Factors promoting and ameliorating the development of obesity

Physiology & Behavior 86 (2005) 633 – 639

Factors promoting and ameliorating the development of obesity Barry E. Levin 385 Tremont Avenue, VA Medical Center, Neurology Service (127C) E.Orange, NJ 07018-1095, United States Received 5 July 2005; accepted 25 August 2005

Abstract Obesity develops when energy intake exceeds expenditure. A constant neural, metabolic and hormonal ‘‘conversation’’ between the brain and periphery underlies the defense of a given level of adiposity. For the majority of humans, obesity becomes a permanent condition once it develops, possibly because of irreversible changes in the distributed network of specialized ‘‘metabolic sensing’’ neurons which regulate energy intake, expenditure and storage. Plasma leptin and insulin are catabolic hormones whose levels reflect the amount of adiposity and act as signal to metabolic sensing neurons. Obesity-prone individuals have an inborn reduction in their catabolic responses to glucose, leptin and insulin. These raised metabolic and hormonal sensing thresholds precede the development of obesity and predispose individuals to become and remain obese on energy dense diets. High fat diets exacerbate this problem by independently inhibiting central insulin and leptin signaling. In addition, intake of highly palatable diets overrides the homeostatic controls of ingestion because it is regulated by neural systems mediating reward and motivation. The genetic predisposition to become obese is accentuated in offspring of mothers who are obese or nutritionally deprived during gestation and/or lactation or by overfeeding during the early postnatal period. On the other hand, chronic stress and illness can both reduce adiposity, as does gastric bypass surgery. However, for chronic obesity treatment, both exercise and pharmacotherapy help but both must be continued chronically to provide sustained lowering of body weight in obese subjects. Given the permanent upward resetting of body weight set-point that occurs when genetically predisposed individuals become obese, identification of factors that prevent the development of obesity is likely to be the most successful means of ameliorating the current obesity epidemic. Published by Elsevier Inc. Keywords: Brain; Leptin; Insulin; Metabolic sensing; Hypothalamus; Thrifty gene

The main hypothesis of this review is that there is a movable set-point which resides in a distributed network of metabolic sensing neurons in the brain. This set-point determines the way in which energy homeostasis is regulated to defend a specific level of body weight and adiposity. This concept is controversial because there is no one absolute set-point and because some models propose that no active regulation is required to maintain body weight when the input of external variables is taken into account [1,2]. However, none of these models accounts for the fact that body weight and adiposity can increase over the lifetime of obesity-prone individuals but, with few exceptions, can rarely be lowered permanently. I propose here that obesity-prone individuals are born with a genetically raised threshold for sensing a variety of hormonal and metabolic signals which normally inhibit weight gain by acting on the network of metabolic sensing neurons which control

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energy homeostasis. This raised threshold minimizes the impact of inhibitory signals which inform the brain when there is an excess of energy stores. Such a raised threshold is highly adaptive for survival when food is only intermittently available. However, when there is a surfeit of cheap, readily available palatable high fat foods in an environment that discourages physical exercise, this raised threshold promotes obesity in genetically predisposed individuals. Their obesity becomes irreversible because of permanent changes established in the network of metabolic sensing neurons. Many of the phenomena involved in the upward resetting of body weight in obesity can be studied with relative ease in human beings. However, this is not the case with the central neural systems which regulate body weight. These can only be studied with any real precision in animal models. We and others have used the rat model of diet-induced obesity (DIO) where outbred rats are fed a diet relatively high in calorie and fat content [3– 5]. In some strains, approximately half of these rats do not compensate for the increased caloric and fat content of

