July 2016 Issue

Weight Loss Resistance — Myth or Harsh Reality?
By Carrie Dennett, MPH, RDN, CD
Today's Dietitian
Vol. 18 No. 7 P. 32

Learn about the possible explanations for why weight loss sometimes eludes clients' best efforts.

What happens when you have a patient who's trying to lose weight but can't? The tendency is to assume "user error," and certainly there are times when patients aren't forthcoming—with themselves or their health care providers—about what and how much they're eating. Research shows that adherence to a weight loss plan is a significant factor in weight loss success, but what if your patient is doing everything right, eating healthfully, and exercising regularly, and the number on the scale isn't going down?

Is it possible that their body is truly resistant to weight loss? There are a number of science-based reasons why that might be the case. As with chronic disease, and obesity itself, it's likely that weight loss resistance is multifactorial. This is a different phenomenon from having difficulty maintaining weight after a weight loss, although there is some overlap.

Fuel Efficiency and the Thrifty Genotype
One of the hopes that came with the completion of the human genome-mapping project in 2003 was that scientists could identify a gene or genes that explained why some people develop obesity. While a number of genes that may contribute to weight gain or resistance to weight loss have been identified, genetic variation alone doesn't explain the obesity epidemic, and our genes themselves haven't changed significantly over the time period that we've seen an increase in the obesity rate. However, many key environmental factors have changed over this same period, most notably shifts in diet and physical activity patterns.1

Some individuals seem to have greater susceptibility to our society's obesogenic food and activity environment, which promotes calorie-dense foods and sedentary activities, so if genes aren't responsible for much of the variance we see in BMI, other factors must be at play.2 One possibility is epigenetic mechanisms, which allow our behaviors and environment, and those of our parents and grandparents before we were born, to influence the activity and expression of our genes without alterations in the genes themselves.1

David Katz, MD, MPH, FACPM, FACP, an associate professor of public health and founding director of Yale University's Yale-Griffin Prevention Research Center, says both genetics and epigenetics play a role in how fuel efficient we are. "Essentially, throughout all of human history, starvation has been a threat; obesity, not so much," he says. "We are, in general, a fuel-efficient species, because if we weren't, given our ecological niche, we wouldn't be a species at all—we would be gone."

Fuel efficiency, or metabolic thrift, was a valuable trait when food was scarce, but may contribute to obesity in an environment where calorie-dense foods are readily available. "It's quite clear that there are whole populations, like the Pima Indians and the Samoans, who are extraordinarily fuel efficient, and thus prone to obesity and weight loss resistance," he says.

As for the rest of us, Katz says that there's considerable interindividual variation in fuel efficiency and tendency to gain weight. "Those at the extreme—who can function best on subsistence fare—are the very ones most prone to gain weight easily and lose it with extreme difficulty. We're just beginning to learn about the genes and pathways involved."

Individuals Aren't Averages
Mathematically, weight loss should be simple and easily achieved with an energy deficit, but often it's not. Weight loss—either starting or maintaining—is difficult on biological, behavioral, and psychological levels for many people. Simply eating less isn't enough, nor does adjusting macronutrients seem to be the answer, when you look at average weight loss among participants in weight-loss interventions.3

Although low-carbohydrate diets produce better short-term weight loss than low-fat diets, when you look at average final results across studies, there's no significant difference. This led many researchers to conclude that it's calories, not macronutrients, that count, but this shift in thinking ignores two things, says Christopher Gardner, PhD, a research professor of medicine at Stanford Prevention Research Center. One is that not all carbs or fats are the same, and "low" may represent varying percentages. The other is the fact that not every individual is average. Even though one weight loss diet may have the same average results as another diet, the difference in individual responses is substantial, Gardner says.3

For example, at least three studies have demonstrated that the weight-loss response to low-fat vs low-carb diets is different for insulin-resistant vs insulin-sensitive individuals. This suggests that low-carb diets may work best for some people, and low fat for others, and that individuals need to be guided to a weight-management plan that's tailored for them, taking their insulin-resistance status into account.3 Gardner points out that no expert would suggest that there's only one drug, at one dose, that works for everyone with a given health condition, so why are we suggesting that very thing for diet?

"Our old school thinking has been, 'What's the one diet, the one way, the one thing?' Then we randomize people, and we miss it," Gardener says. "In this new wave of studies, we're going to have to embrace variability."

This also brings up some interesting questions about genotype. Since mapping the human genome, researchers have linked several single-nucleotide polymorphisms (SNPs) to obesity. (SNPs are the most common type of genetic variation, and most have no effect on health.) Thus, it's possible that some genotypes may be better suited to particular weight loss diets than others.3,4 Gardner says his research team has some promising preliminary data from his current study based on the 609 participants who were genotyped for the approximately 20 SNPs that appear to be responsible for common genetic variants related to how we metabolize dietary fat and carbohydrate.

