Infection with Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, results in chronic infection that leads to cardiomyopathy with increased mortality and morbidity in endemic regions. In a companion study, our group found that a high fat diet protected mice from Trypanosoma cruzi-induced myocardial damage, and significantly reduced post-infection mortality. In the present study, the lethality of T. cruzi (Brazil strain) infection in CD-1 mice was reduced from 55% to 20% by an 8 week pre-feeding of a high fat diet (HFD) to induce obesity and the metabolic syndrome. The addition of metformin reduced mortality to 3%. It is an interesting observation as both the high fat diet and metformin, which are known to differentially attenuate host metabolism, effectively modified mortality in T. cruzi infected mice. In humans, the metabolic syndrome, as presently construed, produces immune activation and metabolic alterations that promote complications of obesity and diseases of later life, such as myocardial infarction, stroke, diabetes, Alzheimer's disease and cancer. Using an evolutionary approach, we hypothesized that for millions of years, the channeling of host resources into immune defenses starting early in life ameliorated the effects of infectious diseases, especially chronic infections, such as tuberculosis, and Chagas disease. In economically developed countries in recent times, with control of the common devastating infections, epidemic obesity, and lengthening of life span, the dwindling benefits of the immune activation in the first half of life have been overshadowed by the explosion of the syndrome's negative effects in later life.

1Obesity paradox, obesity orthodox, and the metabolic syndrome: An approach to unity 1 Obesity paradox and the metabolic syndrome. Abstract: 26Obesity and the accompanying metabolic syndrome are strongly associated with heightened morbidity 27 and mortality in older adults. In our review of more than 20 epidemiologic studies of major infectious 28 diseases, including leaders such as tuberculosis, community-acquired pneumonia, and sepsis, obesity was 29 associated with better outcomes. A cause-and-effect relationship between over-nutrition and survival with 30 infection is suggested by results of two preliminary studies of infections in mice, where high fat feeding 31 for 8-10 weeks provided much better outcomes. The better outcomes of infections with obesity are 32 reminiscent of many recent studies of "sterile" non-infectious medical and surgical conditions where 33 outcomes for obese patients are better than for their thinner counterparts ---and given the tag "obesity 34 paradox". Turning to the history of medicine and biological evolution, we hypothesize that the metabolic 35 syndrome has very ancient origins and is part of a lifelong metabolic program. While part of that program 36 (the metabolic syndrome) promotes morbidity and mortality with aging, it helps infants and children as 37 well as adults in their fight against infections and recovery from injuries, key roles in the hundreds of 38 centuries before the public health advances of the 20th century. We conclude with speculation on how 39 understanding the biological elements that protect obese patients with infections or injuries might be 40 applied advantageously to thin patients with the same medical challenges. experts to predict that obesity will shortly become the leading personal health problem worldwide. 52Obesity and the accompanying metabolic syndrome are typically associated with shortened life 53 expectancy, premature disability, and heightened prevalence of cardiovascular disorders, cancer, diabetes, 54and Alzheimer disease as well as multiple other disorders linked to advancing age. 55 ( ¶2) In the jeremiads inspired by obesity, the modest but deeply rooted health advantages of 56 obesity are typically neglected (Table 1). In this paper we add further to the list of advantages of obesity; 57 we review over 20 epidemiology studies of six serious infectious diseases, including tuberculosis, 58 pneumonia, and sepsis, where outcomes are inversely related to body mass index. The consistency of the 59 obesity advantage is especially remarkable because the usual measurements to express adiposity i.e. body 60 mass index (BMI; the weight in kilograms divided by the square of the height in meters) as well as waist 61 circumference or neck circumference are such rough approximations of total body fat or of visceral fat or 62 of metabolic syndrome. The connection between body mass index and the metabolic syndrome in 63 epidemiology studies is further loosened by impressive ethnic differences (Figure 1) [1] and changes in 64 individuals with aging. ...