PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Obesity: A Reckoning for Genetic Immunity to Infection and Xenogamy by Sergey N. Rumyantsev, M.D., Ph.D. Introduction Obesity is named as a disease of civilization, but it is not a recent phenomenon. Its history can be traced back at least to 25,000 years ago thanks to sculptures of corpulent women, made by stone-age’s artists. But to the end of 20th Century the number of obese people in some countries began to increase like a real epidemic. In the USA the epidemic began since 1960, and continues to progress [1]. In just two decades, incidence of adult obesity has increased by 80 percent: from 15 percent in 1980 to over 27 percent in 2000 [2, 3]. Today the obese peoples form more than 60 percent of Americans aged 20 years and older. Nevertheless obesity is more prevalent in African-American women than in their white counterparts [4]. Differences among ethnic and racial groups in obesity-related traits have been clearly established in the scientific literature [5]. More than half of non-Hispanic black women aged 40 years or older were obese. The childhood obesity epidemic is with us too [6]. Obesity is fare more than a cosmetic problem. It is accompanied with a plethora of very dangerous chronic illnesses such as heart diseases, diabetes, high blood pressure, stroke, different kinds of cancer, liver disease, gout, disease of joints, and so on. Over 300,000 adult excess deaths in the United States each year are related to obesity. Now obesity is the second leading cause of excess deaths in the USA. [2]. Obesity may reduce the life expectancy for mostly affected populations [7]. Despite its toll taken in death and disability, as well as considerable molecular and genetics efforts to understand how obesity develops, many questions about nature of the disease did not receive answers they deserves. Nothing is known about epidemic spread of obesity, as well as about the origin of extraordinary diversity in clinical manifestations of the disease. Role for Genetic Immunity in the Origin and Spread of Obesity Every kind of living beings is provided by physiological systems that maintain normal body structure within a genetically predetermined shape and size. The physiological system that regulates the body fat is now discovered up to molecular level [8]. It acts through molecular physiological mediators of energy intake and energy expenditure. The ability to burn fat for energy, and satiety is performed by function of a set of molecular physiological agents. The system includes hormonal regulation of food intake in the first place by leptin and insulin. In a case of obesity the work of this precise and powerful system is disturbed. In normal organism leptin performs inhibition of food intake [9]. Development of obesity is determined either by the disturbance of the leptin production or function. Deficiency of leptin production resulted in insatiable appetite leading to severe early-onset obesity. The same result is achieved by mutant modification of leptin structure which forms incongruence between leptin and its receptor. Both states can be corrected by leptin treatment [10]. On the other hand, in an obese body the leptin can be normal and its content can be increased but its action is stifled by a derangement of their reception by cells i.e. by constitutional immunity to leptin’s influence because of incongruent receptors [10, 11]. The blocking effect of mutant modification of leptin receptors can not be corrected by leptin treatment. Analogous dramatic immunity of cells to specific action of relevant physiological agents (hormones, enzymes, mediators, chalones or so on) functions also in many kinds of hormonal pathology. The principles of cell immunity to physiological agents are analogous to those ones in constitutional (genetic) immunity to infections. Although the spread of obesity is progressing like a real world-wide pandemic the possibility that infections might be etiologic agents in obesity has received relatively little confirmation. Experiments link to obesity five animal viruses (rabies virus, Rous-associated virus, Borna virus, and SMAM-1). A human virus, adenovirus 36 increases adiposity in experimentally infected chickens, mice, and marmosets. But direct correlation of human obesity epidemic with epidemic of any infection was not found out [12, 13]. Nevertheless indirect action of infections on obesity genesis and spread can not be denied today. The hypothesis has been formulated and examined that spread of obesity is predetermined by the spread of genetic immunity to infections. The study has been performed by mutual exposure and analysis of epidemiological, clinical, immunological, genetic and experimental data concerning principal characteristics that are common both for obesity and many other kinds of diseases especially of infectious ones . In a case of infection this kind of immunity is provided by constitutional