred strains were reported by Heston and Vlahakis (1966). These maternal effects probably were due, at least in part, to differences in lactating ability of the dams. Lactating ability is, of course, a genomically determined factor.

Although a mutation may result in dysregulation of some of the intra- or extracellular processes of the metabolic/physiologic network, no overt effects may be apparent because of homeostatic adjustments in the system. However, when the dysregulation cannot be modulated in this fashion, a disease syndrome results. This syndrome has a number of different overt manifestations because of the interdependence of the metabolic/physiologic network. If excess lipid deposition is one of the manifestations, it will be highlighted because of its easily identifiable nature. The specific dysregulation induced by the mutation, however, may be more directly related to other, less visible and more subtle manifestations. The latter may provide better clues for alleviating the basic dysregulation than the obesity per se.

Table 1. Differences between the Avy/ and Lepob/Lepob syndromes [View Table]

Some "obesity" syndromes result from mutations in genes that play direct or indirect roles in the regulation or modulation of neuroendocrine factors that influence feeding and/or hormonal synthesis/release and thus indirectly affect intermediary metabolism. The metabolic/physiologic/neuroendocrine dysregulations induced by these mutations affect several basic cellular processes, one or more of which result, more or less incidentally, in excess fat deposition.

Obesity, per se, can be temporarily ameliorated in mice, rats and humans by reducing caloric intake and increasing calorie utilization by exercise. However, to prevent its recurrence, identification and subsequent modulation of the specific metabolic/physiologic dysregulation(s) that underlie each type of obesity is essential. Weight-reducing regimens generally have no permanent effect in most individuals because these treatments do not alter the basic dysregulations but only decrease net fat deposits temporarily (Keesey and Hirvonen 1997). In short, they treat the symptom but not the disease.

In mice, and most likely also in humans, mutant genes, whose presence is associated with obesity, have other primary physiologic and metabolic effects, with obesity an easily recognized secondary result. Regarding the Lep^ob/Lep^ob mouse,² Chehab et al. (1996) have stated, "The recent finding that a leptin receptor is expressed in non-neural tissues such as lung, kidney and ovary further implicates leptin in pathways other than (emphasis added) energy metabolism."

Although homologous murine and human genes may be almost identical structurally, their expression in mouse and human may be very different. Most likely this is due to tissue-specific differences in the regulation of their transcription. As an example, the human agouti homolog, ASIP (agouti signalling protein), with an unknown function, is normally expressed in several tissues at very low levels (Kwon et al. 1994, Wilson et al. 1995). In nonmutant mice, on the other hand, the agouti gene is expressed only in the skin and then only during the short periods in each hair cycle when the subapical yellow band is being laid down in the hair (Yen et al. 1994).

The genetic etiologies of the obesities of Lep^ob/Lep^ob and A^vy/a mice differ markedly. The Lep and agouti proteins differ structurally and have completely different functions. Lep^ob/Lep^ob obesity results from lack of the protein leptin (Muzzin et al. 1996). The mutation Lep^ob specifies synthesis, by adipocytes, of a truncated inactive leptin molecule in which arginine 105 has mutated to a stop codon (Zhang et al. 1994). In contrast, the A^vy/- obesity is associated with an overabundance of the agouti protein (Miltenberger et al. 1997). The "yellow" mutations at the agouti locus are characterized by constitutively active heterologous promoters that supersede regulation of agouti transcription by the agouti promoters. This results in ectopic overexpression of the agouti gene in essentially all tissues. The agouti protein itself is unchanged (Duhl et al. 1994).

Table 2. Change in carcass lipogenesis rate with age in C57BL/J-Lepob/Lepob and Lep/ mice1 [View Table]

Table 3. Change in carcass lipogenesis rate with age in VY/WfL-Avy/a and a/a mice1 [View Table]

The peptide hormone leptin binds to products of the leptin receptor (Lepr) locus (Chen et al. 1996) in the choroid plexus (Malik et al. 1996). Binding of leptin to its receptor transduces the leptin signal to its intracellular target(s), resulting in a decreased feeding impulse. Absence of either active leptin, as in the mutant Lep^ob/Lep^ob, or its receptor (mutant Lepr^db/Lepr^db) prevents leptin's inhibitory effect on the postulated hypothalamic "satiety center." Overeating occurs and leads to obesity.

Agouti protein is a ligand that competitively inhibits binding of -melanocyte stimulating hormone (-MSH) to melanocortin receptors such as MC1-R on hair follicle melanocytes. Binding of -MSH activates adenylyl cyclase, which results in increased intracellular cAMP concentration. This, in turn, induces eumelanin formation. In contrast, prevention of binding of -MSH to MC1-R by agouti protein results in the default process, namely, phaeomelanin synthesis, during formation of the subapical yellow band that is characteristic of the agouti hair pattern (reviewed in Cone et al. 1996).

Agouti protein also competitively inhibits binding of -MSH to another melanocortin receptor, MC4-R, which is found in the central nervous system and the brain (Cone et al. 1996). Disruption of the MC4-R gene in C57BL/6J mice results in a maturity-onset obesity syndrome similar to that of yellow mice, except for the hair pigment effect (Huszar et al. 1997). A working hypothesis postulates that the competitive inhibition, by agouti protein, of the binding of -MSH to MC4-R receptors on unknown cells in the central nervous system results in the neuroendocrine stimulation of -cell proliferation in the pancreas and subsequent increased secretion of insulin. The latter is suggested by the observation that at 21 d of age, there were significantly more  cells in the pancreatic islets of yellow A^vy/a mice than in those of their agouti A/a sibs (Warbritton et al. 1994). The higher circulating plasma insulin level is postulated to stimulate lipogenesis by the adipocytes. The resulting increased fat deposition then induces peripheral insulin resistance, which in turn stimulates greater compensatory insulin secretion and results in hyperinsulinemia.

