Metabolic changes make weight loss maintenance difficult, but not impossible

On their own, most individuals are rarely able to lose a substantial amount of body weight and keep it off. Although record numbers of U.S. adults have an elevated BMI, more than 80% of respondents with overweight or obesity told a 2013 Gallup Poll that they had lost a large amount of weight at least once in their life. According to the National Weight Control Registry, adults who pursue weight loss through behavioral treatment programs typically decrease their body weight by 7% to 10% during the first year of participation but maintain only about a 5% loss by a year or so after treatment. Only about 20% of U.S. adults have been able to maintain their weight loss.

“The expectation that many people have that just going on the diet is going to lead to much weight loss over the long term is one of the biggest barriers we have for successful treatment of obesity,” Scott Kahan, MD, MPH, FTOS, director of the National Center for Weight and Wellness and medical director of the Strategies to Overcome and Prevent (STOP) Obesity Alliance at the George Washington University Milken Institute School of Public Health, told Endocrine Today. “Unrealistic expectations like this make it that much more challenging for health care providers, that much more frustrating for patients, and increase the likelihood of people falling off.”

As weight decreases, unavoidable physiologic changes lead the body to defend a higher weight by ratcheting up appetite and expending less energy. This process serves to keep weight relatively stable or at a small upward trajectory throughout adult life in people with normal BMI but often prevents those with obesity from reducing to a normal weight.

“The pathophysiology of the disease is such that obesity protects obesity,” W. Timothy Garvey, MD, FACE, professor of medicine and chair of the department of nutrition sciences at the University of Alabama at Birmingham, told Endocrine Today.

Although these metabolic adaptations are extremely difficult to resist, attempts at long-term weight-loss maintenance are not futile, obesity experts said. Success requires adherence to a structured lifestyle of choosing healthy behaviors — including a good measure of willpower — and may incorporate medications.

“The message I give patients is this is not an easy thing to do,” Daniel H. Bessesen, MD, professor of medicine and endocrinology fellowship program director at the University of Colorado Anschutz Medical Campus, told Endocrine Today. “This is almost like trying to get someone to drink less water than they want or to breathe less. It’s hard to do, but humans can do hard things if they are highly motivated to do them.”

Metabolic adaptation

The common notion that an individual can lose 1 lb of body weight by consuming 3,500 fewer calories or expending that amount in physical activity is incorrect because such calculations fail to account for adaptations of metabolism as people lose weight. Adults who lose more than about 5% of their body weight experience a decline in metabolic rate and an increase in appetite that make it difficult to continue losing weight or even to maintain weight loss.

As weight decreases, resting energy expenditure also decreases, not only because there is less body mass to be maintained, but also because energy efficiency increases as weight is lost, Bessesen said. A person who loses 50 lb expends less energy with exercise, in part, because they weigh less, but they also expend fewer calories at the same absolute workload than they did before they lost weight.

An even larger adaptation occurs on the energy intake side of the equation, according to Kevin D. Hall, PhD, senior investigator in the integrative physiology section in the Laboratory of Biological Modeling at the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH.

“For every kilogram of weight that you lose, your appetite increases so that you want to be eating more than you were before your diet or weight-loss program by about 100 calories per day,” Hall told Endocrine Today. “[This] is a pretty big effect, compared to the 20 to 30 calories a day slowing of metabolism or total energy expenditure that you experience when you’re losing weight.”

Even more discouraging, these adaptations to weight loss are likely to persist, according to Bessesen. “These people ... are fighting a physiologic battle that is going to stay there for the rest of their life,” he said.

Little clinical evidence about long-term metabolic adaptation is available, but in a study of participants in the weight-loss reality TV show The Biggest Loser, Hall and colleagues found that the decreased metabolic rate in response to extreme weight loss did not normalize over time despite partial weight regain. Most participants had regained a large amount of their lost weight 6 years after the competition, although there was wide variation and a mean weight loss of 17.6 kg compared with starting weight. The researchers found that the metabolic rates of The Biggest Loser contestants fell much more than expected at the end of the weight-loss competition, and their metabolic rates remained persistently low after 6 years.

“I don’t know if that’s something odd that happened with The Biggest Loser folks,” Hall said in reference to the extreme exercise plans and weight loss in this group. “Other investigators have measured the same sort of metabolic adaptation during the active weight-loss period in much less severe interventions, but there’s a lot of debate about what happens after restabilization at a lower weight.”

Search for mechanisms

Most experts agree that metabolic adaptation is a normal physiologic response to weight change, but what allows a person to become obese in the first place, “that’s been the holy grail of the obesity field,” Michael Schwartz, MD, the Robert H. Williams Endowed Chair in Medicine and director of the Nutrition Obesity Research Center at the University of Washington, told Endocrine Today.

