Every kind of living being is provided with a constitutive physiological system that maintains normal body structure within its genetically predetermined shape and size. The part of the system that regulates body fat in mammals has now been discovered to the molecular level [8,10]. The control of satiety and the ability to burn fat for energy is performed by a particular set of hormones and other molecular physiological agents. The hormonal regulation of food intake is mainly performed by leptin and insulin [6-8]. They stimulate us to eat more when fat storages are low and less when fat storages are high.

Leptin is produced peripherally by fat storages in adipose tissue and controls the appetite through its actions on relevant hypothalamic cells provided with special leptin receptors. The inhibition of excess food intake is initiated by leptin production performed by satiated adipose tissue, continued by leptin interaction with its hypothalamic receptors, and results in the suppressive response of the hypothalamus addressed to the fat-storehouses [8,10]. The disturbance of any of these links leads the adipose tissue to become unsatiated and begin an uncontrollable intake of foodstuff. It has been shown that the mutant change of the structure and function of leptin leads to the development of obesity [11].

Mutative disturbances caused by sporadic mutant modification of either leptin or its receptor may influence regulatory interaction between leptin and its receptor [11,12]. The same effect may be performed by the mutant absence of any of the coactants. In any case, the disturbances lead to structural resistance (constitutional immunity) of the hypothalamus to the signals of the body’s satiety and to its inability to inhibit excess food intake. As a result, the diseased body does not become satisfied and “makes a pig of oneself”, allowing the development of obesity.

Mutant inadequacy in the production of leptin can function on the level of adipose cells that leads to congenital leptin deficiency, resulting in an insatiable appetite and severe early-onset obesity with numerous other clinical abnormalities; all of which leptin treatment can correct [11,12]. The same result could be achieved by mutations leading to a change of leptin structure. Leptin treatment can correct both state [12]. It should be noted that the administration of leptin might be effective only in a small subset of obese individuals who are leptin deficient. It has been shown that subjects who are heterozygous for the leptin mutation also develop obesity but not as severe as in homozygotes [11].

The mutations in the formation of leptin receptors disturb the discussed regulatory function on the level of hypothalamus. Leptin treatment cannot correct the blocking effect of the disturbance. Most obese individuals have been found to have high levels of leptin and are thought to be leptin resistant [8]. Thus, in some obese bodies, the leptin function can be normal or its content increased by leptin treatment, but its performance can be stifled by a derangement of receptor cells, that is, by the body’s immunity to leptin arising because of incongruent receptors [12,13]. This state of hypothalamus immunity to leptin is thought to explain why the administration of leptin has not been shown to be effective in suppressing appetite in most obese people [6].

An analogous mutant decrease in the sensitivity of cells may prevent the specific action of physiological agents (hormones, enzymes, mediators, chalones, and so on). Constitutional immunity of cells to insulin is a major determinant in the decline of glucose tolerance. The non-insulin-dependent (type II) diabetes mellitus is characterized by hyperglycemia in the presence of higher than normal levels of plasma-insulin. Similarly, an immunopathogenic decrease in cell sensitivity to vitamin D3 determines the familiar forms of rachitis. Constitutional immunity of cells to androgenes causes the phenomenon of testicular feminization. The analogous genetic resistance of cells to corticosteroids determines the pathogenesis of Cushing disease [14].

Although the spread of widely dispersed cases of obesity is progressing as a worldwide pandemic, the possibility that infections might be etiologic agents in obesity has currently received relatively little confirmation. Animal experiments link obesity to four animal viruses (rabies virus, Rous-associated virus, Borna virus, and SMAM-1). Only one human virus, adenovirus 36 (AD36), has been shown to increase adiposity in experimentally infected chickens, mice, and marmosets. Virus-induced obesity in mice alters their response to leptin [15] that act on the thalamus cells. On the other hand the attempts have been made in the past allowed the adenovirus infection alters lipid metabolisms in animal adipocytes too [16]. But a direct correlation of human obesity with an epidemic of any infection has not been found for a long time [11,18-22]. The situation began to change after it had been argued that obesogenic function does not belong to infection by itself but to a constitutional post-infectious immunity induced by it [34].