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the diet by reducing their intake [4 –6] or by increasing their fat oxidation [4] or energy expenditure [7] for up to 3 –4 weeks. By that time, they have become irreversibly obese. On the other hand, obesity resistant rats make the appropriate adjustments in energy intake and expenditure and do not become obese [4,6]. The DIO and obesity-resistant phenotypes are likely to be inherited as polygenic traits since they can be selectively bred with complete fidelity [8] and the DIO phenotype is completely preserved when DIO rats are bred with obesity resistant strains [9]. Thus, the DIO model not only shares a common polygenic mode of inheritance with many forms of human obesity [10,11], but these rats also develop the metabolic syndrome with hypertension, insulin resistance and hyperlipidemia [3,12 – 14]. Once the higher body weight and adiposity are attained, these animals avidly defend their elevated body weight. When calorically restricted for up to 3– 4 months they lower their energy expenditure to conserve energy stores [5,15]. When allowed to feed ad libitum, they quickly increase their intake while maintaining their lowered energy expenditure until they regain their previous level of obesity [5,15]. The first real recognition that the brain even played a role in the regulation of energy homeostasis came when Hetherington and Ranson made lesions in the ventromedial hypothalamus [16]. These animals became hyperphagic and massively obese [17]. On the other hand, lesions of the lateral hypothalamic area produced aphagia [18,19] which persisted until a new lower, defended body weight was reached [19 – 21]. Although it was originally postulated that these two brain areas represented the major ‘‘centers’’ for mediating hunger and satiety [22], it is now clear that the control of energy intake, expenditure and storage is much more complex and is regulated by a distributed network of central neurons [23]. There is a constant dialogue between the brain and periphery. Signals from the periphery are transmitted to the brain via ‘‘hard-wired’’ neural afferents from viscera and the external environment, as well as by hormonal and metabolic inputs. These signals are sensed by specialized ‘‘metabolic sensing’’ neurons which lie in a distributed network of anatomically discrete clusters within areas such as the hypothalamus, striatum, amygdala, nucleus tractus solitarius and groups of medullary serotonin and catecholamine neurons [24 – 26]. Most neurons utilize substrates to fuel their activitydependent metabolic requirements; in contrast, in metabolic sensing neurons, metabolic substrates such as glucose, fatty acids, lactate and ketone bodies and peripheral hormones such as insulin and leptin additionally provide signals that alter membrane potential, firing rate and transcriptional activity [24 – 26]. Metabolic sensing neurons integrate these signals, and their summated activity is transmitted via neural and hormonal outputs to the periphery to alter energy intake, expenditure and storage. Brain neurotransmitters such as norepinephrine, serotonin, GABA and glutamate were first shown to alter energy homeostasis, particularly when injected in the hypothalamus or brainstem [27 – 30]. A host of central neuropeptides which alter energy expenditure has been identified as well. Most of these transmitters and peptides are expressed in the brain and in peripheral organs such as the gut and in the autonomic nervous system [23].

Two of the most important mediators of energy homeostasis in the brain are neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons within the hypothalamic arcuate nucleus, and arcuate NPY and POMC neurons are prototypical metabolic sensing neurons. They alter their activity in response to changes in ambient glucose, fatty acid, leptin and insulin levels [37 – 44] and receive inputs from hindbrain metabolic sensing neurons through which direct visceral afferents relay information from the periphery [23,45 –48]. NPY is one of the most potent anabolic peptides known. When injected into the hypothalamus, it produces hyperphagia associated with reduced energy expenditure and fatty acid oxidation [31,32]. POMC is cleaved to produce a number of neuropeptides including the melanocortin agonist, a-melanoctye stimulating hormone, which is a powerful catabolic effector. Its injection reduces intake and increases energy expenditure [33,34]. NPY and POMC neurons are located in both the hindbrain and hypothalamus [23,35,36]. Those in the hypothalamus have been best characterized with regard to their role in the regulation of energy homeostasis. These anabolic and catabolic neurons lie adjacent to each other at the base of the hypothalamus in the arcuate nucleus and project by parallel pathways to hypothalamic neurohumoral effector areas such as the paraventricular nucleus and lateral hypothalamus [23,26]. Leptin and insulin inhibit NPY and increase POMC synthesis [49,50]. During fasting, leptin and insulin levels fall resulting in increased NPY and decreased POMC production and this establishes a net anabolic tone which drives the individual to seek and ingest food to correct the imbalance [51 – 53]. On the other hand, increased leptin and insulin levels can lead to a net catabolic state which should act as a physiologic brake to limit excess ingestion and promote storage of calories [54]. Of the two, the anabolic drive is the most important for survival of the species since there is little need for a catabolic brake during times of either energy surfeit or scarcity. Rather, when food is only intermittently available, it is in the best interests of the individual to be able to ingest and store as many calories as possible to act as a buffer during later periods of energy deficit. The term ‘‘thrifty genotype’’ describes a hypothetical genetic trait which allows the individual to maximize the ability to consume and store calories [55]. Unfortunately, it is this very trait which predisposes such individuals to become obese when there is a constant excess of food which can be obtained with little need for energy expenditure. Our work in the DIO rats suggests that they possess such a thrifty genotype, which mediates the phenotype by a raised threshold for sensing catabolic signals such as leptin, insulin and glucose [6,56 – 59]. Thus, when the energy density and fat content of the diet are increased, DIO rats overeat and accumulate excess adiposity, despite early increases in plasma leptin and insulin levels which should inhibit this storage [6]. If the energy homeostasis system was completely balanced, this would not be a problem. However, once such individuals become obese, a new higher level of defended body weight is established which cannot be reversed. We have postulated that this is due to neural plasticity which establishes new neural connections similar to what occurs during memory and learning

