More Misleading Information for Patients

February 15th, 2015 No comments »

So, “misleading” is a pretty strong term. Unfortunately, misleading advice to patients, the public and policy makers is so widespread in the obesity field as to acceptable as the norm, not the exception. For example, recently several obesity researchers (David Allison, Diana M. Thomas and Steven B. Heymsfield) commented on a “Patient Page” in JAMA. In the page, Dr. E. Guth w rote, “A total of 3500 calories equals 1 pound of body weight…This means if you decrease (or increase)your intake by 500 calories daily, you will lose (or gain) 1 pound per week. (500 calories per day X 7 days= 3,500 calories.)”

Allison et al pointed out that “over time the calorie deficit slowly closes as energy expenditure gradually declines with the loss of body mass and metabolic adaptations. Unlike the linear weight loss pattern described by Guth, actual weight loss follows a smooth curve and then plateaus at the new energy requirement level…For example, if a 5’6”, 30-year-old woman weighing 180 lb and consuming 2622 calories daily reduced her intake by 500 calories per day, the 3,500 calorie rule would estimate her weight loss at 1 year to be almost 52 lb. The validated dynamic model predicts a weight loss of 12 lb. At 10 years, the 3,500-calorie rule would yield a negative body weight, whereas the weight loss prediction of the dynamic model would stabilize at a 31-lb loss after 3 years.

(The validated dynamic model is available at http://www.pbrc.edu/researc-and-faculty/calculators/weight-loss-predictor.)

Interestingly, Dr. Guth replied with a curt toss of this point, stating that the Patient Page was intended to provide “easily understood information and accessible guidelines for the majority of patients.” Dr. Eve Guth acknowledges that since most patients regain their weight after loss, “it is unlikely that an individual would continue to restrict calories for 10 years, ultimately resulting in a negative weight.” (ED: also known as death.) After dumping on patients too ignorant to starve to death, Dr. Guth dumps on primary care providers who are seeking to meet patient demands for simple advice involving minimal effort on their part, oh, and by the way, there isn’t good reimbursement either for misleading patients.  Dr. Guth’s perception is that this is all between the physician providing simplistic advice to an overweight or obese patient too dumb or ill-informed to know better. Small wonder that physicians don’t counsel and patients don’t think doctors know what they are talking about. Moreover, these  simplistic strategies spill into policy-making, implying that weight loss is easy and, with the right incentives, maintainable over the long-term.

For more information on

More accurate weight loss calculators:

http://www.downeyobesityreport.com/2012/02/the-calorie-out-math-is-all-wrong/

http://www.downeyobesityreport.com/2012/05/the-new-math-of-obesity/

Adaptive thermogenesis effect on weight loss:

http://www.downeyobesityreport.com/2014/01/where-is-your-new-years-resolution-or-where-did-i-put-my-adaptive-thermogenesis/

 

Rose Frisch, Pioneer in body fat research, passes away

February 14th, 2015 No comments »

Rose Frisch, a pioneering researcher on body fat and reproduction has died. A New York Times obituary pays tribute to her contribution which laid the theoretical basis for the discovery of leptin.

 

How Obesity is Changing the Environment

January 5th, 2015 No comments »

The association of overweight and obesity with type 2 diabetes is one of the strongest in the scientific literature. Well known to many is that the drug, metformin, is a front-line treatment for type 2 diabetes. But now come researchers with something unexpected: high levels of metformin in the Great Lakes is affecting the fish population and may be changing the expression of genes in some fish. According to a report in MedScape Today, researchers at the School of Freshwater Sciences at the University of Wiscon-Milwaukee found such high levels of metformin in the waters of Lake Michigan. There are some 180 million prescriptions written for diabetes drugs in 2013, a $213 billion market. Metformin has about 70 million prescriptions written in 2013.

The level of metformin, measured in fathead minnows in the lab, were enough to disrupt gene expression in the endocrine system of male fish but not females. The males were producing biochemical that are associated with female minnows. It has been assumed that the volume of water in the Great Lakes would dilute such a drug. The new study casts doubt on that assumption.

