Microbial Influences on Weight Regulation

| April 26, 2007 | 0 Comments

by Louis J. Aronne, MD, FACP, and Kathy Keenan Isoldi, MS, RD, CDE

The increased prevalence of obesity has undoubtedly been influenced by a multitude of factors. Some factors are obvious, such as an increased consumption of calories and decreased usage of energy. There are, however, more subtle instigators in the development of obesity. For example, sleep debt, a shift in the population’s ethnic composition, and medications, among other factors, have shown an association with the increased body weight of our population.1 Scientists have recently presented data suggesting two new, unconventional culprits that may affect weight gain.2,3 The type of microbes that inhabit the human gut and exposure to certain viruses have emerged as potential catalysts in the development of obesity.2,4


It is estimated that there are up to 100 trillion microbes in the human gut living a mutualistic existence within the human body.4 Microbes allow for the extraction of calories from indigestible polysaccharides in the diet. Gut microbes are so plentiful and influential, that they are described as a metabolic organ that communicates with and complements many metabolic systems in humans.4

To investigate the influence gut microbes exhibit on body weight, researchers raised mice in a germfree environment and compared weight and insulin resistance with conventionally raised mice. Conventionally raised mice were exposed to microbes from birth. Researchers reported that within 8 to 10 weeks, the conventionally raised mice had 42 percent more body fat, even though they ate 29 percent less chow than germ-free mice. Additionally, germ-free mice were later exposed to microbes from conventionally raised mice, and within 14 days experienced a 60-percent increase in body fat and an increase in insulin resistance, without any increase in food intake.6

To explain the increase in weight after exposure to microbes, researchers point to the microbial enhancement of absorption of monosaccharides from the gut. This increased absorption serves as a promoter of de novo hepatic lipogenesis. In addition, fasting-induced adipocyte factor (FIAF), a member of the angiopoietin-like family of proteins, is suppressed in conventionally raised mice. FIAF serves as a circulating lipoprotein lipase inhibitor, and when suppressed—as it is in conventionally raised mice, it allows for the deposition of liver-derived triglycerides in adipocytes.3,4,7

Another mechanism that sheds light on how microbes may promote weight gain is explained via AMP-activated protein kinase (AMPK) activity.4 AMPK activation exerts influence over glucose homeostasis, fatty acid metabolism, glycogen metabolism, and ultimately, overall energy homeostasis. Once activated, AMPK-mediated phosphorylation events switch cells from active ATP consumption to active ATP production. Backhed and colleagues exposed germ-free and conventionally raised mice to a typical Western-style, highfat, sugar-rich diet and measured phosphorylated AMPK levels.4 The germfree mice had increased skeletal muscle and liver levels of phosphorylated AMPK. Therefore, researchers suggest that germ-free animals are protected from diet-induced obesity by increased AMPK activity, which serves to activate a cascade of events that counters weight gain. Increased AMPK activity, along with increased levels of FIAF, appear to work complementarily yet independently to counter fat deposition.4

Gut microbes are dominated by two main groups, the Bacteroidetes and the Firmicutes.3 Interestingly, variations in the density of colonization of these two microbe varieties have been associated with variations in weight.3 Researchers have found that mice with a genetic mutation of the gene for leptin (ob/ob mice) have a 50- percent reduction in gut Bacteroidetes and a significantly greater proportion of Firmicutes relative to lean mice.3 Similar proportions of gut microbes have been found in humans. In a study of 12 humans followed over a one-year period, obese subjects had fewer Bacteroidetes and more Firmicutes than did lean controls. Once started on a calorie-reduced diet (either fatreduced or carbohydrate-reduced), the relative abundance of Bacteroidetes increased and the abundance of Firmicutes decreased, regardless of diet-type.8 Researchers believe that the observed link between obesity and gut microbial ecology may eventually lead us to new approaches for the treatment of obesity.8


