Reward mechanisms in obesity: new insights and future directions

Food is consumed in order to maintain energy balance at homeostatic levels. In addition, palatable food is also consumed for its hedonic properties independent of energy status. Such reward-related consumption can result in caloric intake exceeding requirements and is considered a major culprit in the rapidly increasing rates of obesity in developed countries. Compared with homeostatic mechanisms of feeding, much less is known about how hedonic systems in brain influence food intake. Intriguingly, excessive consumption of palatable food can trigger neuroadaptive responses in brain reward circuitries similar to drugs of abuse. Furthermore, similar genetic vulnerabilities in brain reward systems can increase predisposition to drug addiction and obesity. Here, recent advances in our understanding of the brain circuitries that regulate hedonic aspects of feeding behavior will be reviewed. Also, emerging evidence suggesting that obesity and drug addiction may share common hedonic mechanisms will also be considered.     

Metabolic and hedonic drives in the neural control of appetite: who is the boss?

Obesity is on the rise in all developed countries, and a large part of this epidemic has been attributed to excess caloric intake, induced by ever present food cues and the easy availability of energy dense foods in an environment of plenty. Clearly, there are strong homeostatic regulatory mechanisms keeping body weight of many individuals exposed to this environment remarkably stable over their adult life. Other individuals, however, seem to eat not only because of metabolic need, but also because of excessive hedonic drive to make them feel better and relieve stress. In the extreme, some individuals exhibit addiction-like behavior toward food, and parallels have been drawn to drug and alcohol addiction. However, there is an important distinction in that, unlike drugs and alcohol, food is a daily necessity. Considerable advances have been made recently in the identification of neural circuits that represent the interface between the metabolic and hedonic drives of eating. We will cover these new findings by focusing first on the capacity of metabolic signals to modulate processing of cognitive and reward functions in cortico-limbic systems (bottom-up) and then on pathways by which the cognitive and emotional brain may override homeostatic regulation (top-down).     

Transgenic study of energy homeostasis equation: implications and confounding influences.

Recently novel molecular mediators and regulatory pathways for feeding and body weight regulation have been identified in the brain and the periphery. Mice lacking or overexpressing these mediators or receptors have been produced by molecular genetic techniques, and observations on mutant mice have shed new light on the role of each element in the homeostatic loop of body weight regulation. However, the interpretation of the phenotype is under the potential influence of developmental compensation and other genetic and environmental confounds. Specific alterations of the mediators and the consequences of the altered expression patterns are reviewed here and discussed in the context of their functions as suggested from conventional pharmacological studies. Advanced gene targeting strategies in which genes can be turned on or off at desired tissues and times would undoubtedly lead to a better understanding of the highly integrated and redundant systems for energy homeostasis equation.     

Ghrelin modulates brain activity in areas that control appetitive behavior

Feeding behavior is often separated into homeostatic and hedonic components. Hedonic feeding, which can be triggered by visual or olfactory food cues, involves brain regions that play a role in reward and motivation, while homeostatic feeding is thought to be under the control of circulating hormones acting primarily on the hypothalamus. Ghrelin is a peptide hormone secreted by the gut that causes hunger and food consumption. Here, we show that ghrelin administered intravenously to healthy volunteers during functional magnetic resonance imaging increased the neural response to food pictures in regions of the brain, including the amygdala, orbitofrontal cortex, anterior insula, and striatum, implicated in encoding the incentive value of food cues. The effects of ghrelin on the amygdala and OFC response were correlated with self-rated hunger ratings. This demonstrates that metabolic signals such as ghrelin may favor food consumption by enhancing the hedonic and incentive responses to food-related cues.     

The principle of homeostasis in the hypothalamus-pituitary-adrenal system: new insight from positive feedback

Feedback control, both negative and positive, is a fundamental feature of biological systems. Some of these systems strive to achieve a state of equilibrium or "homeostasis". The major endocrine systems are regulated by negative feedback, a process believed to maintain hormonal levels within a relatively narrow range. Positive feedback is often thought to have a destabilizing effect. Here, we present a "principle of homeostasis," which makes use of both positive and negative feedback loops. To test the hypothesis that this homeostatic concept is valid for the regulation of cortisol, we assessed experimental data in humans with different conditions (gender, obesity, endocrine disorders, medication) and analyzed these data by a novel computational approach. We showed that all obtained data sets were in agreement with the presented concept of homeostasis in the hypothalamus-pituitary-adrenal axis. According to this concept, a homeostatic system can stabilize itself with the help of a positive feedback loop. The brain mineralocorticoid and glucocorticoid receptors-with their known characteristics-fulfill the key functions in the homeostatic concept: binding cortisol with high and low affinities, acting in opposing manners, and mediating feedback effects on cortisol. This study supports the interaction between positive and negative feedback loops in the hypothalamus-pituitary-adrenal system and in this way sheds new light on the function of dual receptor regulation. Current knowledge suggests that this principle of homeostasis could also apply to other biological systems.     