 

New Insight on the Effect of Time on Genetic Expression

January 5th, 2015 No comments »

A New Year’s Eve story in the New York Times reported on a new study about a well-studied gene, FTO, which is strongly correlated with the development of obesity.  Previous research had established that, on average, one copy of a variant of FTO tended to have an extra 3.5 pounds. Persons with two copies of the gene have an extra 7 pounds, significantly increasing the risk of becoming obese.

The new study, published in the Proceedings of the National Academy of Sciences, indicates that this effect did not exist before World War II. Using the longitudinal data from the Framingham Heart Study the researchers led by James Niels Rosenquist of Massachusetts General Hospital found a “robust” relationship between birth cohort and the genotype-phenotype correlation between the FTO risk allele and Body Mass Index (BMI) with an observed inflection point for those born after 1942. The authors observe that “genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance.”

 

The Memory of Starvation

November 13th, 2014 No comments »

Movie buffs may remember the 1999 movie A Bridge Too Far and the book by Cornelius Ryan of the same title on which it was based. The book and movie told the tale of an Allied operation to liberate Holland and achieve a bridgehead over the Rhine and into Germany. It failed. The book and movie only dealt with the military aspects of Operation Market-Garden, as it was called. Left out was what happened afterward.

The Nazi regime was going to punish the Dutch for their support to the combined English-American invasion of Holland. So they cut off food supplies to Holland in the winter of 1944-5. Thousands starved. Subsequently, researchers found that women who were pregnant during this period had offspring who were more prone to obesity, diabetes and cardiovascular disease and who were also smaller than those who were not exposed to the “Hunger Winter.” But, they also found that the grandchildren of those women had similar health problems. This helped establish the field of epi-genetics, i.e., that there were inheritance factors other than genes which might respond to early environmental stimulus, or the lack thereof. Now, in perhaps a groundbreaking paper, Dr. Oded Rechavi and colleagues may have found the mechanism. By studying worms exposed to starvation conditions, they observed a mechanism they call, ‘small RNA inheritance’ that enables worms to pass on the memory of starvation to at least three generations, perhaps more. At the very least, the study demonstrates that we still have a lot to learn about the gene-environment interaction as it affects the development of obesity and that those who say obesity is not genetic  only show they don’t know much about genetics or obesity.

 

Big Problems Undercut Research Findings

May 21st, 2014 No comments »

Research is the key to understanding obesity and developing accurate and effective treatments, prevention approaches and public policies. However, researchers have found significant problems in observational studies  and the interpretation of research results.

One study has found that statistical results in psychological studies are biased toward researcher’s own expectations and authors often dismiss data inconsistent with their own hypothesis. Bakker and Wicherts found that, of 281 articles examined, around 18% of the statistical results are incorrectly reported and around 15% contained at least one statistical conclusion that proved to be incorrect. Errors were often in line with researchers’ expectations. Errors were higher in journals with low impact factors.

A study published in Radiology by Ochodo and colleagues examined the diagnostic accuracy in studies found errors in journals with high impact factors. Errors included over-interpretation, overly optimistic abstract, discrepancy between study aim and conclusion, conclusions based on selected subgroups, failure to include a sample size calculation, failure to state a test hypothesis as well as failure to report confidence Intervals.

In a study published in Statistics in Medicine in January 2014, Schuemie and colleagues found that a majority of observational studies would declare statistical significance when no effect is present. At least 54% of findings with p <0.05 are not actually statistically significant.

Closer to home, Jayawardene and colleagues found significant discrepancies in self-reported height and weight among adolescents in the National Youth Physical Activity and Nutrition Study, 2010. Underweight students under-reported height and over-reported weight while overweight and obese students over-reported height and under-reported weight. Weight loss behaviors, both healthy and unhealthy were associated with BMI underestimation while fast food consumption and screen time were associated with overestimation. These problems can work their way into more general views of obesity. For example, many people believe that obesity is much higher in the Southeastern United States but Allison and colleagues, using direct measurements, found that the West North Central and East North Central Census division have higher prevalence. Likewise, Hattori and Sturm found that approximately one in six to seven obese individuals were misclassified as non-obese due to underestimation of BMI.

