The Biology of Obesity

Educational Objectives

The goal of this program is to improve the treatment of diabetes. After hearing and assimilating this program, the clinician will better be able to:

1. Educate patients about the roles of various factors that affect weight regulation.
2. Use combination therapies to increase rates of response in patients with obesity.

Summary

Overview: Obesity is a chronic disease that requires long-term treatment. Decision making and recommendations for lifestyle interventions, pharmacotherapy, or weight-loss surgery are facilitated when evolution of the disease is considered.

Drivers of obesity: Weight gain occurs when calorie intake exceeds energy expenditure. However, many other contributors, including social and genetic factors, the environment, and the biologic makeup of the individual, play a role in the pathogenesis of obesity.

Biologic regulation of body weight: The brain is the center that regulates food intake, expenditure of energy, and processing of nutrients. The regulation of these processes determines the amount of adipose tissue, which produces the hormone leptin. In turn, this sends feedback to the brain about the stores in the adipose tissue.

Muscle, liver, and bone communicate the metabolic needs of the body to the brain, and the sensory organs transmit information about food availability in the environment.

Set-point theory: Murine studies published decades ago showed that rats receiving an energy-dense diet gained more weight than those receiving a regular diet, whereas those subjected to caloric restrictions lost weight. However, once the energy-dense diets and calorie-restricted diets were stopped and the rats were allowed to self-regulate, the previously overfed and underfed animals returned to the expected body weight for their age.

Studies conducted on humans showed that when participants were overfed and gained 10% of their body weight, they burned ≈500 more calories than when they maintained their baseline weight. Conversely, a 10% weight loss decreased the number of burned calories. These results support the theory that the human body usually returns to a preset body weight.

In a series of studies published in 2011, individuals who lost ≈15 kg while following a calorie-restricted diet for 8 to 10 weeks gained back ≈50% of the lost weight over a period of one year, during which they did not follow any specific regimens.

In addition, a study that followed participants in “The Biggest Loser” competition showed that after 6 years, most contestants had regained all the weight they had lost. This research suggests that the set point does not change automatically and must be reset.

Weight regain: A forced calorie deficit results in short-term weight loss. If the set point does not change, the calorie deficit leads to physiologic compensation, increased appetite, and reduced expenditure of energy, which in turn reduce adherence and result in an increased caloric intake. Many patients who lose a significant amount of weight initially regain weight due to the action of multiple biologic mechanisms. These must be recognized and addressed in order to prevent weight regain.

Underlying mechanisms: Obesity develops as a result of altered regulation mechanisms that increase appetite and promote weight gain.

Diet: Research has shown that diet chemistry plays an important role in changing the set point for body weight. In a series of studies, animals that were given a processed diet high in fat and sugar content ate more and gained more weight than those who ate a low-fat diet. However, animals in a third group that were given the same amounts of calories as the animals in the low-fat diet group also experienced more weight gain. This phenomenon was attributed to the inflammation around the hypothalamus that was present in those animals. Similar inflammation has been observed in imaging studies of humans. Certain foods have been shown to drive this phenomenon.

A study published in 2016 showed that commercially used emulsifying agents increased the appetite in animals when placed in their water, leading to weight gain. The authors reported that the food additives caused changes in the gut microbiota of these animals, increasing endotoxemia in the gastrointestinal tract. Many low-fat foods contain emulsifying agents, which are added to improve their texture and taste.

Data from a 2-week pilot study showed that participants who ate highly processed foods consumed ≈500 calories in excess compared with those who ate unprocessed foods, although the 2 dietary plans had similar macronutrient and fiber contents. Participants in the 2 groups had a similar protein intake, but the fat and carbohydrate intake differed, leading to a difference in body weight of ≈1.75 kg between the groups over a 2-week period.

Exercise: The effects of exercise include more than calorie burning. A study showed that animals that ate high-fat, processed foods gained more weight than those that ate a regular, high-fiber diet, and presented with inflammation as well. However, exercising on treadmills reduced brain inflammation and weight in the animals exposed to the processed foods. Exercise had a fundamental effect on the metabolism, offsetting the effects of the diet.

Exercise exerts multiple effects on muscle, including changes in muscular hypertrophy, which result in increased expenditure of energy. Additionally, an increase in myokine secretion leads to increased mitochondrial levels in adipose tissue, which increase leptin sensitivity in the brain, decreasing appetite and promoting satiety. The higher mitochondrial levels in the adipose tissue also cause increased expenditure of energy.

Clinicians should encourage healthy behaviors rather than focusing exclusively on counting calories.

