Set-point theory and obesity.

6 Pages • 4,527 Words • PDF • 119.7 KB
Uploaded at 2021-09-24 06:22

This document was submitted by our user and they confirm that they have the consent to share it. Assuming that you are writer or own the copyright of this document, report to us by using this DMCA report button.


METABOLIC SYNDROME AND RELATED DISORDERS Volume 9, Number 2, 2011 ª Mary Ann Liebert, Inc. Pp. 85–89 DOI: 10.1089/met.2010.0090

Set-Point Theory and Obesity Maria Magdalena Farias, M.D.,1 Ada M. Cuevas, M.D., M.Sc.,2 and Fatima Rodriguez, M.P.H.3

Abstract Obesity is a consequence of the complex interplay between genetics and environment. Several studies have shown that body weight is maintained at a stable range, known as the ‘‘set-point,’’ despite the variability in energy intake and expenditure. Additionally, it has been shown that the body is more efficient protecting against weight loss during caloric deprivation compared to conditions of weight gain with overfeeding, suggesting an adaptive role of protection during periods of low food intake. Emerging evidence on bariatric surgery outcomes, particularly gastric bypass, suggests a novel role of these surgical procedures in establishing a new set-point by alterations in body weight regulatory physiology, therefore resulting in sustainable weight loss results. Continuing research is necessary to elucidate the biological mechanisms responsible for this change, which may offer new options for the global burden of obesity.

The set-point theory suggests that the body has an internal control mechanism that is a set-point located in the lateral hypothalamus, which regulates metabolism to maintain weight at a predetermined level. Environmental changes in diet or temperature may be detected by this set-point to maintain fat stores at a certain level by promoting feedback mechanisms.7 These mechanisms include roles and complex interactions between appetite, nutrients, dietary composition, hormones, metabolic rate, neural pathways, brown fat, and many neurotransmitters in the regulation of food intake.8



besity is becoming a global epidemic as the body mass index (BMI), an indicator of relative weight for height [weight (kg)/height (m)2], continues to increase among all age groups1 in most of the developed and developing countries.2 Health expenditures of morbidly obese people (defined as a BMI >40) are estimated to be 81% higher than those for nonobese adults.3 Similarly, obesity affects almost every organ system in the body and is directly associated with increased risk of diabetes, hypertension, dyslipidemia, cardiovascular disease, osteoarthritis, cancer, and depression.4 Obesity is a consequence of the balance between energy intake, energy expenditure, and energy storage. A better understanding of how weight is regulated—how biological, behavioral, and environmental factors interact to affect energy balance and body weight regulation—is necessary in the development of strategies for the prevention and treatment of obesity.5 Observations that body weight is maintained much more stably over long periods of time than would be expected from the wide variations in daily energy intake and that obese people tend to have a rapid regain of lost weight suggest that biological factors are important contributors to body weight regulation.6 Further evidence indicates that manipulating one component of energy balance produces compensatory changes in other components (for example, food restriction produces a decline in energy expenditure).7

Appetite Regulation The hypothalamus is a processing center that integrates signals from the brain, the peripheral circulation, and the gastrointestinal tract to regulate energy intake and expenditure. Within the hypothalamus, the arcuate nucleus contains peptide neurotransmitters associated with appetite. Neuropeptide Y (NPY) and agouti-related peptide (AGRP) are orexigenic (induce feeding), whereas propiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) are anorexigenic (inhibit feeding). Neurons expressing these neuropeptides communicate with each other and with many peripheral signals, including mechano- and chemoreceptors; with nutrients such as glucose, amino acids, and fatty acids; with gastrointestinal (GI) peptide hormones (i.e., cholecystokinin and ghrelin); and with other hormones,


Department of Nutrition and Metabolism, Pontificia Universidad Catolica de Chile, Santiago, Chile. Department of Nutrition, Clinica Las Condes, Santiago, Chile. 3 Harvard Medical School, Harvard University, Boston, Massachusetts. 2