One of the most disturbing research flaws was a paper published in 2013 by Hand, Hebert and Blair which found that across the 39 year history of the NHANES, energy intake data for 67% of women and 59% of men were “not physiologically plausible.” The authors stated, “The confluence of these results and other methodological limitations suggest that the ability to estimate population trends in caloric intake and generate empirically supported public policy relevant to diet-health relationships from US nutritional surveillance is extremely limited.”

The Body Mass Index (BMI) has been problematic for some time, resulting in misreporting and misclassification. (See article)  Another study found that 29% of subjects classified as lean and 80% of individuals classified as overweight according to BMI had a body fat percentage within the obesity range. Cardiometabolic risk factors were higher in lean and overweight by BMI-classified subjects with percent of body fat within the obesity range. A study using bioelectrical impedance analysis to estimate body fat found that BMI-defined obesity was present in 19% of men and 25% of women, while percent body fat-defined obesity was present in 44% of men and 52% of women. Again BMI had a high specificity but low sensitivity. They found a BMI cutoff of > 30 misses more than half of people with excess fat. They speculate that this might explain the unexpected better survival in overweight/mild obese patients.

Klesges and colleagues examined 77 papers in the important area of prevention of childhood obesity from 1980 to 2008. They found all studies lacked full reporting of generalizing elements including the intervention staff, the implementation of the intervention content, costs and program sustainability. Somewhat similar results were found in 27 publications covering community-based interventions for diet, exercise and smoking cessation. Dzewaltowski et al found that while 88% reported participation rates among eligible members of the target audience, only 11% reported the “adoption” rate among eligible community-based organizations or settings. They also found few studies reported on the representativeness of the participants. Few reported whether individuals maintained the behavior change or whether organizations maintained or institutionalized interventions.

These disturbing results come amid profound doubts arising in several areas, not only psychological science, but  cancer research where several large pharmaceutical have reported that many studies had results which could not be replicated. Concerns go back to a paper by JP Ioannidis, “Why most published research findings are false.”  Ioannidis was an author of another paper which found that many observational studies published in the New England Journal of Medicine, JAMA and the Annals of Internal Medicine made clinical practice recommendations without stating the need for a randomized clinical trial.

In 2010, Graham Colditz noted that, “Prevention trials recruit large numbers of healthy participants, offer them a therapy and then follow them over many years because the chronic diseases being prevented are relatively rare. With substantial noncompliance (often in the range of 20% to 40% over the duration of the trial), an intention-to-treat analysis is no longer unbiased, but rather gives a biased estimate of the effect, typically underestimating the magnitude of the association that is seen in observational studies in which those participants who have had exposure to a particular lifestyle component are compared with those without such an exposure. “

Tajeu et al reported that, in the peer-reviewed obesity literature, of 855 articles examined, 7.3% presented odds ratios. Of these, 23% were presented incorrectly. Overall, almost one-quarter of the studies presenting odds rations misinterpreted them. Menachemi et al reviewed 937 papers in the nutrition and obesity literature found that nearly 10% had overreaching conclusions.

These problems are only amplified when the university or journal press office writes up a press release and then, in many cases, the media boil down the findings to a 10-second sound bite. Funding agencies, journals and professional societies need to more diligent in making sure that obesity research is conducted at the highest level of scientific accuracy for many lives and millions of dollars may be affected.

 

Where is Your New Year’s Resolution? Or, Where did I put my Adaptive Thermogenesis?

January 17th, 2014 No comments »

It’s mid-January: do you know where your New Year resolution went? You know the one about losing weight.

So maybe you are losing the weight you put on over the holidays? Maybe you are underway with a good weight loss program? Maybe you have already given up? No matter what your status, there is something you should know:

The human body is programmed to defend its weight and, when it senses weight loss, it starts cutting down its energy expenditure…big time!