Other microbial agents have also been implicated in obesity. Viralinduced obesity is not a new concept. Infectobesity is a term coined by researchers who have been gathering data and support for an association between viral infections and obesity for more than two decades.2 Several viruses have been identified as having a link to obesity causation in animals and humans.2,9

There are four animal viruses and a scrapie agent that have been reported to induce obesity in animals. In 1982, Lyons published the first report of viral-induced obesity in animals. He reported that canine distemper virus (CDV) produced obesity in mice. Bernard, et al., later demonstrated downregulated expression of the leptin receptor in the hypothalamus of CDVinfected obese mice, suggesting this as the probable pathway leading to weight gain.2 The second obesity-inducing virus discovered was the Rous-associated virus-7 (RAV-7). Exposure to RAV-7 resulted in growth stunting, hyperlipidemia, and obesity in infected chickens. RAV-7 infected chicks were found to have decreased levels of thyroid hormone, which is implicated as the mechanism causing obesity and dyslipidemia in infected animals.2 The third obesityinducing animal virus identified was the Borna disease virus (BDV). BDV exposure in rats produces lympho-monocytic inflammation of the hypothalamus and hyperplasia of the pancreatic islets. After exposure to BDV, the rats exhibited elevated serum glucose and serum triglycerides levels, as well as obesity.2 The fourth virus causing obesity in animals was identified in India. SMAM- 1 avian adenovirus created an epidemic causing the death of thousands of poultry in India. Surprisingly, these infected animals were found to have excessive body fat. Experimental trials with threeweek- old chicks inoculated with SMAM-1 resulted in excessive visceral fat, low levels of cholesterol and triglycerides, and pale and enlarged liver and kidneys in the infected chicks. A group of uninoculated chicks sharing the same pen as the infected chicks also developed the obesity syndrome.2 Finally, the scrapie agent (the ME7 stain) induced obesity in infected mice. Performing an adrenalectomy prior to exposure to the virus prevented ME7-induced obesity. Hence, researchers suggest that scrapie ME7 targets the hypothalamicpituitary- adrenal axis.2

At the time of the discovery of the obesity-inducing affect of SMAM-1, there were no known cases of avian adenoviruses infecting humans. However, Dhurandhar, et al.,10 subsequently examined the blood of 52 obese humans for the presence of antibodies to SMAM-1, indicating prior exposure. Antibody positive subjects were indeed found. The subjects who were antibody positive for SMAM-1 had significantly higher body weights, 15- percent lower serum cholesterol and 60-percent lower triglyceride levels than the antibody negative group.

Dhurandhar’s work on obesityinduced viral exposure continued in the US with Richard Atkinson. SMAM-1 was not available for experimentation in the US, and the group was not allowed to import the virus from India. After reviewing the 50 possible adenoviruses available for research in this country, the group decided to begin testing with adenovirus 36 (Ad-36) because it does not cross-react with most other human adenoviruses.13,15 In humans, adenoviruses are associated with acute upper respiratory tract infections, enteritis, and conjunctivitis.2

In separate experiments, mice, chickens, and nonhuman primates were inoculated with Ad-36. In each study, the infected animals exhibited excessive body weight and low serum levels of triglycerides and cholesterol, similar to the findings from animals infected with SMAM-1.2,11-13 Experiments with hamsters revealed similar weight gain results in the Ad-36 infected animals; reduction in cholesterol levels was not evidenced in this short, five-week study. However, a significant elevation in serum LDL-cholesterol and reduction in HDL-cholesterol fractions were reported. The potentially atherogenic lipoprotein metabolism following exposure to Ad-36 is a question of concern, as hamsters exhibit a lipid metabolism similar to humans. To date, the effect on lipoprotein fractions of humans exposed to Ad-36 is unknown.14

To test for exposure to Ad-36 and investigate its influence on weight status in humans, Atkinson and Dhurandhar investigated the presence of serum antibodies in overweight (BMI>27Kg/m2) and lean subjects at three sites in the US (Florida, Wisconsin, and New York).

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