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[60 –62]. Whatever the cause, once obesity develops in an obesity-prone individual, only chronic interventions are likely to be effective in successfully lowering the maintained body weight for sustained periods. The major exception to this permanent upward resetting of the defended body weight is the hyperphagia associated with intake of highly palatable diets. This type of ‘‘non-homeostatic’’ intake appears to be moderated by reward rather than metabolic control circuits [63,64]. It is not substantially inhibited by normal catabolic signals such as insulin and leptin even though they may decrease the rewarding properties of the diet [65,66]. Such hyperphagia is so profound that the significant increases of resting energy expenditure that such increased intake produces [67] cannot avert the development of obesity [66]. Thus, even obesity-resistant individuals become obese on these diets [15,20,66]. However, unlike the obesity that develops more slowly on less palatable diets which have high energy and fat densities, palatability-driven obesity does not produce a permanent increase in the defended body weight. Even obesityprone individuals voluntarily reduce their intake and rapidly lose weight once the palatability of such a diet is reduced [15,66]. However, these same rats will rapidly and completely regain their lost weight when re-exposed to the same highly palatable diet [66]. This suggests that there may actually be a different set-point for regulating reward-mediated intake and that such a set-point resides in a network of neurons which is separate from those that regulate the metabolic aspects of energy homeostasis [64,66]. 1. Factors that promote obesity To avoid the adverse health consequences associated with the development of obesity, it behooves us to consider first those factors which promote the development of obesity, i.e., obesity prevention is probably the best obesity treatment. Recognition of those at risk individuals should be the first task since at least 60% of human obesity occurs in those with a genetic predisposition [10]. Intervention early in development appears to be critical since the perinatal environment can have an enormous impact on the development of obesity, particularly in those with a genetic predisposition. Epidemiological work in humans suggests that maternal nutritional deprivation during the first trimester of pregnancy [68] or maternal obesity throughout gestation and lactation [62] can increase the incidence of obesity in offspring. However, these are complex issues which have only been studied retrospectively to date in humans. On the other hand, animal studies provide more direct evidence that factors within the perinatal environment can promote the development of obesity in offspring, often in association with altered brain development. Exposure of offspring to an ‘‘obesogenic’’ environment during gestation and lactation promotes the development of obesity in adult life when those offspring have an obesity-prone genotype [69 –71]. It is likely that both gestational and postnatal factors contribute to this effect. In rats, administration of insulin [72,73] or dexamethasone [71] to dams during the third trimester produces obese offspring, as does maternal undernutrition during the first