According to Schwartz, weight is maintained through a feedback loop. The body stores fat as its main fuel source, and these adipocytes secrete the hormone leptin — and likely others — which signals neurons in the hypothalamus to activate pathways that regulate food intake and energy expenditure. The greater the amount of body fat, the more leptin is produced to signal the brain to promote negative energy balance — to reduce food intake and increase energy expenditure or both. If body fat is lost, less leptin is produced, and the brain promotes positive energy balance by increasing appetite and conserving energy.

In normal-weight individuals, the system works so well that they maintain their body weight over decades with little increase or decrease.

“Most people cannot weigh less than they would normally weigh simply because that’s what they want,” Schwartz said. “If you lose weight beyond about 5%, you are going to engage responses designed to return you to the weight you started from. Those responses are powerful and persistent over time.”

In obesity, Schwartz said, “The hypothesis is that the system controlling body weight, that is, reading that negative feedback in the form of leptin and other signals ... behaves as if it’s receiving the same signal in an obese individual as in a lean individual. In other words, the system doesn’t know that you’re obese.”

Working with rats, Schwartz and colleagues discovered that inflammatory activation of microglia and astrocytes in the arcuate nucleus of the hypothalamus blocked normal leptin signaling and led to disruption of the weight-control circuits.

“You need a higher leptin signal than normal to achieve the same effect to overcome that block,” Schwartz said. “And the only way to have a higher leptin signal is to have a higher fat mass, because leptin is secreted in proportion to fat.”

The glial responses were observed within days of starting the animals on an obesogenic diet, before obesity occurred.

Not a hopeless project

Obesity results from complex interaction among genetics, the environment and personal behaviors (see accompanying story on this page).

Although the work of Schwartz and others suggests that obesity prevention might be more successful than weight-loss maintenance without surgery, many people sustain substantial weight loss in the long term.

The National Weight Control Registry has been tracking successful weight-loss maintainers since 1994. The more than 10,000 enrollees, 80% of whom are women, have maintained at least a 30-lb weight loss for a year or longer, but some participants have lost up to 300 lb and some have maintained their weight loss for more than 60 years.

Nearly all registry members report maintaining weight loss through lifestyle modifications: 98% watch what they eat, 90% exercise about an hour each day, 62% watch television less than 10 hours per week and 75% weigh themselves at least weekly.

Kahan begins treating obesity by managing expectations.

“It’s important to be open and honest with patients and have a transparent discussion,” Kahan said. “It’s not easy to lose weight, and expectations that most people have of the amount of weight they’re going to lose is wildly overinflated.”

He frames the discussion in terms of the health benefits patients can see with a relatively small weight reduction, in particular, better control of diabetes and hypertension, better liver function and often much improved mobility and quality of life.

“Usually after the fact, people agree with that, once they’ve experienced the benefits” he said. “Before the fact, you tell someone you can lose 5% of your weight, and most people chuckle at that or even get angry.”

Bessesen emphasizes motivation to change.

“Does a change in physical activity and habits align with something that’s important to them?” Bessesen asks patients. “Is weight something this person is going to invest some time, energy and money in? The more the lifestyle changes align with some basic values that are important to people, like being more functional and able to do things with their family, then they will invest the energy in it.”

Schwartz puts the pursuit of weight loss in terms of limiting future obesity.

“The risk of obesity is persistent, and just because you are obese doesn’t mean that you are not at risk for becoming more obese,” he said. “There’s a rationale for a healthy lifestyle no matter what your weight is.”

Successful strategies must include long-term support along with permanent, structured lifestyle interventions and often use of FDA-approved drugs for weight loss and weight maintenance.

Lifestyle changes are key

Lifestyle interventions begin with a reduced-calorie meal plan that is consistent with a patient’s personal and cultural preferences. The macronutrient composition is less important than adherence, according to Garvey.

His clinic supports patients on meal plans as varied as low-carbohydrate, low-fat, Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets, which can be tailored based on personal preferences. Patients may opt for a very low-calorie diet — 800 to 900 calories per day — that includes meal substitutes, such as shakes and bars, for the first month or two. Normal food is gradually introduced for one or more meals per day.

“Many patients like to keep the meal replacements for one or two meals,” Garvey said. “It adds structure to the diet, it takes the guesswork out of it, and there is always good nutrition built into these products.”

Physical activity is another component.

“Increasing physical activity in the short run doesn’t lead to that much extra weight loss,” Kahan said. “But long term, we have data showing that a lot of people have done better at keeping the weight off when they increase their activity over long periods of time.”

The Biggest Loser participants who maintained the largest weight losses were those who exercised the most, according to Hall.

“Even though increased physical activity was the best predictor of who was able to keep the most weight off in The Biggest Loser, the exercise per se may actually slow down metabolism,” Hall said. “The people who had the greatest slowing of metabolism during the active weight-loss period, also were the ones who were most successful at losing the most weight.”