Leptin and the agouti protein both induce their effects via specific cell surface receptors that transduce their respective signals to intracellular processes; however, the processes affected, presumably, are quite different. Therefore, manifold differences in the phenotypic characteristics of different tissues between these two types of obese mutant mice are to be expected (Table 1); obesity may be the only common phenotypic endpoint shared by the two mutants.

Susceptibility to tumor formation in some strain-specific tissues differs quite markedly between the two mutants. Lep^ob/Lep^ob mice develop fewer lung tumors, whereas yellow mice develop more lung tumors than their respective nonmutant sibs (reviewed in Wolff 1987). Mammary tumors occur earlier in Lep^ob/Lep^ob than in Lep/- mice, but with a lower cumulative prevalence. In yellow mice, on the other hand, mammary tumors also occur earlier but with a greater cumulative prevalence than in non-yellow mice (reviewed in Wolff 1987). The prevalence of hepatocellular neoplasms is elevated in both types of mutants, possibly indicating an effect of excess fat deposition in the liver.

The metabolic basis for this difference resides in the differential regulation of the rate of carcass lipogenesis in the two mutants. In younger Lep^ob/Lep^ob mice, this rate was 68% higher than in their lean Lep/- siblings. At 10 d of age, Lep^ob/Lep^ob mice already had a 20% higher fat content than their normal lean Lep/- controls (Thurlby and Trayhurn 1978). With age, the rate decreased to such an extent that there was no difference between the mature Lep^ob/Lep^ob and Lep/- mice (Table 2) (Yen et al. 1976).

Among younger yellow A^vy/a mice, the carcass lipogenesis rate was 24% higher than among black a/a mice. In contrast to the Lep^ob/Lep^ob mice, however, carcass lipogenesis in mature yellow mice decreased only 9% with age (Table 3). In mature lean Lep/- as well as black a/a mice, carcass lipogenesis decreased by 22-23% with age (Tables 2 and 3) (Yen et al. 1976). Younger Lep^ob/Lep^ob mice had 339% more body fat than younger Lep/- mice (Table 4). In contrast, younger A^vy/a mice had only 94% more body fat than younger a/a mice (Table 5) (Yen et al. 1976).

Table 4. Change in percentage of body fat with age in C57BL/J-Lepob/Lepob and Lep/ mice1 [View Table]

Table 5. Change in percentage of body fat with age in VY/WfL-Avy/a and a/a mice1 [View Table]

Of the body weight of mature Lep^ob/Lep^ob mice, 42% was fat compared with only 26% among mature yellow A^vy/a mice (Tables 4 and 5). Even considering the greater strain-related increase in body weight of lean Lep/- mice compared with the lean a/a mice, the A^vy/a mice were less obese, with a net (A^vy/a  a/a) body fat percentage of 19, than the ob/ob mice with a net (Lep^ob/Lep^ob  Lep/-) body fat percentage of 28 (Yen et al. 1976).

Plasma corticosterone levels in C57BL/6J-Lep^ob/Lep^ob mice were ~2.7 times higher than in Lep/- mice (Saito and Bray 1983), whereas in strain VY mice there was either no difference in plasma corticosterone levels between A^vy/a and a/a male mice (Wolff and Flack 1971) or these levels were only up to 1.6 times higher in the yellow mice (Shimizu et al. 1989). Adrenalectomy reverses the obesity of Lep^ob/Lep^ob mice (Feldkircher et al. 1996), but has relatively little effect on the obesity of A^vy/a mice (Shimizu et al. 1989).

Altered regulation of growth hormone and prolactin synthesis/release leading to variably lower serum hormone levels characterize Lep^ob/Lep^ob mice (Larson et al. 1976). No definitive data on regulation of growth hormone or IGF synthesis/release and serum levels in A^vy/- mice have been published, although aberrant regulation of these hormones may possibly be involved in their larger fat-free body mass and endogenous tumor promotion.

Pituitary insufficiency in Lep^ob/Lep^ob mice is also implicated by their sterility or at best marginal fertility, which is alleviated by gonadotropin administration (Smithberg and Runner 1957). In contrast, yellow mice are fully fertile until they have become quite obese in early middle age. Recently, Chehab et al. (1996) reported that leptin injections also resulted in restoration of the fertility of Lep^ob/Lep^ob females. These treated mice were also able to raise their litters successfully. Administration of leptin to lean Lep/Lep females resulted in earlier reproductive function. This observation led these authors to suggest that leptin may play an important part in reproductive physiology per se, beyond its effects of depressing appetite and promoting lipolysis (Chehab et al. 1997).

There is a striking parallelism between syndromes of "obesity" and "cancer." In both, similar endpoints, e.g., malignancy in "cancer" and excess fat deposition in "obesity," can result from a multiplicity of different genetic etiologies. Therefore, both represent umbrella categories of regulatory diseases that include a diversity of patterns of gene-based metabolic and physiologic alterations.

Energy metabolism is an integral part of the homeostatic mechanisms that maintain the organism in a steady state under widely varying environmental conditions. When energy metabolism is altered, the functioning of other bodily processes is modulated. Conversely, altered regulation of diverse bodily processes may result in modified regulation of energy metabolism. Therefore, "obesity" is a chicken-and-egg problem, which may not be amenable to direct solution.

More than 60 years ago Sewall Wright (1934) stated "All characters are affected by many genes and each gene affects many characters." Even in the era of molecular genetics and molecular biology, this is still a valid concept, one that is certainly applicable to the public health problem of obesity.