incongruence between acting molecules of infectious agents and its molecular targets in the attacked organism. The success of microbial aggression depends of precise molecular congruence of infectious agents with molecular make-up of attacked organism, especially of its receptors. Structural modifications of relevant molecular attribute of a victim able to reduce or even eliminate the success of microbial intrusion [14-16]. The incongruence arise as a result of mutations and is propagated in population thanks to natural selection as evolutionary adaptation to the life threatening environmental agents. All “viral” and “bacterial” specific receptors have not been evolved to interact with microbial pathogens but to provide physiological functions of hormones or other physiologically active molecules. Evolutionary adaptation of harmful microbes to parasitic way of life has been performed by exploitation of pre-existent physiological receptors or others cell structures and functions [14, 16]. Subsequent evolution and spread of genetic immunity to infections created constitutional genetic immunity to molecular physiological agents responsible for regulation of fat intake and metabolism thus providing the spread of relevant forms of pathology. Many hormones share their specific targets with acting molecules of infectious agents. Tetanus toxin binds specifically with thyroid thyrotropin receptor [17]. The rabies virus receptor appears to be closely associated with the acetylcholine receptor. Epstein-Barr virus has a strong tropism for lymphocytes and was thought those of the complement C3 receptor [18]. The human T-cell leukemia virus preferentially infects the cells of helper/inducer class [19]. 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 [20]. Virus-induced obesity in mice alters their response to leptin [21]. Mutant formation of for life-saving genetic immunity to infection could create life-threatening resistance to relevant hormone. This kind of individual molecular constitution could spread in a population as a result of natural selection for genetic immunity to infections that has been performed differently in ecologically distinct populations] thus forming ethnic differences in molecular constitution of both hormones and their targets. Any change in one molecular physiological agent should entail relevant changes in all other molecules connected to it 22. Evolutionary process removes molecular physiological incongruence within ethnic group but creates incongruence between the groups. Thus molecular physiological agents of one ethnic group become xenobiotic to analogous agents of another group and vice versa. Function of Xenogamy in the Spread of Obesity Humans are extraordinarily diverse in their predisposition to obesity. Affected people have many differences in manifestations of their obesity as well as in the grade of its expression. The shape, location, size and rate of obesity progression may be different in different individuals or different organs as well. Equally with total affection of almost all the body, there are several key areas of restricted focal fat-storehouses locations around the body. In most cases, obesity is presented by focal manifestations of individually different grade and locations. Someone has only one small bulge whereas another person has one two, three or four local areas where excess fat exists. Extra fat bulges may be symmetric or asymmetric. Someone can be heavier on the right side, but another one on the left. The focality of affection is the principal feature of obesity. Within every obese human body there are at least two co-existing clones of homogenous fat cells with unequal predisposition to obesity. The clones exist in a form of separate populations stochastically dispersed around the body. The sizes of obese cell masses and their dislocation around the body predestine individual diversity in the course and severity of obesity. Should one suppose that physiological functions of fat metabolism and its regulations in obesity are disturbed differently in different populations, different generations as well as in different body areas of the same person? How can we account for the fact the identical cells of an organism differ from each other when all contain the same genome complex? It is a riddle both for pathology and genetics [23-25]. The origin of this very important feature has been ignored by systematic investigation before. Up to now, the origin of individual and intra-individual differences in locations, shapes and sizes of fat-storehouses forms an unsolved riddle of obesity. Although it is now an obvious truism that a person's genetic makeup has principal influence on the development of obesity, the special characteristics of genome that determine zonal distribution of obesity around the body was unknown. In contrast, the origin of analogous features of infectious diseases and many noninfectious ones has been deciphered [14, 25]. The