Contributors to weight regulation: Many medications used in primary care (eg, sleep aids, antihistamines, β-blockers) may cause weight gain. Other factors that influence weight regulation include nutrient signaling, muscle activation, sleep, stress, and circadian rhythms. The timing of meals is critical because the body has different responses to the same caloric intake at different times of the day. These factors interact with a person’s genetic makeup, age, sex, and developmental phases and affect the regulation of the body weight set point.

Defects in metabolic pathways: Obesity is the result of multiple defects in different metabolic pathways. Evolving research may enable clinicians to pinpoint the various defects that may contribute to the development of obesity.

Physical activity has multiple mechanisms of action and may affect multiple pathways. Medications typically target specific pathways. Gastric bypass surgery also has a number of mechanisms of action, which affect multiple pathways simultaneously.

Heterogeneity of response: Researchers who compared the Atkins, Zone, LEARN, and Ornish diets found that the Atkins diet caused more significant weight loss at 1 year compared with the other diets. However, at the end of 2 years, all diets had similar effects. A follow-up study showed that some participants achieved significant weight loss while following the Atkins diet, while others gained weight with the diet. All of the diets elicited different responses in different participants. In clinical practice, patients who do not respond to a particular diet may achieve weight loss with another dietary plan. This may be the result of better adherence or because the new diet elicits a different physiologic response.

In a 6-month study, postmenopausal women who performed supervised exercise achieved a modest median weight loss. However, some participants had a better response to the regimen.

Variations in response have also been reported with the use of medications (eg, liraglutide) and gastric bypass surgery.

Management strategies: After a lifestyle intervention has been initiated, a second therapy may be added. This may take the form of additional lifestyle changes, medications, or other interventions.

Pharmacotherapy: A medication should be discontinued if the patient does not achieve a minimum weight loss of 5% at 3 months. Monotherapy may be continued when the medication is effective in promoting significant weight loss. If weight loss is over the 5% threshold but not significant, combination therapy is recommended. Clinicians must consider the heterogeneity of response to various treatments.

Combination therapy should always be considered. Obesity is a chronic disease that should be approached and treated in the same manner as diabetes. The efficacy of different combinations is variable. Phentermine-topiramate (Qsymia) has shown additive effects. Other combinations, such as naltrexone-bupropion, have a synergistic effect, conferring more benefit than the 2 separate components. Some combinations do not confer additional benefit. The sibutramine-orlistat combination, for example, has proven no more effective than sibutramine alone. When the mechanisms of action of the 2 components are completely different, the combination has additive effects. Synergistic effects result when complementary pathways are activated.

Sequential therapies are recommended. Patients who do not respond to a first or second treatment may be prescribed a third therapy. Selection should be guided by the reported response rates. Assuming there is little overlap between different therapies, the overall response rate may be as high as ≈56%, ensuring that a majority of patients receive adequate treatment even in the absence of biomarkers that can predict treatment response.

Stepwise treatment approach: Self-directed lifestyle changes constitute the first step in the algorithm. Patients receive information (eg, handouts) and follow instructions to make changes on their own. The second step consists of professionally directed lifestyle changes. Patients participate in formal programs in which they receive support and coaching from exercise physiologists, dietitians, and other therapists, as needed. Additional options include antiobesity medications, weight-loss surgery, and postsurgical combination therapies.

Patients often gain weight after bariatric surgery. The postsurgical management of these patients is challenging. Options include lifestyle therapy combinations and medication combinations.

Key points: The set point of body weight is regulated by precise mechanisms. Short-term weight loss caused by a calorie deficit triggers metabolic mechanisms compensating for this, which leads to weight regain. To achieve long-term weight loss, clinical strategies must evolve beyond the creation of a calorie deficit. Comprehensive lifestyle changes, pharmacotherapy, and bariatric surgery are key tools that may be used to lower the set point and help patients maintain an optimal weight.

The heterogeneity of response to treatment indicates that there are many possible causes of obesity. Sequential therapies may increase response rates and improve outcomes. Treatment regimens that reflect the heterogeneity of response and include combination therapies may help eliminate some of the challenges and limitations of the obesity therapies that are currently available.

Readings

Online Resources

Centers for Disease Control and Prevention: Physical Activity for a Healthy Weight.
https://www.cdc.gov/healthyweight/physical_activity/index.html

The National Weight Control Registry: Research Findings.
www.nwcr.ws/Research/default.htm

Disclosures

For this program, the following was disclosed: Dr. Anderson reported relationships with Amylin Pharmaceuticals (G), Daichi Sankyo Company (B), Eli Lilly and Company (B), Novo Nordisk (B), and sanofi-aventis (A). Dr. Machineni reported relationships with Novo Nordisk (C), Rhythm Pharmaceuticals (A), and Johns and Johnson (C). The members of the planning committee reported nothing to disclose.

A=Advisory panel B=Speakers bureau C=Consultant G=Grant or other research support

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

DI102301

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.