86 including insulin, leptin, and adiponectin to influence appetite level, feeding, and energy expenditure.9 The role of GI hormones in the regulation of appetite has been reviewed. The GI tract is the largest endocrine organ in the body. Gut hormones optimize the process of digestion and absorption of nutrients by a local effect on GI motility and secretion. Many of these gut peptides have shown to influence energy intake. The most studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin, and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake by different mechanisms. Local effects, such as the inhibition of gastric emptying, might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brain centers of appetite control. The median eminence and area postrema in the brain are characterized by a deficiency of the blood–brain barrier. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus, including other energy-regulating centers of the central nervous system. In this way, hormonal signals from the GI may be translated into the subjective sensation of satiety. Additionally, many gut peptides are both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance.10 As physiological mediators of satiety, gut hormones represent an attractive mechanism involved on weight regulation and energy balance.11

Energy Expenditure Total energy expenditure (TEE) is the sum of resting energy expenditure (REE), thermic effect of food (TEF), and physical activity–related energy expenditure (PAEE). The majority of human energy expenditure occurs at rest conditions, corresponding, in most of the people, to 70% of TEE. Studies have also shown that by eliminating the sex differences that occur with the accumulation of adipose tissue, by TEE per unit of ‘‘fat-free’’ or lean body weight, the values between sexes for basal metabolism are essentially the same.7 REE is the energy required by the body to maintain basic physiologic functions such as pumping blood, making hormones, and maintaining body temperature. REE normally increases in conditions such as trauma and infections and in physiological conditions such as pregnancy, establishing a ‘‘new set-point’’ due to impact of the hypermetabolic state.8 TEE is regulated by the brain. Information from the body periphery is carried by an affector to a central controller located in the hypothalamus. The controller integrates and transduces the information into an effect signal to correct any deviation in body weight from its inherent set-point.7 The primary efferent pathway regulating energy expenditure is believed to be the sympathetic nervous system, which innervates the thermogenic brown adipose tissue.8 Brown adipose tissue is important for TEE in the form of thermogenesis (mediated by the ability to dissipate energy by producing heat rather than storing it as triglycerides), due the expression of the tissue-specific uncoupling protein-1 (UCP1). Brown adipose tissue affects whole-body metabo-

FARIAS ET AL. lism, modifies susceptibility to weight gain, and may alter insulin sensitivity. This tissue is present in rodents throughout life. In humans, brown adipose tissue is found primarily in infants and young children, and it has been considered to be essentially nonexistent and without physiologic relevance in adults. However, estimates suggest that if it were present, as little as 50 g of maximally stimulated brown adipose tissue could account for up to 20% of daily energy expenditure in an adult human.12 Animal studies have suggested that expansion and/or activation of brown adipose tissue counteracts diet-induced weight gain and related metabolic disorders, such as type 2 diabetes mellitus. Despite its potential physiologic importance, methods to measure the mass and activity of brown adipose tissue in humans have been lacking and controversial. Recently, combined positron-emission tomography has been used to identify brown adipose tissue in humans, for whom this tissue could potentially be beneficial given its association with both low BMI and low total adipose tissue content.13 However, correlation of these findings with evidence of UCP1 expression or metabolic impact has been inconclusive.13–15

Obesity: Is There Low Energy Expenditure in Obese People? It has been hypothesized that obesity is caused by metabolic or behavioral defects that result in a reduced energy expenditure.16 Many studies have demonstrated that TEE is elevated with increasing BMI. The TEE value for obese people is estimated to be 40% higher than the TEE for nonobese people.17 However, other studies have reported the inability of some obese patients to respond to overfeeding with the normal increase of energy expenditure.18 Evidence suggests that obese people may have individual variations in energy expenditure; some obese patients have increased energy expenditures whereas others have decreased energy expenditures with similar caloric intakes. Therefore, there is no established consensus on whether metabolic rates are necessarily abnormal in obese individuals.16–19