Let’s talk about energy expenditure or “EE”. About 65-70% of calories burned each day are used to keep the routine body functions going, e.g. pumping blood, working the lungs, kidneys and liver. About 10% are used up in thermogenesis or the digestion of food. The rest, about 20%, is spent by the muscles in physical activity.

As far back as 1987, researchers compared the daily resting metabolic rate (RMR) of obese women who had lost weight and were no longer obese with women who were  never obese. The researchers found that the post-obese women had metabolic rates approximately 15% lower than the never-obese group and they ate less.

So, metabolism in persons who have lost weight and those who are lean may not be the same.

Exercise and the heat value of food are skewed against those with obesity. In one experiment, 10 lean women and 10 women with moderate obesity were measured during periods of eating and exercise. Eating before exercise increased the exercise metabolic rate in lean women by 11% but only by 4% in women with obesity. The thermic effect of food was 2.54 times greater during exercise than at rest for the lean group, but only 1.01 greater for the women with obesity.

In a now classic 1995 paper by Jules Hirsch, Rudy Leibel and Michael Rosenbaum at Columbia University found that when a body loses weight, it adjusts by reducing its energy expenditure. This effect is so strong that an obese person who went from 250 lbs to 200 lbs would have to consume about 30% less than a 200 lbs person who had not lost weight just to maintain the same weight. This extra-reduction in food intake would have to continue indefinitely if the person were to maintain their weight loss.

This process, called by researchers “Adaptive Thermogenesis” can persist after active dieting for up to a year in one study.  In an experiment involving subjects with severe obesity who were on a program of diet restriction and vigorous physical activity, researchers saw dramatic weight loss (over 30%) but a slowing of the resting metabolic rate (RMR) “out of proportion to the decrease in body mass, demonstrating a substantial metabolic adaption.”

Some researchers considered adaptive thermogenesis a major factor in the plateauing one sees in dieters, the increase in hunger and the eventual regain of lost weight. In one study of short-term severe diet and exercise subjects, the ‘metabolic compensation’ was seen as a major contributor to the less-than-expected weight loss. Individuals will have different adaptions to weight loss. In some cases, the effect can be significant. Tremblay et al state, “Indeed, as it is difficult to prescribe food intake that imposes an energy deficit exceeding 700-800 kcal per day to obese individuals, the decrease in energy expenditure in response to weight loss can entirely compensate for this prescribed deficit.”

Others are less sure. They seem to accept adaptive thermogenesis but see measurement problems and questions as to its utility in weight management.

The point is that our bodies contain a defensive mechanism against the disease of obesity. Until we realize that our strategies for prevention and treatment are like a novice chess player going up against a Grand Master. The point is: obesity is a lot tougher than our simplistic policy prescriptions assume.

The quandary of obesity has been expressed by Tremblay Chaput and Doucet in their article “Obesity: a disease or a biological adaption? An Update,“ Additionally, substantial body fat loss can complicate appetite control, decrease energy expenditure to a greater extent than predicted, increase the proneness to hypoglycaemia (low blood sugar) and its related risk towards depressive symptoms, increase the plasma and tissue levels of persistent organic pollutants that promote hormone disruption and metabolic complications, all of which are adaptations that can increase the risk of weight regain. In contrast, body fat gain generally provides the opposite adaptations, emphasizing that obesity may realistically be perceived as an a priori biological adaptation for most individuals. Accordingly, prevention and treatment strategies for obesity should ideally target the main drivers or root causes of body fat gain in order to be able to improve the health of the population.”

 

Hunger, Prader-Willi Sydrome and differences between the brains of persons at normal weight and with obesity

January 15th, 2014 No comments »

A New York Times report today by Andrew Pollock details the efforts of researchers and drug companies to unravel the mysteries of Prader-Willi Syndrome. Prader-Willi Syndrome is marked by insatiable appetite and obesity. Patients often slow metabolisms, intellectual difficulties and autistic behavior. (For more information see the Prader-Willi Syndrome Association website.) The condition is known to be caused by missing segments on chromosome 15. While Prader-Willi is a genetic disease, it is not necessarily found in families. 70% of cases are due to a deletion in chromosome 15 from the father; deletion from the maternal side is responsible for about 20%.  This is known as genomic imprinting where the gene turns on or off depending on which parent contributes it.