phenomenon of dapple distribution as well as the diversity in the grade of focal diseased affections is not new for general paradigm about pathology, but its origin and significance have been discovered only at the end of 20th Century [23-25]. All diseases (heart, circulatory, pulmonary, mental, skeletal, renal, gastrointestinal, endocrine or metabolic) are characteristic of diverse grade and focal dislocation of specific lesions. Every infectious disease affects only focal areas in the infected organism and is manifested by variable amount of those spotty clinical signs in different cases. Mosaic distribution of infectious lesions is associated with distinct diversity of cell clones and populations in genetic sensitivity/immunity to relevant infectious agent. Sensitivity may involve only a few cells or the majority of cells in a population. Constitutionally immune organisms do not contain susceptible cellular, subcellular and molecular structures whereas organisms in which the number of constitutionally susceptible structures is high infectious process develops in very severe form and their chances for life and reproduction are diminished very sharply [14 24]. In an affected organism every infection manifests at least two clones of homogeneous cells which differ sharply from each other with regard to one highly specific feature: cells of the first clone are constitutionally (genetically) immune to the infection, whereas those of the second one are susceptible to the same agent. It was shown by many experiments and observations, the mating of resistant and susceptible individuals gives rise to progeny with intermediate degrees of infectious lesions [9, 24, 26-28]. Mating of constitutionally susceptible and constitutionally immune organism makes the diversity. Thus the genetically predetermined intra-individual differences are proof of heterozygosity, i.e. a result of genetic admixture, i.e xenogamy. The constitutionally immune parent passes on to the descendant a lack of receptivity to a certain infection in some parts of a tissue, while the susceptible foci are inherited from the second parent. The quantity, dispersion and localization of susceptible structures are individually diverse. The genesis of those intra-individual diversity in a case of obesity can also be explained by hybridization of persons with different genetic immunity/susceptibility to internal factors determining obesity. The mating of resistant and susceptible individuals gives rise to progeny with intermediate degrees of obesity and extent of obese foci. One can suppose that focal diversity in the rate and kind of dispersion of obesity manifestations is a such thing as a result of hybridization between two genetically different organisms: one of them was constitutionally immune to leptin, insulin or so on whereas its mating partner was normally sensitive to this molecular physiological agent. This conclusion was supported by observations that subjects who are heterozygous for the leptin mutation develop obesity which is not as severe as in homozygotes [29] and that variation in obesity-related traits is associated with interethnic genetic admixture [5]. Modern increase of obesity incidence in some countries can be associated with spread of constitutional immunity to a lot of infectious diseases performed by natural selection, followed by increased hybridization between representatives of populations with different genetic make-up that could provide incongruence between a hormone and its receptor thus determining the state of leptin deficiency. At least four variants of the incomplementariness could be considered here: 1) Aboriginal hormone meets mutant aboriginal receptor; 2) Mutant aboriginal hormone meets aboriginal receptor; 3) ‘Alien’ hormone meets aboriginal receptor; 4) Aboriginal hormone meets ‘alien’ receptor. Conclusion The existed set of observations allow us to conclude that the spread of obesity is determined by arising of heterozygosity in the population under observation. Extraordinary diversity in the obesity course, manifestations and severity of specific affections, their sizes and focal disposition around the body could be created by inter-ethnic hybridization (xenogamy) of persons with different grades of hormone-receptor heterozygosity. Prerequisites for intensive performance of this mechanism arise today everywhere in the World especially among more mixed population. Most of the ethnic groups in the United States have resulted mainly from intensive intermixing of European, African, and Native-American populations during the colonization and continued mutual habitation of the New World. Genetic variants or alleles from these previously isolated parental populations were brought together in new combinations establishing the gene pools of the various contemporary European-, African-, Hispanic-, and Native-American resident populations. Heterozygous individuals of these populations, who inherit