Direct relationship of a child’s obesity with their previous infection with AD36 has recently been confirmed. The bodies of 124 children were searched for traces of previous AD36 infection—the presence specific antibodies against this virus. Nineteen children revealed specific antiviral antibodies, the responsive signs of past AD36 infection (15%). The majority of children found to be AD36-positive were obese (15 (78%) of 19 children). The responsive signs of foregoing infection, AD36 antibodies, were significantly more frequent in obese children (15 (22%) of 67 children) than in non-obese children (4 (7%) of 57 children) [23].

The studies demonstrated a link between AD36 and obesity, but did not deliver the evidence of how the virus itself causes people to become obese because a long time had passed between the infection and the obesity manifestation. By the time a person becomes obese, the virus is long gone and the person is no longer infectious. Next was an attempt to answer the question from the viewpoint of the nature of constitutional post-infectious immunity [24,25]. The approach was based on the discovery of an unexpected commonality in the structures and functions of molecular physiological and infectious agents.

Tetanus toxin interacts with the thyroid thyrotropin receptor. Its binding can be inhibited by thyrotropin [26]. The rabies virus receptor appears to be closely associated with the acetylcholine reception [27]. The EpsteinBarr virus has a strong tropism for lymphocytes and was thought those of the complement C3 receptor [28]. The human T-cell leukemia virus preferentially infects cells of the helper/inducer class [29]. The cardioviruses and influenza A and B viruses bind to the glycophorin A molecule on human erythrocytes, and this glycoprotein also carries the M and N blood group antigens [30]. The B chain of cholera toxin and the beta-subunits of thyrotropin, luteinizing hormone, human chorionic gonadotropin, and follicle stimulating hormone are shown to have a region of sequence analogy believed to correlate with their ability to bind to the receptor on cell membranes. A sequence analogy is also defined in the alpha-subunits of these glycoprotein hormones and in the region of the cholera toxin A1 chain responsible for adenylate cyclase activation [31].

Following the data, it was permissible to suppose that in fact, all “viral” and “bacterial” receptors have initially been evolved to provide physiological functions of hormones or other physiologically active molecules [9,25]. Evolutionary adaptation of relevant microbes to a parasitic way of life could be performed using pre-existent hormonal receptors.

A constitutional component of post-infectious immunity is formed during a relevant infectious process by the annihilation of susceptible cell structures, including relevant receptors. After recovering, the individual becomes constitutionally immune against re-infection [24,25]. In the discussed case of proposed exact sameness of a receptor both for the AD36 virus and leptin, the formation of post-infectious immunity against infection means a simultaneous formation of both hypothalamus immunity to leptin and its inability for the signaling of adipose tissue regarding excess food intake. The prevalence of post-infectious obesogenesis depends on the intensity of relevant infectious epidemic, that is, the number of susceptible people existent in the observed population [25].

The origin of cell immunity to specific molecular physiological agents is analogous to those in constitutional immunity to infections. In a case of molecular ecological aggression of harmful infectious agents, the specific features of the molecular constitution of the attacked body provide constitutional immunity. The success or failure of microbial aggression also depends on the precise molecular complementariness of the infectious agents with the molecular make-up of the attacked organism, namely its cellular, subcellular, and molecular structures [25].

The organisms possessing this modified molecular constitution are insusceptible to the relevant infectious agent. They do not contain susceptible cellular, subcellular, and molecular structures, whereas organisms in which the number of constitutionally susceptible structures is high, the infectious process develops in a very severe form. Their chances for everlasting life by means of self-reproduction are diminished sharply. Corresponding microbes do not affect those organisms, which are able to produce genetically immune offspring, while susceptible individuals of the same species become ill and die without progeny [32]. On repeated exposures of a population to a given pathogen, the progeny of immune mutants comes, in evolution, to predominate in the population; an individual protective mutation becomes the property of a group, then of a population, ethnoses, and finally of the species. The beneficial attributes of constitutional immunity to infectious agents are propagated in the population thanks to natural selection as an adaptation to life-threatening environmental agents. The selection for the life-saving modification of viral receptors means the simultaneous formation of the life-threatening disturbance of the leptin reception.

Humans are very diverse in their predisposition to obesity, as well as in the grade of its expression [9,25]. The forms and rates of obesity progression may be different not only in various individuals, but also in different organs. Equally with the total affection of almost all the body, there may be several areas of restricted fat locations around the body (Figure 1).

