What causes obesity? To many people, the answer is obvious. Obesity is caused by eating too much food and/or not getting enough exercise. Obese and overweight people lack “personal responsibility” or have become addicted to food the same way that one becomes addicted to smoking. The alarming worldwide rise in obesity over the past several decades is due to an increasing lack of personal responsibility, perhaps as the result of the lure of bad eating habits and lack of exercise caused by increasing affluence.
This “common-sense view” of obesity is gaining increased currency, as the result of rising health care costs and health insurance premiums, and the drive to rein in these costs. Even some leaders of health insurance and health care providers blame the lack of personal responsibility of the obese for rising health care costs, and advocate using education, exhortation, and “economic incentives” (i.e., penalizing the obese, perhaps by raising their insurance rates) to combat obesity.
However, genetic and physiological research shows that obesity is a disease, not just the result of bad habits. This research has shown that weight is as heritable as height, and has uncovered a set of complex pathways that control energy balance. According to this “enlightened, science-based view”, the worldwide epidemic of obesity is mainly the result of the interaction between a set of social and economic factors (e.g., increased consumption of meals away from home, decreased prices for unhealthy versus healthy food, and decreased requirements for physical activity at work and for transportation) and genetic factors that make some people more susceptible to obesity than others. In the industrialized world, between 60%–70% of the variation in obesity-related phenotypes such as body mass index (BMI) and hip circumference appears to be heritable. People who undertake even the best systematic weight-loss programs are fighting a set of complex physiological pathways that have evolved to combat starvation. These pathways are only partially understood. Most people who manage to lose a significant amount of weight usually regain it over the medium to long term.
The “enlightened, science-based view” is discussed, for example, in our 2008 book-length report on obesity, and in our October 25, 2009 article on this blog. It is also the view of pharmaceutical and biotechnology companies that are developing antiobesity drugs, and the view of basic researchers who are endeavoring to understand pathways that control energy balance and may render individuals subject to obesity and its comorbidities.
Recent genetic studies provide an increasing amount of evidence that favors the “enlightened, science-based view”. For example, researchers have recently identified associations between common variants in the fat mass and obesity-associated (FTO) geneand increases in BMI and waist circumference in several human populations. The FTO gene codes for a 2-oxoglutarate-dependent nucleic acid demethylase. It is expressed in the hypothalamus, a region of the brain that is involved in regulation of feeding and energy metabolism. Hypothalamic FTO appears to be involved in the regulation of energy intake, but not feeding reward. However, the mechanism of action of FTO in control of energy balance is not understood.
The findings on FTO adds to the large amount of evidence for the genetic determination of obesity, and thus for the “enlightened, science-based view” of this condition. Many academic and corporate researchers, including most of the recognized leaders in obesity research, believe that continued basic and translational research on the genetic and molecular basis of obesity will lead to new therapeutic strategies to control this disease.
Now comes a new research report that might result in a “game-changing view” of obesity, published in the 9 April issue of Science. Andrew Gewirtz (Emory University, Atlanta, GA) and his colleagues studied T5KO mice, which are genetically deficient in TLR5, a Toll-like receptor (TLR) that recognizes bacterial flagella as a ligand and is expressed on the surface of both intestinal epithelial cells and cells that mediate innate immunity. TLRs are receptors that recognize conserved molecules derived from bacteria or viruses, and activate immune responses, thus serving as a first line of defense against infection. Researchers hypothesize that TLR5 in gut mucosa may have a role in maintaining a harmonious relationship between the host and the complex population of intestinal microbes.
The researchers found that as compared to wild-type mice, T5KO mice showed increased fat mass and body weights 20% higher than wild-type mice, and features of the metabolic syndrome (insulin resistance, elevated serum cholesterol and triglycerides, and elevated blood pressure). The adipose tissue of TK5KO mice exhibited higher production of the proinflammatory cytokines interferon-γ and interleukin-1β. T5KO mice were also hyperphagic, eating 10% more than wild type mice. When the researchers restricted the food fed to T5KO mice to the amount eaten by wild type mice, they no longer exhibited increased fat mass or body weight, or abnormalities in blood glucose and lipids. However, they still were insulin resistant.
When both wild type and T5KO mice were fed a high-fat diet, both populations showed increases in fat mass and body weight, as well as elevated levels of blood lipids. However, unlike wild type mice, T5KO mice fed a high-fat diet has blood glucose levels of greater than 120 milligrams per deciliter, and thus were diabetic. The T5KO mice also showed inflammatory infiltrates in their pancreatic islets, and hepatic steatosis. Thus a high-fat diet exacerbated the metabolic syndrome shown by T5KO mice.
The researchers asked whether other mediators of the immune system were involved in the induction of metabolic syndrome shown by T5KO mice. Deletion of the Toll-like receptors TLR2 and/or TLR4 in T5KO mice had no effect on their metabolic syndrome. Deletion of RAG1 (which is necessary for development of the T and B cells of the adaptive immune system) also had no effect. However, deletion of the intracellular protein MyD88 in T5KO mice resulted in normalization of the metabolic syndrome. Since MyD88 is necessary for signaling by all TLRs except for TLR3, and for signaling by receptors for interleukin-1β and interleukin-18, this suggests that another TLR and/or signaling by one or both of these two cytokines might be necessary, together with TLR5 knockout, for induction of the metabolic syndrome.
