Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Monthly Archives: June 2010

Is it good to be overweight (but not obese)?

While researching the material for the June 11 2010 article on obesity, I ran across the recent work of Katherine M. Flegal and her colleagues at the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC). Dr. Flegal has long been a leading obesity epidemiologist, and led the research that first identified the increased prevalence of obesity in the United States beginning in the 1980s.

Dr. Flegal’s recent work has been based in large part on the most recent data from the National Health and Nutrition Examination Survey (NHANES), and on long-term data from NHANES between 1960 and the early 2000s. In 2005, she and her colleagues published a report in the Journal of the American Medical Association (JAMA) on mortality as a function of Federally-defined weight class–underweight, normal weight, overweight, and obese. These categories were determined on the basis of the body mass index (BMI), with underweight at <18.5, normal weight at 18.5-24.9,  overweight at 25-29.9, and obesity at >30.  Subsequently, in 2007, Dr. Flegal and her colleagues published a report in the JAMA analyzing excess deaths in the underweight, overweight, and obese classes by cause (e.g., cardiovascular disease, diabetes, cancer, etc.).

Dr. Flegal has published other reports relevant to her analyses in these two papers between 2005 and 2010, and has lectured widely on her findings.  Her research was also discussed in a New York Times article in 2005, a 2007 article in the British newspaper The Independent, and in a January 2010 interview in the Association for Psychological Science Observer.

The surprising conclusion of Dr. Flegal’s research is that people in the overweight class have a lower risk of death than those in either the normal weight or the obese class. According to the 2005 study, obesity is associated with about 112,000 excess deaths per year (with most deaths [about 82,000 deaths] concentrated in the extreme obesity class, BMI >35), and underweight is associated with about 26,000 excess deaths per year, but overweight is associated with preventing 86,000 excess deaths per year. (“Excess deaths” refers to the number of deaths per year as compared to the normal weight class).

According to the 2007 study, underweight was associated with significantly increased mortality due to noncancer, non-cardiovascular disease (CVD) causes, but obesity was associated with associated with significantly increased mortality due to obesity-associated cancers, CVD, diabetes, and kidney disease. Thus excess deaths in the underweight and the obese classes vary by cause. Overweight was not associated with either increased or decreased deaths due to CVD, and overweight was not associated with excess deaths due to obesity-associated cancers. However, overweight was associated with a significantly reduced number of excess deaths due to noncancer, non-CVD causes.

Dr. Flegal and her colleagues found that the association of mortality with BMI appears to be much weaker in the most recent surveys as compared to earlier ones. In the most recent data, the association of overweight and mild obesity with risk of death appears to be weak and not statistically significant. This suggests that the association between mortality and weight has been decreasing with time, perhaps due to improvements in medical treatments and in public health. The results of other researchers confirm this hypothesis, and indicate that better management of the risk of death from CVD (e..g, the use of preventive measures such as blood pressure medications and statins, as well as better management of heart attacks via such procedures as angioplasty and stent placement) is responsible for the decreasing risk of obesity-associated death.

The other interesting issue is the risk of weight-related mortality and age. The association  of mortality with weight decreases in older people, especially for those over 70, with the overweight group again having a lower risk of death than the underweight and the obese. Since most people die when they are over 70, this may account, at least in part, for the reduced risk of death in the overweight group in Dr. Flegal’s studies.

Dr. Flegal’s analysis of population weight data over time leads her to dispute the term “obesity epidemic” that most researchers and commentators in the field (including me) have been using. The prevalence of obesity had been stable between 1960 and 1980, but then increased markedly between 1980 and 2000. This increase is what has been referred to as an “epidemic”, since it was expected to continue. However, the increase in prevalence of obesity appears to have diminished since 2000. Moreover, limited data going back to the Civil War suggests that weight in the American population has been increasing since that time, and increasing at a slower rate in recent decades than in the latter half of the 19th century. Dr. Flegal therefore sees obesity as endemic, rather than epidemic.

As might be expected, Dr. Flegal’s conclusions have generated a lot of controversy. Many researchers do not believe the findings, in some cases on the basis of their own earlier studies. Others are simply reluctant to go against the received wisdom that excess weight is a major health hazard, and perhaps the biggest public health problem facing the United States and many other countries. Many researchers note that Dr. Flegal’s studies measure only mortality, not the incidence of such diseases as diabetes and CVD. This is a valid criticism, calling for more epidemiological research. However, many epidemiologists note that Dr. Flegal’s methodology and data are solid, and that she and her colleagues are well respected in their field.

Dr. Flegal’s studies indicate that the designation of obesity and overweight as America’s biggest health problem, and the main cause cause of the rise in health care costs–as discussed in our June 11 2010 blog post–may be overblown. The emphasis for most overweight and moderately obese people may need to be exercise and diets that promote health, whether patients lose weight or not. Given the difficult that most overweight or obese people have in losing weight and keeping it off over the long term, this may be a more realistic approach.

What is a “diet that promotes health”? What is considered “healthy” changes over time, as the result of new research as well as other factors. It is not the purpose of this blog to prescribe or discuss different diets. There are many, many blogs–not to mention books, television programs and other media–that do that. A good place to start, however, might be the work of Walter Willett. (Dr. Willett has disputed the findings of Dr. Flegal’s research, which indicates the level of complexity and disagreement in the obesity field.) Diet and exercise issues should of course be discussed with one’s doctor, but informed patients will usually get better results than uninformed ones.

For those of us in the pharmaceutical and biotechnology industry, the controversies about weight and diet affect the enterprise of drug discovery and development, especially in the metabolic disease and CVD fields. Drugs for such conditions as diabetes and dyslipidemia, as well as antiobesity drugs, are indicated as “adjuncts to diet” or “adjuncts to diet and exercise”. Clinical studies do indicate that these drugs work best when combined with diet and exercise. However, which diet and exercise regimens might be best for various groups of patients, and which diet and exercise regimens might best potentate the efficacy of a drug for various groups of patients, is called into question by the results of Dr. Flegal’s research and the debate over them in the obesity research community. And if weight-associated mortally has been decreasing with time due to improvements in medical treatments, we need to keep up the good work, and develop improved treatments and preventives for such diseases as diabetes and its complications, and for CVD.  (It is the complications of diabetes that are responsible for the greatest level of mortality and disability due to diabetes, as well as the bulk of diabetes-related health care costs.) These new drugs should address unmet medical needs in the metabolic disease and CVD fields.

Health care policy makers should also stop blaming the overweight and the obese and their “lack of personal responsibility” for the woes of the health care system. As we discussed in our June 11 article, this is true whether Dr. Flegal’s conclusions are valid or not.

Can gut bacteria cause obesity?

Fatmouse_1What 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.”