In most cases, obesity is presented by local manifestations of individually different grades. Their sizes vary from solitary small lipomas to multiple massive bulges forming abnormal enlargements of involved parts of the body. The local areas of a human body where obesity can be observed both on women and men include the facial jowls, neck, upper back of the arms, upper back underneath the bra straps, areas near the underarms, waist, love handles, hips, breast, buttocks, abdomen, belly, thighs, knees, calves, and inner organs as well [34]. Any local fat-storehouse is a growth of fat cell population surrounded by a thin, fibrous capsule.

Local character of affections is a very important feature of obesity, the origin of which has been ignored by previous pathogenetic investigations [9,25]. Meanwhile, its observations allow that physiological functions of fat metabolism and its regulations in obesity are disturbed differently in different body areas of the same person. It can also be concluded that within every obese human body, there are at least two co-existing clones of fat cells with the opposite predisposition to obesity and two distinct systems for regulation of food intake and fat metabolism. One of the clones is predisposed to the development of obesity. The size of obese cell populations and their dislocation around the body predestine individual diversity in the course and severity of obesity.

Despite the vastness of differences between existing diseases, one striking similarity unites all of them without exception. This similarity is seen in the mosaic locations and sizes of the lesions [32,35]. Mosaicism of a diseased state is the condition in which the phenomenon genetically determines the variations in its manifestations. Mosaicism of affections is a syndrome universal for any kind of pathology. All diseases (heart, circulatory, pulmonary, mental, skeletal, renal, gastrointestinal, endocrine, or metabolic) are characteristic of the diverse grade and focal dislocation of specific lesions. The existence of this phenomenon was obvious for the general paradigm of pathology, but its origin and pathogenetic significance were only discovered at the end of the 20th century [32,36].

The dapple dispersion of infectious damages is also caused by intra-individual diversity in the local sensitivity of some parts of outwardly homogenous tissue to the action of relevant pathogen. How can we account for the fact that the identical cells of an organism differ from one another when they all contain the same genome complex? Up to the end of the 20th century, it was a riddle for both pathology and genetics [32,36]. Recent advances in the discovery of hereditary immunity [25], especially of its constitutional mechanisms, allowed the understanding of the origin of this phenomenon.

The existence of local intraindividual differences in susceptibility/resistance to infection explains why a given agent affects some parts of a tissue, while other morphologically identical components of the same organism remain uninvolved, although both exist under the same conditions and may be equally influenced by the agent. According to data from many experiments and observations, the mating of resistant and susceptible individuals gives rise to progeny with intermediate degrees of infectious lesions [32,37-40]. The spotty disposition of obesity manifestations can also be considered as an example of same universal law of pathology.

Modern humankind is characteristic of the hugeness of racial and ethnic differences formed in evolution. Anatomically, modern humans emerged in one place, probably northern Africa’s savannah over 200,000 years ago [41]. But the evolution of humankind was not finished at that time. Nearly 60,000 years ago, different groups of early Homo sapiens began to sweep out of Africa and disperse around distinct parts of other continents. Their wanderings around the world substantially expanded both the quantity and quality of the evolutionary driving forces they encountered on their ways. Inhabiting ecologically disparate geographical areas, migrants continued to evolve independently into five anatomically different races and a multiplicity of segregated ethnic groups. Nearly all differences between current human races, ethnoses, and populations are due to events that occurred outside of Africa [42]. The subsequent genetic admixture between distinct human populations increased the number of new traits in human constitution, while many thousands of wandering generations were subjected to various selective pressures acted on by the plethora of unprecedentedly distinct physical, chemical, and bioecological agents. Interethnic differences in the regulation of fat metabolism should be subjected to the same kind of genesis.

These genetically predetermined differences are proof of heterozygosity: one parent passes a lack of receptivity to relevant regulators in some parts of the descendant body on to the descendant, while unaffected parts are inherited from the second parent. This analogy allows us to suppose the same genetic origin in the case of the intraindividual diversity in obesity. According to epidemiological and clinical observations, xenogamy functions as an important co-maker of obesity genetics and its variable manifestations [9,25]. The cross-breeding between healthy persons possessed different structures for the regulation of fat metabolism, giving rise to obese progeny with different degrees of the disease.

The view of heterozygous origin of local obesogenesis can explain why the disease affects some parts of a body, while other parts of the same organism remain uninvolved, although both exist under the same conditions. The loci of affections appear as encapsulated bulges, and the distribution of such foci are distinct for different people and for different parts of the same person. The heterozygous body of the descendant can contain at least either a set of two distinct clones of adipose tissue or two distinct regulators of fat metabolism.