Transsynaptic control of presynaptic Ca²⁺ influx achieves homeostatic potentiation of neurotransmitter release

Given the complexity of the nervous system and its capacity for change, it is remarkable that robust, reproducible neural function and animal behavior can be achieved. It is now apparent that homeostatic signaling systems have evolved to stabilize neural function. At the neuromuscular junction (NMJ) of organisms ranging from Drosophila to human, inhibition of postsynaptic neurotransmitter receptor function causes a homeostatic increase in presynaptic release that precisely restores postsynaptic excitation. Here we address what occurs within the presynaptic terminal to achieve homeostatic potentiation of release at the Drosophila NMJ. By imaging presynaptic Ca(2+) transients evoked by single action potentials, we reveal a retrograde, transsynaptic modulation of presynaptic Ca(2+) influx that is sufficient to account for the rapid induction and sustained expression of the homeostatic change in vesicle release. We show that the homeostatic increase in Ca(2+) influx and release is blocked by a point mutation in the presynaptic CaV2.1 channel, demonstrating that the modulation of presynaptic Ca(2+) influx through this channel is causally required for homeostatic potentiation of release. Together with additional analyses, we establish that retrograde, transsynaptic modulation of presynaptic Ca(2+) influx through CaV2.1 channels is a key factor underlying the homeostatic regulation of neurotransmitter release.     

Homeostatic activity-dependent paradigm for neurotransmitter specification

Calcium-signaling plays a central role in specification of the chemical transmitters neurons express, adjusting the numbers of cells that express excitatory and inhibitory transmitters as if to achieve homeostatic regulation of excitability. Here we review the extent to which this activity-dependent regulation is observed for a range of different transmitters. Strikingly the homeostatic paradigm is observed both for classical and for peptide transmitters and in mature as well as in embryonic nervous systems. Transmitter homeostasis adds another dimension to homeostatic regulation of function in the nervous system that includes regulation of levels of voltage-gated ion channels, densities of neurotransmitter receptors, and synapse numbers and strength.     

Eating Motives and the Controversy over Dieting: Eating Less Than Needed versus Less Than Wanted

Anti‐dieting sentiment has grown in recent years. Critics of restrained eating suggest that it evokes counter‐regulatory responses that render it ineffective or even iatrogenic. However, restrained eaters are not in negative energy balance and overweight individuals show reduced eating problems when losing weight by dieting. A distinction is often drawn between physiological and psychological hunger, and neuroscience research has shown that there is a neurophysiological reality underlying this distinction. The brain has a homeostatic system (activated by energy deficits) and a hedonic system (activated by the presence of palatable food). The omnipresence of highly palatable food in the environment may chronically activate the hedonic appetite system, producing a need to actively restrain eating not just to lose weight but to avoid gaining it. Just as restricting energy intake below homeostatic needs produces physiological deprivation, restricting intake of palatable foods may produce “perceived deprivation” despite a state of energy balance. In summary, the motivation to eat more than one needs appears to be every bit as real, and perhaps every bit as powerful, as the motivation to eat when energy deprived.     

Sexes on the brain: Sex as multiple biological variables in the neuronal control of feeding

Neuronal interactions at the level of vagal, homeostatic, and hedonic circuitry work to regulate the neuronal control of feeding. This integrative system appears to vary across sex and gender in the animal and human worlds. Most feeding research investigating these variations across sex and gender focus on how the organizational and activational mechanisms of hormones contribute to these differences. However, in limited studies spanning both the central and peripheral nervous systems, sex differences in feeding have been shown to manifest not just at the level of the hormonal, but also at the chromosomal, epigenetic, cellular, and even circuitry levels to alter food intake. In this review, we provide a brief orientation to the current understanding of how these neuronal systems interact before dissecting selected studies from the recent literature to exemplify how feeding physiology at all levels can be affected by the various components of sex.     

Information coding in vasopressin neurons—The role of asynchronous bistable burst firing

The task of the vasopressin system is homeostasis, a type of process which is fundamental to the brain's regulation of the body, exists in many different systems, and is vital to health and survival. Many illnesses are related to the dysfunction of homeostatic systems, including high blood pressure, obesity and diabetes. Beyond the vasopressin system's own importance, in regulating osmotic pressure, it presents an accessible model where we can learn how the features of homeostatic systems generally relate to their function, and potentially develop treatments. The vasopressin system is an important model system in neuroscience because it presents an accessible system in which to investigate the function and importance of, for example, dendritic release and burst firing, both of which are found in many systems of the brain. We have only recently begun to understand the contribution of dendritic release to neuronal function and information processing. Burst firing has most commonly been associated with rhythm generation; in this system it clearly plays a different role, still to be understood fully.     