Garvey said he believes that increased activity has metal health benefits that help with long-term adherence.

“It makes you feel better, and increases your morale,” Garvey said. “It can help with comorbid depression and low self-esteem. It has benefits that translate into the overall lifestyle intervention program that are important.”

Medications for maintenance

The final component of long-term weight maintenance is strategies that encourage lifelong adherence to a reduced-calorie meal plan and exercise program. Garvey includes self-monitoring of weight and addressing mental health issues, such as depression and binge-eating syndrome, as well as the newer drugs that help reduce appetite.

“In our country, we underutilize these medications tremendously,” Garvey said.

Medications approved for weight loss since 2012 include lorcaserin (Belviq, Eisai), a serotonin 2C receptor agonist; phentermine-topiramate (Qsymia, Vivus), a combination sympathomimetic amine anorectic plus an antiepileptic drug; naltrexone-bupropion (Contrave, Orexigen Therapeutics), an opioid antagonist plus an aminoketone antidepressant; and liraglutide (Saxenda, Novo Nordisk), a GLP-1 receptor agonist.

These agents work to counter the metabolic changes that can lead to increased appetite. Patients who respond to them report feeling as if they need less effort to resist overeating, Bessesen said.

Liraglutide, in particular, has data supporting long-term use specifically for weight maintenance; and although the monoamine reuptake inhibitor sibutramine is no longer marketed, studies with that drug serve as proof of concept for similar agents, Kahan said.

“If you first lose weight by diet, exercise, counseling, etc, and only then you take the medication to help keep it off, these studies are positive showing that this strategy works very well,” Kahan said. “People who take the medication after they lose the weight keep it off much better than people who only receive counseling after weight loss.”

Future targets

Obesity is a chronic disease, just like diabetes and hypertension, Garvey said, and just as patients with those conditions must continue pharmacologic treatment, so must those with obesity. “We need to learn how to use these drugs over the lifetime,” he said.

Bariatric surgery is an option for patients with BMI at least 40 kg/m² or for those with BMI at least 35 kg/m² with obesity-related comorbid conditions, according to the American Society for Metabolic and Bariatric Surgery. Surgical interventions are the only way most people can keep off large weight reductions of 20% or more, Schwartz said. Although many patients regain some of the weight after surgery, the metabolic adaptation to weight loss is attenuated.

“As we make progress with understanding the underlying mechanisms [of obesity], you can begin to imagine how using healthy lifestyle with a medical approach that blocks the glial activation, for example, would be a major breakthrough,” Schwartz said.

“If you can understand the underlying mechanisms, you can use that [understanding] for more informed effective treatment — drug discovery and, ultimately, treatment interventions. ... It’s just that obesity is a lot more complicated than maybe any other endocrine disease,” he said. – by Jill Rollet

• References:
• Fothergill E, et al. Obesity. 2016;doi:10.1002/oby.21538.
• Gallup. Personal Weight Situation. Available at: news.gallup.com/poll/7264/personal-weight-situation.aspx. Accessed April 30, 2018.
• Graham TJ, et al. ACSM Health Fitness J. 2011;doi:10.1249/FIT.0b013e31820b72b5.
• National Weight Control Registry. NWCR Facts. Available at: www.nwcr.ws/Research/default.htm. Accessed April 27, 2018.
• Schwartz MW, et al. Endocr Rev. 2017;doi:10.1210/er.2017-00111.
• Wadden TA, et al. Int J Obes (Lond). 2013;doi:10.1038/ijo.2013.120.

• For more information:
• Daniel H. Bessesen, MD, can be reached at the Anschutz Health and Wellness Center, 12348 E. Montview Blvd., Aurora, CO 80045; email: daniel.bessesen@ucdenver.edu.
• W. Timothy Garvey, MD, FACE, can be reached at the University of Alabama at Birmingham, Director, UAB Diabetes Research Center, 1720 Second Ave. South, Birmingham, AL 35294; email: garveyt@uab.edu.
• Kevin H. Hall, PhD, can be reached at Building 12A, Room 4007, 12 South Drive, Bethesda, MD 20892; email: kevinh@niddk.nih.gov.
• Scott Kahan, MD, MPH, FTOS, can be reached at National Center for Weight Loss and Wellness, 1020 19th St. NW, Suite 450, Washington, D.C. 20036; email: kahan@nationalweight.org.
• Michael Schwartz, MD, can be reached at University of Washington, South Lake Union Campus, 850 Republican St., UW Mailbox 358055, Seattle, WA 98109; email: mschwart@uw.edu.

Disclosures: Bessesen reports he serves on a data safety monitoring board for EnteroMedics. Garvey reports he is a consultant for the American Medical Group Association, Merck and Novo Nordisk. Kahan reports he has consulted for Novo Nordisk, Orexigen and Vivus. Hall, Kahan and Schwartz report no relevant financial disclosures.