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[74 – 76] or third trimester of pregnancy [71,76]. Some of these manipulations result in altered development of hypothalamic neurotransmitter and peptide systems involved in the regulation of energy homeostasis [70,72,73,76,77]. During the postnatal period, cross-fostering obesity resistant offspring to obese dams can produce obesity [78]. Similarly, raising pups in small litters [79,80] or artificially rearing pups apart from their dams on a high carbohydrate diet [81 –83] both produce adult obesity. In the latter case, the obesity can also be carried over into the next generation of offspring. This reinforces the idea that maternal obesity begets offspring obesity [84]. Finally, providing juvenile pups with a relatively high fat diet from weaning can produce obesity, even in obesity-resistant individuals [85]. The common thread is that manipulations carried out during the period of active brain development can alter the development and cause permanent changes in neural circuits involved in energy homeostasis. Since both leptin and insulin have neurotropic properties which can affect neuronal development and survival, their presence in excess or absence during this development may be important mediators of these permanent changes [86 – 91]. Depending upon the way in which they are provided to adults, high fat diets can produce obesity, even in obesityresistant individuals [61,92]. Part of this effect is due to the high energy density of such diets. But high fat diets also reduce the ability of animals to respond to the catabolic effects of both leptin and insulin by reducing their transport across the blood – brain barrier [58,93 – 96] and by reducing their ability to activate downstream signaling pathways [59,97]. Such effects may result from changes in plasma membrane lipid composition or intracellular metabolism which lead to altered function of receptors, ion channels and transporters involved in metabolic sensing [60,98 – 100]. Finally, removal of sex hormones can also promote obesity. At least in rodents, females are more sensitive to the anorectic effects of leptin and males are more sensitive to insulin’s anorectic effects [101]. However, in both cases, gonadectomy leads to impaired signaling of both hormones. These changes may be partially responsible for the increasing incidence of obesity with aging. Thus, a number of environmental manipulations beginning in utero and extending through adult life can promote the development of obesity. Again, the value of identifying these factors is that we might be able to intervene to prevent either the development of obesity or its recurrence after weight loss. 2. Factors that ameliorate obesity As with factors that promote obesity, those interventions carried out during the perinatal period may be amongst the most important for primary prevention. This is best illustrated by postnatal studies whereby raising pups in large litters or cross-fostering obesity-prone pups with lean dams reduces body weight [78,79,102] and insulin resistance [103] in adult life. The importance of intervening during the period of active brain development is emphasized by studies showing that exercise during the immediate post-weaning period can lead to long-term reductions in adiposity which appear to ‘‘perma-

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nently’’ outlast the termination of exercise, even in obesityprone individuals on high fat diets [104]. Once the period of active brain development is passed, few interventions or conditions aside from illness, surgical procedures or high levels of stress permanently lower the defended body weight [105 – 108]. In adults, exercise lowers the defended body weight and adiposity of obesity-prone male rodents [104,109 –113] but has little effect on obesity-resistant ones [109,111]. Importantly, even though this loss of adiposity is associated with lowered leptin levels, an effect which should promote increased food intake, exercising rats do not compensate by eating more [104,110 –112]. This is due to the fact that exercise prevents the anabolic tilt in central neuropeptide pathways which normally occurs with such lowering of leptin levels [110,114]. However, unlike the effect of early onset exercise, the beneficial effects of exercise on adiposity do not persist once exercise is terminated in adults [114,115]. In rats, the exercise and reduced adiposity provided by running in wheels are highly rewarding [116]. Unfortunately, exercise is rarely as rewarding to most obese humans where high levels of exercise are required to help reduce their level of adiposity [117 – 119]. However, there are those rare obese individuals who are capable of maintaining chronic weight loss and many of these maintain their reduced weight through high levels of exercise [119]. This may help to normalize the lowered resting metabolic rate normally associated with chronic weight loss [118,120]. Aside from the obvious problem of having few efficacious, safe and acceptable drugs currently available, pharmacotherapy of obesity is still probably the method most likely to succeed in the treatment of obesity in the long run. Before it was removed from the market, fenfluramine, a drug whose main effect is on serotonin metabolism, was widely used and reasonably effective in lowering body weight [121,122]. As with exercise, drugs such as fenfluramine and sibutramine, a combined norepinephrine and serotonin reuptake inhibitor, lower the defended body weight [52,121,123]. Like exercise, sibutramine prevents the anabolic tilt in central neuropeptide pathways that occurs with lowering of adipose mass and leptin levels [52]. However, as with exercise in adults, the effects of weight lowering drugs last only as long as they are taken. Thus, it is likely that anti-obesity drugs will have to be administered for life as are drugs for hypertension, diabetes and other chronic diseases. Finally, the amount of weight a given drug produces is limited [52,122], probably because of the extensive redundancy and plasticity of central systems which are called into play to prevent loss of energy stores. This suggests that multi-drug therapy aimed at different central and peripheral targets will be required to achieve relatively large amounts of sustained weight loss. 3. Summary and conclusions The regulation of energy homeostasis is controlled by the brain whose development and function are regulated by the interaction of the individual’s genotype with signals from the internal and external environment. A distributed network of