A Relationship between Reduced Nucleus Accumbens Shell and Enhanced Lateral Hypothalamic Orexin Neuronal Activation in Long-Term Fructose Bingeing Behavior

Fructose accounts for 10% of daily calories in the American diet. Fructose, but not glucose, given intracerebroventricularly stimulates homeostatic feeding mechanisms within the hypothalamus; however, little is known about how fructose affects hedonic feeding centers. Repeated ingestion of sucrose, a disaccharide of fructose and glucose, increases neuronal activity in hedonic centers, the nucleus accumbens (NAc) shell and core, but not the hypothalamus. Rats given glucose in the intermittent access model (IAM) display signatures of hedonic feeding including bingeing and altered DA receptor (R) numbers within the NAc. Here we examined whether substituting fructose for glucose in this IAM produces bingeing behavior, alters DA Rs and activates hedonic and homeostatic feeding centers. Following long-term (21-day) exposure to the IAM, rats given 8–12% fructose solutions displayed fructose bingeing but unaltered DA D1R or D2R number. Fructose bingeing rats, as compared to chow bingeing controls, exhibited reduced NAc shell neuron activation, as determined by c-Fos-immunoreactivity (Fos-IR). This activation was negatively correlated with orexin (Orx) neuron activation in the lateral hypothalamus/perifornical area (LH/PeF), a brain region linking homeostatic to hedonic feeding centers. Following short-term (2-day) access to the IAM, rats exhibited bingeing but unchanged Fos-IR, suggesting only long-term fructose bingeing increases Orx release. In long-term fructose bingeing rats, pretreatment with the Ox1R antagonist SB-334867 (30 mg/kg; i.p.) equally reduced fructose bingeing and chow intake, resulting in a 50% reduction in calories. Similarly, in control rats, SB-334867 reduced chow/caloric intake by 60%. Thus, in the IAM, Ox1Rs appear to regulate feeding based on caloric content rather than palatability. Overall, our results, in combination with the literature, suggest individual monosaccharides activate distinct neuronal circuits to promote feeding behavior. Specifically, long-term fructose bingeing activates a hyperphagic circuit composed in part of NAc shell and LH/PeF Orx neurons.     

Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens

Ghrelin, a powerful orexigenic peptide released from the gut, stimulates feeding when injected centrally and has thus far been implicated in regulation of metabolic, rather than hedonic, feeding behavior. Although ghrelin's effects are partially mediated at the hypothalamic arcuate nucleus, via activation of neurons that co-express neuropeptide Y and agouti-related protein (NPY/Agrp neurons), the ghrelin receptor is expressed also in other brain sites. One of these is the ventral tegmental area (VTA), a primary node of the mesolimbic reward pathway, which sends dopaminergic projections to the nucleus accumbens (Acb), among other sites. We injected saline or three doses of ghrelin (0, 0.003, 0.03, or 0.3 nmol) into the VTA or Acb of rats. We found a robust feeding response with VTA injection of ghrelin, and a more moderate response with Acb injection. Because opioids modulate feeding in the VTA and Acb, we hypothesized that ghrelin's effects in one site were dependent on opioid signaling in the opposite site. The general opioid antagonist, naltrexone (NTX), injected into the Acb did not affect feeding elicited by ghrelin injection into the VTA, and NTX in the VTA did not affect feeding elicited by ghrelin injected into the Acb. These results suggest interaction of a metabolic factor with the reward system in feeding behavior, indicating that hedonic responses can be modulated by homeostatic factors.     

Startling Sweet Temptations: Hedonic Chocolate Deprivation Modulates Experience,Eating Behavior,and Eyeblink Startle

Many individuals restrict their food intake to prevent weight gain. This restriction has both homeostatic and hedonic effects but their relative contribution is currently unclear. To isolate hedonic effects of food restriction, we exposed regular chocolate eaters to one week of chocolate deprivation but otherwise regular eating. Before and after this hedonic deprivation, participants viewed images of chocolate and images of high-calorie but non-chocolate containing foods, while experiential, behavioral and eyeblink startle responses were measured. Compared to satiety, hedonic deprivation triggered increased chocolate wanting, liking, and chocolate consumption but also feelings of frustration and startle potentiation during the intertrial intervals. Deprivation was further characterized by startle inhibition during both chocolate and food images relative to the intertrial intervals. Individuals who responded with frustration to the manipulation and those who scored high on a questionnaire of impulsivity showed more relative startle inhibition. The results reveal the profound effects of hedonic deprivation on experiential, behavioral and attentional/appetitive response systems and underscore the role of individual differences and state variables for startle modulation. Implications for dieting research and practice as well as for eating and weight disorders are discussed.     