Drug developers Ferring Pharmaceuticals, Rhythm, Arena Pharmaceuticals (which sells Belviq, an FDA approved drug for weight loss) and Zafgen are looking at drugs for the condition. Zafgen is releasing results of a small clinical trial today.

While Prader-Willi is a rare condition and is well-understood regarding its genetic cause, research on the syndrome is helping to open up research on the fundamental aspects of hunger.

One of the great gaps in public and policy-makers understanding of obesity is the role of hunger, driven by powerful networks within our bodies. Hunger is clearly one of the most powerful of human emotional states as it involves existential survival, much like the inability to breathe or drowning. In my experience, many persons with obesity report nearly constant states of hunger which our food-laden environment is almost universally able to slake. But reports from individuals are a poor substitute for research. Now, in the past decade, science has filled in the gaps.

After a meal, appetite is suppressed; after energy expenditure hunger is increased. Those sensations, satiety and hunger, are caused by changes in nutrients and hormones, including PYY, GLP-1, ghrelin, leptin and insulin circulating in the body. In normal physiology, the hypothalamus balances the food intake with the metabolic requirements. This system works, usually, with great precision. This appetite process is called homeostatic. Non-homeostatic food control is driven by sight, smell, taste, habits, emotional and economic influences. The brains areas involved in nonhomeostatic food control include the hippocampus, the amygdala, insula, striatum and orbitofrontal cortex. The two systems are not independent but highly integrated.

Recent research points to understanding that higher food intake in persons with obesity is due, probably in substantial part, to differences in how the brains of  persons with obesity respond to food cues compared to  persons at “normal” weights.

Researchers using techniques such as functional Magnetic Resonance Imaging (fMRI) are mapping the physiological networks of hunger and are understanding  why we get hungry and why maintaining weight loss is so hard. FMRI allows scientists to locate specific areas of the brain which show responses to specific stimuli. Thus they can compare obese and lean subjects in different conditions. (For an explanation of the use of fMRI studies in appetite regulation see this article from de Silva and colleagues and from which this illustration is taken.

Using fMRI, researchers at Emory University have identified areas in the brain identified with taste and the reward system that ‘light up’ when subjects just looked at pictures of appetizing food.  Meanwhile, other researchers, also using fMRI, found different reactions to pictures of high-calorie foods between men and women. When healthy subjects were given injections of ghrelin, fMRI scans showed increased brain activity in response to pictures of food and were correlated with self-reported hunger ratings. (Ghrelin is a peptide hormone that stimulates hunger and food consumption.) Just in October, a study was published showing that images of high fat foods produced stimulation of the brain’s reward network in Hispanic females.

It isn’t only pictures of food which tweak the brain. Subjects with obesity differed from lean subjects in which area of the brain responded to food aromas. The brain areas affected by food aromas are similar to those affected by addictive substances, like alcohol.

In short, individuals prone to weight gain and obesity have altered neuronal responses to food cues in brain regions known to be important in energy intake regulation and these differ from lean person’s responses.

Of great concern is when such differences occur? A study from the University of Kansas Medical Center used fMRI on children and adolescents, ages 10-16, half at a healthy weight and half with obesity. They found the obese group showed greater activation to food pictures both before and after a meal than the healthy weight group. Unlike the healthy weight group, the obese group’s response to food stimuli did not diminish significantly after eating. The authors concluded, “This study provides initial evidence that obesity, even among children, is associated with abnormalities in the neural networks involved in food motivation, and the origins of neural circuitry dysfunction associated with obesity may begin in early life.”

This understanding of obesity has great implications for the prevention and treatment of obesity and for the establishment of effective public policies.