specialized metabolic sensing neurons integrates signals from the periphery to provide a coordinated output to neurohumoral and motor effector systems involved in the seeking, ingesting and assimilating nutrients. Possibly because of permanent changes elicited in the network of metabolic sensing neurons, the development of obesity in genetically predisposed individuals leads to an upward resetting of the defended body weight and adiposity which rarely can be moved downward. Given the permanence of such changes, the best therapy is actually prevention. This may be most easily accomplished in the perinatal period during the development of critical energy homeostasis regulatory pathways. During adult life, it is likely that only drug therapy and surgical intervention will provide long-term, effective loss of adiposity. While exercise provides an excellent adjunct to weight loss and maintenance, only very high levels are likely to make a significant difference in successful weight loss in adults. In summary, it is clear that we have a lot to learn about the factors that predispose individuals to become obese. These factors work against our efforts to overcome a built in resistance to loss of energy stores which has evolved over the centuries to ensure the survival of the species. I propose that studies which shed more light on where the hypothetical set-point resides and why it only moves in one direction in obesity-prone individuals under most conditions will be a productive avenue for future research. References [1] Wirtshafter D, Davis JD. Set points, settling points, and the control of body weight. Physiol Behav 1977;19:75 – 8. [2] Flatt JP. Influence of body composition on food intake. In: Allen L, King J, Lonnerdal B, editors. Nutrient regulation during pregnancy, lactation and growth. New York’ Plenum Press; 1994. p. 27 – 44. [3] Levin BE, Triscari J, Sullivan AC. Relationship between sympathetic activity and diet-induced obesity in two rat strains. Am J Physiol 1983;245:R367 – 71. [4] Chang S, Graham B, Yakubu F, Lin D, Peters JC, Hill JO. Metabolic differences between obesity-prone and obesity-resistant rats. Am J Physiol 1990;259:R1103 – 10. [5] MacLean PS, Higgins JA, Johnson GC, Fleming-Elder BK, Donahoo WT, Melanson EL, et al. Enhanced metabolic efficiency contributes to weight regain after weight loss in obesity-prone rats. Am J Physiol 2004;287(6):R1306 – 15. [6] Levin BE, Dunn-Meynell AA, Ricci MR, Cummings DE. Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats. Am J Physiol 2003;285(5):E949 – 57. [7] Boozer CN, Lauterio TJ. High initial levels of plasma leptin predict dietinduced obesity in rats. Int J Obes 1998;22(Suppl. 3):S166. [8] Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE. Selective breeding for diet-induced obesity and resistance in Sprague – Dawley rats. Am J Physiol 1997;273:R725 – 30. [9] Levin BE, Dunn-Meynell AA, McMinn JE, Cunningham-Bussel A, Chua SC Jr. A new obesity-prone, glucose intolerant rat strain (F.DIO). Am J Physiol 2003;285:R1184 – 91. [10] Bouchard C, Perusse L. Genetics of obesity. Ann Rev Nutr 1993;13: 337 – 54. [11] Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Eng J Med 1990;322:1483 – 7. [12] Davies AD, Dobrian RL, Prewitt RL, Lauterio TJ. Metabolic syndrome in a diet-induced obesity model. Obes Res 1999;7(Suppl. 1):127S.

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