Effect of disrupted episodic memory on food consumption: no impact of neuronal loss of endophilin A1 on food intake and energy balance

Food intake is generally assumed to reflect a regulatory tension between homeostatic and hedonic drivers. Information from individuals with memory dysfunction suggests that episodic memory may also play a significant role. We reasoned that if memory influences food intake, then disrupting a genetic factor that is important in episodic memory formation should affect food intake and energy balance. We performed spatial learning tests on neuronal specific endophilin A1 (EENA1) KO mice using the four-arm baited version of the radial arms maze (RAM). Energy regulation has also been evaluated. As anticipated neuronal EENA1 KO mice had impaired spatial memory. However, loss of endophilin A1 did not result in greater food intake, or altered energy absorption efficiency, relative to wild-type (WT) mice, when fed either low or high fat diets. Moreover, loss of EENA1 did not significantly affect other features of energy balance—physical activity and energy expenditure. No statistically significant changes were observed in the expression of hypothalamic neuropeptides related to food intake regulation, or circulating levels of leptin. We conclude that food intake and energy balance are largely governed by homeostatic and hedonic processes, and when these processes are intact memory probably plays a relatively minor role in food intake regulation.     

Modulatory actions of dopamine and serotonin on insect antennal lobe neurons: insights from studies in vitro

Biogenic amines play diverse roles in the development and modulation of invertebrate neurons and ultimately also, in the regulation of animal behaviour. Here we examine the contribution that analyses of antennal lobe neurons in vitro have made towards our understanding of the mechanisms through which dopamine and serotonin operate in primary olfactory centres of the brain of the moth, Manduca sexta and the honey bee, Apis mellifera. This chapter reviews evidence suggesting that these biogenic amines function as regulators of neuronal development and as mediators of cellular and behavioural plasticity, in part at least, through the modulation of K(+) conductances in the cells. Insect neurons in vitro provide an excellent model for exploring basic principles of amine function and their impact on neuronal excitability.     

Robust Concentration and Frequency Control in Oscillatory Homeostats

Homeostatic and adaptive control mechanisms are essential for keeping organisms structurally and functionally stable. Integral feedback is a control theoretic concept which has long been known to keep a controlled variable robustly (i.e. perturbation-independent) at a given set-point by feeding the integrated error back into the process that generates . The classical concept of homeostasis as robust regulation within narrow limits is often considered as unsatisfactory and even incompatible with many biological systems which show sustained oscillations, such as circadian rhythms and oscillatory calcium signaling. Nevertheless, there are many similarities between the biological processes which participate in oscillatory mechanisms and classical homeostatic (non-oscillatory) mechanisms. We have investigated whether biological oscillators can show robust homeostatic and adaptive behaviors, and this paper is an attempt to extend the homeostatic concept to include oscillatory conditions. Based on our previously published kinetic conditions on how to generate biochemical models with robust homeostasis we found two properties, which appear to be of general interest concerning oscillatory and homeostatic controlled biological systems. The first one is the ability of these oscillators (“oscillatory homeostats”) to keep the average level of a controlled variable at a defined set-point by involving compensatory changes in frequency and/or amplitude. The second property is the ability to keep the period/frequency of the oscillator tuned within a certain well-defined range. In this paper we highlight mechanisms that lead to these two properties. The biological applications of these findings are discussed using three examples, the homeostatic aspects during oscillatory calcium and p53 signaling, and the involvement of circadian rhythms in homeostatic regulation.     