Since TLR5 is expressed in the gut mucosa and recognizes bacterial flagellin, the researchers tested the hypothesis that the metabolic syndrome seen in T5KO mice might be due to alterations in the population of gut microbes as the result of the loss of TLR5 function. When the researchers treated newly weaned T5KO mice with broad-spectrum antibiotics, the number of gut bacteria was reduced by 90%. This treatment eliminated the metabolic syndrome, hyperphagia, and obesity of the T5KO mice. Conversely, when the researchers transplanted the gut microbiota of T5KO mice to the guts of wild type germ-free mice, the recipient mice exhibited hyperphagia, obesity, metabolic syndrome, and elevated levels of proinflammatory cytokines in their adipose tissue. Analysis of the gut microbiota of T5KO and wild type mice showed that the species composition of the gut bacteria of T5KO mice was significantly different from that found in wild type mice.
These results suggest that obesity and metabolic syndrome may be caused at least in part by genetically determined differences in interactions between the innate immune system of the gut mucosa and the intestinal flora. Obesity-prone individuals may develop a gut microbe population that interacts with the immune system in such a way as to promote obesity. Interactions between gut microbes and innate immunity that promote obesity might result in changes in proinflammatory cytokines and in adipokines in adipose tissue (and perhaps also in muscle and liver) that not only cause increased inflammation and metabolic syndrome, but also disrupt signals within the brain that promote appetite control and energy balance. They further suggest that treatments that target intestinal microbes may be effective therapies for obesity and its sequelae.
These conclusions are based on a mouse model, which may or may not have much to do with the pathogenesis of human obesity. However, there is evidence that the the composition of gut bacteria differs between obese and nonobese humans in similar ways to differences in gut flora between obese and nonobese mice. Colonization of germ-free mice with the gut microbiota of obese mice results in significantly greater increase in body fat than colonization with the gut microbiota of lean mice. Researchers obtained evidence that gut microbes from obese mice have an increased ability to harvest energy from food than do the gut bacteria of lean mice. They therefore hypothesize that this extra energy harvest may help promote obesity, in both mice and humans. But it is also possible that obesity-associated gut microbe populations might promote systemic low-grade inflammation that contributes to the pathogenesis of metabolic syndrome and obesity.
In addition to the research report itself, two commentaries on the report were published in April 2010–one by Darleen A Sandoval and Randy J Seeley (University of Cincinnati in Ohio) and the other by Ping Li and Gökhan Hotamisligil (Harvard School of Public Health, Boston MA). Drs. Sandoval and Seeley conclude that the new findings may allow researchers to develop means of preventing obesity by manipulating gut microbe-immune system interactions by such means as drugs, diet, or probiotics. Drs. Li and Hotamisligil take a more nuanced view. (Dr. Hotamisligil is a leader in the study of pathways involved in control of energy metabolism, and their relationship to inflammation and metabolic diseases.) They state that the results seen in T5KO mice were relatively mild, and thus probably cannot account for the full spectrum of metabolic dysfunction seen in obesity. They essentially see the gut microbiota/innate immunity interaction as one factor in the complex networks that determine obesity and metabolic syndrome. They call for more research into the gut microbe/immune system relationship, and believe that such research will lead to a better understanding of metabolic syndrome.
What if the gut microbiota/immune system interaction is a major factor in obesity, at least in a subpopulation of obese subjects? That would resemble the situation with peptic ulcers. Peptic ulcers were once considered a disease of “lifestyle”, due to the “type A personality”, “a stressful lifestyle”, and/or eating spicy foods. However, eventually Drs. Barry J. Marshall and Robin Warren of Australia discovered that a high percentage of ulcers were caused by chronic inflammation due to infection with Helicobacter pylori. It is now accepted that this bacterium is responsible for 60% of gastric ulcers and up to 90% of duodenal ulcers. Treatment involves administration of combinations of antibiotics together with a proton pump inhibitor and sometimes a bismuth compound.
The majority of scientists and physicians resisted the idea that peptic ulcers were caused by a microbial infection for a long time. Dr. Marshall even had to do and publish a self-experiment, drinking a culture of bacteria from a patient, before the scientific community would accept his findings. Finally, In 2005, Drs. Marshall and Warren received the Nobel Prize in Physiology or Medicine for their [re]discovery of H. pylori and its role in gastritis and peptic ulcers.
The role of gut microbes in obesity and metabolic syndrome may not be simple as the role of H. pylori in gastric ulcers. Nevertheless, this hypothesis deserves intensive investigation, and it may lead to a game-changing view of metabolic disease and eventually important new treatments. In any event, it would be wise for the scientific, medical, and policy communities to take the advice of Dr. Jeffrey Friedman (Rockefeller University, New York, NY), who is arguably the founder of the “enlightened, science-based view” of obesity and metabolic syndrome, with his breakthrough discovery of the hormone leptin in 1994: “A war on obesity, not the obese.”