variants that predispose them to disease-related traits have a greater chance of acquiring the disease of obesity [5, 30]. At these circumstances should we remember the commandment of Abraham: “… you will not take a wife…from the daughters of the Ca’naan’ites in among whom “ we are dwelling [31]? What the tests for genetic congruence should be elaborated and used today? References: (1) Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002;288(14):1723-7. (2) Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960-1994. Int J Obes Relat Metab Disord 1998;22(1):39-47. (3) Mokdad AH, Ford ES, VF, Marks JS, Koplan JP. . The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286(10):1195-200. (4) Allison DB, Edlen-Nezin L, Clay-Williams G. Obesity among African American women: prevalence, consequences, causes, and developing research Womans Health. Nature 1997;33:243-74. (5) Fernandez JR, Allison DB. Understanding racial differences in obesity and metabolic syndrome traits. 61 ed. 2003. p. 316-9. (6) Pietrobelli A, Steinbeck K S. Paediatric obesity: what do we know and are we doing the right thing? International Journal of Obesity 2004;28(1):2-3. (7) Mann CC. Provocative study says obesity may reduce U.S. life expectancy. Science 2005;307(1716):1717. (8) Friedman JM. Modern science versus the stigma of obesity. Nature Medicine 2004;10(6):563-9. (9) Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;396:763-70. (10) Montague CT, Farooqi IS. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-8. (11) Stunkard AJ, Harris JR, Pedersen NL, McClean GE. The body-mass index of twins who have been reared apart . N Engl J Med 1990;322:1483-7. (12) Atkinson RL, Whigham LD, Kim C, Israel BA, Dhurandhar NV, Strasheim A. . Evaluation of human adenoviruses as an etiology of obesity in chickens. Int J Obes 2001;25 (Suppl. 2):S12. (13) Vangipuram SD, Sheel J, Atkinson RL, Holland TC, Dhurandhar NH. A human adenovirus enhances preadipocyte differentiation. Obes Res 2004;12:770-7. (14) Rumyantsev SN. Constitutional immunity and its molecular-ecological principles [in Russian]. Leningrad: Nauka; 1983. (15) Rumyantsev SN. Observations on constitutional resistance to infection. Immunology Today 1992;13(5):184-7. (16) Rumyantsev SN. Constitutional and non-specific immunity to infection. Rev sci tech Off int Epiz 1998;17(1):26-42. (17) Lee G, Consiglio E, Habig W, Dyer S, Hardegree C, Kohn LD. Structure: function studies of receptor for thyrotropin and tetanus toxin: Lipid modulation of effector binding to the glycoprotein receptor component. Biochem Biophys Res Commun 1978;83:313-20. (18) Jondal M, Klein G, Oldstone MBA, et al. Association between complement and Epstein-Barr virus receptors on human lymphoid cells . Scand J Immunol 1976;5:401-10. (19) Popovic M, Sarin PS, Robert-Gurroff M, et al. Isolation and transmission of human retrovirus (human T-cell leukemia virus) . Science 1983;219:856-9. (20) Enegren BJ, Burness ATH. Chemical structure of attachment sites for viruses on human erythrocytes. Nature 1977;268:536-7. (21) Nagashima K, Zabriskie JB, Lyons MJ. Virus-induced obesity in mice: association with a hypothalamic lesion. J Neuropathol Exp Neurol 1992;51:101-9. (22) Rumyantsev SN. Chemical ecology and biomolecular evolution. Acta Biotheor 1997;45:65-80. (23) Rumyantsev SN. The mosaic of organism: physiological, pathological and biotechnological aspects (in Russian). The state and the development's perspectives of agricultural biotechnology.Moscow: 1986. p. 210-5. (24) Rumyantsev S.N. Structural predestination of individual diversity in the course and severity of infectious diseases. TheScientificWorldJOURNAL 2002;2:205-16. (25) Rumyantsev SN. The intra-individual diversity in senescence. Biogerontology 2003;4:171-8. (26) Vavilov NI. Immunity of plants to infectious diseases (In Russian). Moscow-Leningrad: Nauka; 1964. (27) Robson H.G., Vas S.I. Resistance of inbred mice to Salmonella typhimurium. J Infect Dis 1972;126(4):378-86. (28) Paxton W.A., Martin S.R., Tse D., O'Brien T.R., Skumnick J., VanDevanter N.L., et al. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected dispite multiple high-risk sexual exposure. Nat Med 1996;2:412-7. (29) Farooqi IS. Partial leptin deficiency and human adiposity. Nature 2001;414:34-5. (30) Fernandez JR, Shiver MD. Using genetic admixture to study the biology of obesity traits and to map genes in admixed populations. Nutr Rev 2004;62:S69-S74. (31) Genesis,24, 3. New World Translation of the Holy Scriptures.Brooklyn, NY, USA: Watch Tower Bible and Tract Society of Pensilvania; ed. 1984. p. 33. ### Dr. Sergey N. Rumyantsev is a member of The Science Advisory Board Steering Committee. He invites you to read his profile and other Web site contributions: Bioweapon: The Emperor’s New Suit! Post-Infectious Immunity: the Origin of its Strength and Duration ### << Previous Next >> [ View All Perspectives ] |
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