Myth of the 3,500-Calorie Rule
Weight change is associated with an imbalance between calories eaten and calories expended. This principle is simple, but calculating how a calorie imbalance will translate to weight change is neither simple nor straightforward. One fundamental problem is that calculating the energy deficit needed for an individual to lose weight depends on accurate calculation of how many calories that person needs to maintain their current body weight. There are no methods that will do this with reasonable precision outside of a research setting.5

Another is the flawed—but still frequently used—advice that reducing caloric intake and/or increasing caloric expenditure through physical activity by 500 kcal per day, or 3,500 kcal per week, will result in 1 lb of weight loss per week.5 The so-called 3,500-calorie rule, developed by Max Wishnofsky in 1958, referred to weight loss but is often extrapolated incorrectly to relate to fat loss.6,7 In one of his several papers on the topic, researcher Kevin Hall, PhD, a metabolism expert and researcher at the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, says this 3,500-calorie rule ignores the dynamic physiological adaptations to changes in body weight that alter resting or basal metabolic rate (RMR or BMR) as well as how many kcal we expend during physical activity.5

In fact, most people lose substantially less weight than the amount predicted by the 3,500-calorie rule. At best, weight loss doesn't happen in a linear fashion, but rather shows a curvilinear relationship where weight loss slows with time.8 During low-calorie dieting, hormonal and neural regulatory mechanisms that trigger reductions in BMR, protein turnover, and other metabolic processes develop. The timing of these adaptations isn't exactly clear, but they contribute to plateaus during active weight loss and, in chronic, cyclical dieters, may contribute to weight loss resistance on subsequent attempts.7

"Your body thinks you're starving and it hopes it will save you, so it adjusts and becomes more efficient. This drops your BMR," Gardner says. "One of the things I don't know is if this change is long term."

A recent study published in the journal Obesity assessed weight regain and RMR of 14 competitors on NBC's The Biggest Loser six years after the end of their competition. The participants experienced considerable metabolic adaptation during competition, with average BMR dropping by several hundred kcal, in spite of maintaining lean muscle through intense exercise. In the six years postcompetition, only one competitor kept off the weight, and on average the competitors regained 88% of the weight lost during competition. However, this increase in weight didn't come with a rebound in BMR. The competitors' BMR remained in its lowered state, even continuing to drop slightly, which meant that they required several hundred fewer kcal per day to maintain their weight than they did when they were previously at that weight.9

"The interesting question at hand is whether the protective drop can be minimized so that it doesn't work quite so much against you," Gardner says. His research team is completing a study designed to examine whether different people do better on different diets, not just in terms of absolute weight loss but also in terms of BMR protection.

"We know that we have a lot of people with a similar degree of body fat but a different metabolic rate," Gardner says. "The idea is that some people might do better on one diet while others do better on a different diet, but does that appear to be due to minimization of the protective drop in metabolism, or are their other factors such as how people respond to different macronutrient rations (satiety, fat storage, etc)?"

Gardner and his research team are attempting to answer that question. They measured BMR at baseline, six months, and 12 months in subjects who were randomized to follow either a low-carb or low-fat diet for one year. It's the same study in which they did genotyping, and analysis is under way. "The theory is that the insulin-resistant ones should be on a low-carb diet, while the insulin-sensitive ones should be on a low-fat diet, potentially."

Gut Microbiome: Your Second Genome
The fact that obesity isn't just about calories in, calories out is perhaps most apparent in people whose bodies resist weight loss. Growing evidence supports the idea that we can't attribute the increased prevalence of obesity solely to changes in the human genome, shifting nutrition habits, or reduction of physical activity in our daily lives.10 An alternative explanation may be in a different genome: our microbiome.

Genetic variations do contribute to obesity and cause differences in energy storage and expenditure, but it appears that this may have more to do with the genome—or microbiome—of our gut microbiota (the bacteria and other microbes that live in the gastrointestinal tract, especially the large intestine or colon).11 Our body has about 10 trillion of its own cells, but our microbiota has about 100 trillion cells. This also means that our 20,000 or so genes are greatly outnumbered by the genes in our microbiome.12

One reason that variation in our gut microbiota may be more significant than genetic variation when it comes to susceptibility to obesity is that our microbiota interacts more directly with our environment.1,2 In weight resistant patients, it's possible that microbes in the gut may act as an "endocrine organ" that contributes to obesity.12