Effect of Calorie Restriction and Regulation of the Weight Gain Studies in animals have shown that after weight loss from calorie restriction, body weight is rapidly regained when they are re-fed ad libitum. A proposed explanation for this finding is that, in response to underfeeding, an adaptive energy conservative mechanism emerges with subsequent lowering of the basal energy expenditure. It has also been reported that an adaptive increase in energy expenditure occurs in rats with overfeeding. The reduction in energy required for maintenance is largely explained by a decline in REE. These adaptations may serve to minimize fluctuations in body weight, supporting the notion that body energy is regulated around a ‘‘set-point.’’20 However, overfeeding results in fewer compensatory changes in energy expenditure than food restriction,21 and the degree of conservation is proportional to the degree of underfeeding. Therefore, we can conclude that our organism is better adapted to protect against weight loss compared to weight gain, demonstrating the efficiency of food utilization, particularly when food resources are scarce.22



In humans, some studies have shown similar results. After a 10% weight gain, TEE is significantly higher. Similarly, TEE is significantly lower at 10%–20% of weight loss. These expected changes in energy expenditure occurred during periods of weight changes.22 In addition, it has been reported that during energy restriction there is a downregulation of REE and sympathetic activity and a decrease of serum concentrations of thyroid hormones.23 It has also been reported that there is a sense of extreme hunger that may accompany weight loss, which, in turn, promotes calorie-dense food intake, further widening the gap between energy output and intake.22 It is unclear whether the speed of the weight loss affects the decrease in TEE, or how long the larger-than expected decrease in TEE will persist after weight loss. Perhaps the body will eventually adjust to the new weight and will be able to preserve the reduced weight. Indeed, some investigators have reported that, in sustained weight loss maintained for a long period, changes in energy expenditure could eventually adjust, not leading to weight regain.23

The ‘‘settling-point’’ theory proposes that weight tends to drift around the level at which the group of factors that determine food consumption and energy expenditure achieve an equilibrium. According to this view, weight would remain stable as long as there are no durable changes in any of the factors that influence it. This theory casts a much wider net than our ‘‘set-point’’ theory, which attributes weight stability to specific physiological processes. Another difference is that ‘‘settling-point’’ theory suggests that if an obese person makes long-term changes in eating or exercising, his or her ‘‘settling-point’’ will drift downward without active resistance from the body.6 Although we consistently believe that there are biological systems that attempt to maintain energy balance, the ability of such systems to defend body weight in the face of increasing unidirectional environmental pressures is limited. The fact that obesity rates have gradually increased might suggest that people with high metabolic susceptibility experienced weight gain first as the environment became more obesigenic.21

Genetic Contribution

Food environment

Results of many studies indicate that genetic factors play an important role on the weight set-point. Metabolic studies in monozygotic twins have demonstrated the importance of genetic contributions to weight gain. Experiments have shown that when unrelated individuals were similarly fed, there was a large variation in the degree of weight gain. However, the amount of weight gain was very similar when monozygotic twins were compared. This finding suggests that there is a significant genetic contribution to metabolic efficiency and regulation of body weight.6 Researchers have elucidated some groups of genes that code for proteins involved in the regulation of satiety and food intake, such as leptin (Ob), the leptin receptor (Ob-R), POMC, and the melanocortin-4 receptor (MC4R). Mutations in some of these genes, although attributed to only few families, have revealed the important role of some genes in the neuronal control of satiety, leaving the food intake as the prime driver in body weight regulation.6 Another line of evidence supporting the role of genetics in body weight regulation has come from comparison of metabolic differences in individuals belonging to different ethnicities. In one study, a group of overweight women was kept on a low-calorie diet until BMI decreased to
Set-point theory and obesity.

Related documents

6 Pages • 4,527 Words • PDF • 119.7 KB

384 Pages • 110,828 Words • PDF • 3.3 MB

7 Pages • 4,002 Words • PDF • 482.8 KB

352 Pages • 154,579 Words • PDF • 1.3 MB

203 Pages • 36,163 Words • PDF • 2 MB

356 Pages • 150,875 Words • PDF • 15.6 MB

13 Pages • 4,122 Words • PDF • 112.9 KB

238 Pages • 76,178 Words • PDF • 10.1 MB

830 Pages • 275,808 Words • PDF • 12.4 MB

673 Pages • 279,984 Words • PDF • 3.1 MB

417 Pages • 147,173 Words • PDF • 9.4 MB

12 Pages • 439 Words • PDF • 669.2 KB