GOAT induced ghrelin acylation regulates hedonic feeding

Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. Recent evidence indicates that acylation of ghrelin by the gut enzyme ghrelin O-acyl transferase (GOAT) is necessary to render ghrelin maximally active within its target tissues. Here we tested the hypothesis that GOAT activity modulates food motivation and food hedonics using behavioral pharmacology and mutant mice deficient for GOAT and the ghrelin receptor (GHSR). We evaluated operant responding following pharmacological administration of acyl-ghrelin and assessed the necessity of endogenous GOAT activity for operant responding in GOAT and GHSR-null mice. Hedonic-based feeding behavior also was examined in GOAT-KO and GHSR-null mice using a “Dessert Effect” protocol in which the intake of a palatable high fat diet “dessert” was assessed in calorically-sated mice. Pharmacological administration of acyl-ghrelin augmented operant responding; notably, this effect was dependent on intact GHSR signaling. GOAT-KO mice displayed attenuated operant responding and decreased hedonic feeding relative to controls. These behavioral results correlated with decreased expression of the orexin-1 receptor in reward-related brain regions in GOAT-KO mice. In summary, the ability of ghrelin to stimulate food motivation is dependent on intact GHSR signaling and modified by endogenous GOAT activity. Furthermore, GOAT activity is required for hedonic feeding behavior, an effect potentially mediated by forebrain orexin signaling. These data highlight the significance of the GOAT–ghrelin system for the mediation of food motivation and hedonic feeding.     

Side chain oxygenated cholesterol regulates cellular cholesterol homeostasis through direct sterol-membrane interactions

Side chain oxysterols exert cholesterol homeostatic effects by suppression of sterol regulatory element-binding protein maturation and promoting degradation of hydroxymethylglutaryl-CoA reductase. To examine whether oxysterol-membrane interactions contribute to the regulation of cellular cholesterol homeostasis, we synthesized the enantiomer of 25-hydroxycholesterol. Using this unique oxysterol probe, we provide evidence that oxysterol regulation of cholesterol homeostatic responses is not mediated by enantiospecific oxysterol-protein interactions. We show that side chain oxysterols, but not steroid ring-modified oxysterols, exhibit membrane expansion behavior in phospholipid monolayers and bilayers in vitro. This behavior is non-enantiospecific and is abrogated by increasing the saturation of phospholipid acyl chain constituents. Moreover, we extend these findings into cultured cells by showing that exposure to saturated fatty acids at concentrations that lead to endoplasmic reticulum membrane phospholipid remodeling inhibits oxysterol activity. These studies implicate oxysterol-membrane interactions in acute regulation of sterol homeostatic responses and provide new insights into the mechanism through which oxysterols regulate cellular cholesterol balance.     

Histamine Receptor and its Regulation of Energy Metabolism

In a series of studies on brain functions of histamine, probes to manipulate activities of histaminergic neuronal systems were applied to assess histaminergic function in non-obese normal, and lean and obese Zucker rats. Food intake was suppressed by both activation of H₁-receptors and inhibition of H₃-receptors in the ventromedial hypothalamic nucleus (VMH) and the paraventricular nucleus, each of which is a satiety center. Feeding circadian rhythm was decreased in its amplitude through histaminergic modulation in the hypothalamus. Histamine neurons in the mesencephalic trigeminal nucleus (Me5) were involved in regulation of masticatory functions, particularly eating speed, while histamine-containing neurons in the VMH controlled intake volume of meals. Energy deficiency in the brain enhanced satiation through histaminergic activation of VMH neurons, which in turn produced glycogenolysis in the hypothalamus to maintain homeostatic control of glucose supply. A very-low-calorie conventional Japanese diet, which is a fiber rich and low energy food source, enhanced satiation by increased mastication and because of the low energy supply of the diet. Hypothalamic histamine neurons were activated by high ambient temperature and also by interleukin-1β, an endogenous pyrogen, to maintain homeostatic thermoregulation. Behavioral and metabolic abnormalities of Zucker obese rats were mediated by a deficit in hypothalamic neuronal histamine, and the Zucker rat was evaluated as an animal model of histamine deficiency. Transplantation of the lean fetal hypothalamus into the third cerebroventricle of host obese Zuckers attenuated the abnormalities.     

Developments in the scientific understanding of rheumatoid arthritis

Rheumatoid arthritis (RA) is recognized to be an autoimmune disease that causes preclinical systemic abnormalities and eventually leads to synovial inflammation and destruction of the joint architecture. Recently identified genetic risk factors and novel insights from animal models of spontaneous arthritis have lent support to the concept that thymic selection of an autoreactive T-cell repertoire is an important risk factor for this disease. With advancing age, defects in the homeostatic control of the T-cell pool and in the setting of signaling thresholds lead to the accumulation of pro-inflammatory T-effector cell populations and loss of tolerance to neo-antigens, such as citrullinated peptides. As the breakdown of tolerance to modified self-antigens can precede synovitis by decades, repair of homeostatic defects may open a unique window of opportunity for preventive interventions in RA. The end result of RA, destruction of cartilage and bone, appears to be driven by cytokine- and cell contact-induced activation of synoviocytes and monocytic cells, some of which differentiate into tissue-destructive osteoclasts. Targeting mediators involved in this process has greatly improved the management of this chronic inflammatory syndrome.