Research suggests that the gut microbiota plays an important part in how many calories we extract from our food, how we store them, and how we burn them.10,11,13,14 In some rodent studies, the gut microbiota was shown to regulate the animal's ability to harvest energy for food, as well as play a role in fat storage.1,15 It's therefore possible that humans predisposed to obesity may have gut microbial communities that promote more efficient extraction and/or storage of energy from a given diet.1,15,16

Interest in the role of the gut microbiota in obesity began in earnest about 10 years ago with studies by Ley16 and Turnbaugh17 uncovering the first suggestions of an obesity phenotype based on a particular microbiota ecosystem.1 The "obese gut microbiota" is associated with less bacterial diversity, different ratios of key bacteria, and alterations in the bacterial genes and metabolic pathways that are associated with how we harvest nutrients from food. Obese individuals also have been found to have a higher proportion of a type of bacteria in their microbiota that's also seen in both dieters and individuals with anorexia, suggesting that this bacteria is part of the body's adaptation to low-calorie intake.13

Obese mice have a gut microbiome that's rich in genes that code for enzymes that metabolize carbohydrates; this means that the microbes can extract more kcal from the diet.13 To put that in perspective, the human microbiome may contain upward of 60,000 carbohydrate-degrading enzymes, while the human genome has only about 17 carb-degrading enzymes in the gut, none of which will degrade polysaccharides—complex carbohydrates containing more than 10 saccharide molecules.18

Intestinal microbes affect energy balance through the metabolites they produce, including short-chain fatty acids (SCFAs).19 SCFAs are produced when microbes ferment otherwise-undigestible carbohydrates, and this is one of the beneficial effects of fiber. Many studies have linked dietary fiber and the resulting SCFAs to protection from diet-induced obesity.18 The mechanisms are complicated and not completely understood, but it appears that, depending on the microbial population, production of SCFAs may promote obesity, in part by increased energy harvest, or protect against weight gain, by increasing satiety and promoting insulin sensitivity and fatty acid oxidation.12,20-22

What comes first, obesity or an obese microbiota? Despite what we know about the association of specific microbiota species with obesity, it's unclear if the human gut microbiota actually causes obesity.1,11 Currently, most evidence suggesting that it can comes from animal research.1 Numerous experiments have shown that germ-free mice receiving a transplant of "obesity" gut microbiota (aka fecal transplant) gained significantly more fat mass than mice receiving the "lean" gut microbiota; the evidence suggests that the gut microbiota has an active role in shaping metabolism and possibly inducing obesity.1,2,23,24

Fecal transplants have been used in humans to treat antibiotic-resistant Clostridium difficile infections, but it's unclear whether gut microbiome transfer could lead to significant weight loss, partly because of extremely limited human research on the subject.12 One six-week human trial found that transplanting microbiota from healthy lean men into men with metabolic syndrome resulted in increased insulin sensitivity but no weight loss.1,25

Coping With Weight Loss Resistance
What can dietitians do when presented with a patient who appears to be resistant to weight loss? Indirect calorimetry can provide an idea of whether the patient's RMR is unusually low. A history of chronic dieting with large weight swings also could suggest metabolic impairment. When weight loss seems uncertain, or unlikely, dietitians can provide counseling and education on the benefits of good nutrition and enjoyable physical activity for health even when weight is taken out of the equation. This can include eating foods that nurture beneficial gut microbiota, such as fiber-rich plant foods and fermented food rich in probiotic bacteria.

— Carrie Dennett, MPH, RDN, CD, is nutrition columnist for The Seattle Times and speaks frequently on nutrition-related topics. She also provides nutrition counseling via the Menu for Change program in Seattle.


References

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4. Qi Q, Bray GA, Smith SR, Hu FB, Sacks FM, Qi L. Insulin receptor substrate 1 gene variation modifies insulin resistance response to weight-loss diets in a 2-year randomized trial: the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial. Circulation. 2011;124(5):563-571.

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18. Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 2014;20(5):779-786.

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20. Conterno L, Fava F, Viola R, Tuohy KM. Obesity and the gut microbiota: does up-regulating colonic fermentation protect against obesity and metabolic disease? Genes Nutr. 2011;6(3):241-260.

21. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54(9):2325-2340.

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23. Louis S, Tappu RM, Damms-Machado A, Huson DH, Bischoff SC. Characterization of the gut microbial community of obese patients following a weight-loss intervention using whole metagenome shotgun sequencing. PLoS One. 2016;11(2):e0149564.

24. Goodrich JK, Waters JL, Poole AC, et al. Human genetics shape the gut microbiome. Cell. 2014;159(4):789-799.

25. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(4):913-916.

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