Introduction

The brain plays a critical role in the regulation of physiological processes including energy homeostasis. Central nervous circuits instantly assess and integrate peripheral metabolic, endocrine and neuronal signals, and coordinate a response that modulates both behavioral patterns and peripheral metabolism according to acute and chronic requirements (1 ). The brain directs, coordinates and integrates circulating hormones and metabolites that signal energy availability. As a consequence it modifies energy intake and expenditure to match energy demands on an ongoing homeostatic basis, establishing a metabolic “set-point”. This point is also strongly influenced by central neural circuits that regulate motivation, hedonism, reward and liking of food. The impact of the non-homeostatic “hedonistic” aspects of food intake is now increasingly recognized, highlighted by the fact that animals and most humans in western societies exposed to a highly palatable diet overeat because they “like” to eat (hedonism), rather than “need” to eat (homeostasis).

Changes in body weight reflect respective changes in energy balance resulting from an imbalance between energy taken up (food intake) and energy expended (for locomotor activity, basal metabolism, and thermogenesis). Therefore, any alterations in food intake or energy expenditure precede measurable alteration in body weight. This chapter describes the different components of the central neural control of body weight, including homeostatic regulation and “higher” regulatory systems, i.e. non-homeostatic pathways. In addition, the neuroendocrine regulation of food intake is described considering that the net effect of respective changes in food intake and energy expenditure alters body weight. Further details and components considering the regulation of energy intake and expenditure as well as food intake are discussed in chapters 3, 4 and 7.

How did it all start – a short historical excursion

The development of hunger as a physiological corollary in response to extended periods of food deprivation is a primal motivated behavior and comprises one of the most fundamental responses in all animals. The counterpart of this is satiation, which signals the termination of an ingestive behavior (food or water intake), that is equally important to the survival of animals. Historically, the biological basis of hunger and satiety has received considerable experimental attention, with the role of the brain as the main regulator in the control of food intake maintaining a central focus.

In 1954 Eliot Stellar suggested the concept of a “satiety center” situated in the ventral medial hypothalamus and a “hunger center” centered in the lateral hypothalamus (2 ). Stellar based these hypotheses on lesion studies. Rats with lesions of the “satiety center”, in the ventral medial hypothalamus, showed a marked increase in food intake whereas electrical stimulation of this area decreased food intake. Lesions of the opposing “hunger center” in the lateral hypothalamus showed decreased food intake whereas stimulation of this area increased food intake.

In the 1950s, two hypotheses for the generation of hunger dominated research into underlying brain mechanisms. The first, put forth by Mayer, stated that decreases in glucose utilization stimulated eating and increases in glucose utilization halted eating, with the combined effect being referred to as the “glucostatic hypothesis” of hunger (3 , 4 ). Supporting this hypothesis, two types of glucose sensitive neurons were identified changing their action potential in dependence from surrounding glucose levels. Glucose excited (GE) neurons increase activity and glucose inhibited (GI) neurons decrease activity with rising glucose levels. Intrahypothalamic glucose administration decreases food intake and inhibits hepatic glucose production, suggesting that glucose sensing neurons indeed may regulate appetite and blood glucose concentrations (5 ).The second hypothesis, promulgated by Kennedy, proposed that fat mass produced an inhibitory control of eating and body weight gain, with the inhibitory control mediated by an unidentified humoral signal from white adipose tissue acting on the ventral medial hypothalamus. Thus, food intake increased after lesions of the ventral medial hypothalamus due to the removal of the site of action of the inhibitory signal from the fat. This formed the basis of the “lipostatic hypothesis” of hunger . The inhibitory agent central to the lipostatic hypothesis was later identified as leptin (6 ). The discovery of the so called ob gene that carries the genetic information for the adipose tissue-derived factor leptin represents the most influential milestone in the field of obesity research to date and forms a backdrop to the study of homeostatic mechanisms and modulation of food intake that has dominated the field for the last two decades.

How does the brain work? – A brief anatomical excursion

The main information processing units of the brain are neurons. Neurons are cells of ectodermal origin that have subcellular compartments specialized in receiving (dendrites and perikaryon) and forwarding (axons) information. Neurons interact with each other by synapses that are established between axon terminals and dendritic or perikaryal membranes. The information travels from the axon terminals to the dendritic or perikaryal membranes. Synaptic transmission occurs either electrically, chemically via release of neurotransmitters or (neuro-) modulators from synaptic vesicles of the axon terminal or by release of gaseous substances such as nitric oxide or carbon monoxide. In most cases, synaptic transmission can occur by all three means, although one may predominate depending on the action potential as well as on substances that may directly signal to the axon terminal from the extracellular space (such as other neuromodulators released by nearby). The specificity of signal transduction is ensured by the appropriate connectivity within a given network and by the availability of receptors at specific sites for released neurotransmitters/modulators or peripheral metabolic hormones. It is rather likely that interaction between neurons holds the key to understanding metabolism regulation. However, emerging data clearly suggests that glial cells also play a pivotal role in allowing normal neuronal activity by providing enzymatic activity or substrates leading to changes in activity of adjacent neurons (7-9 ) To this end, it is critical that the principles of neuronal physiology are mastered (beyond the short references provided here) to the deepest possible extent. Otherwise, attempts to decipher the role of the brain in obesity research will remain elusive.

Communication via neurotransmitters

Neurotransmitters belong to a heterogeneous class of signal molecules that transmit the signal of impaired neuronal activation from one neuron to the other. This transmission is thought to happen mainly at synaptic endings of neurons. Impaired activation potential of a neuron leads to secretion of neurotransmitters into the synaptic cleft and binding to corresponding receptors that sit on the opposite, postsynaptic membrane of the adjacent neuron. This process changes the action potential of this neuron and so forth. Among neurotransmitters are several neuropeptides (e.g. α-melanocyte stimulating hormone (α-MSH), neuropeptide Y (NPY), orexins), biogenic amines (e.g. acetylcholine, serotonin, dopamin, histamine, epinephrine, norepinephrine), amino acids (e.g. glutamate, γ aminobutyric acid (GABA), aspartatic acid, glycine) and gases (e.g. nitric oxide (NO), carbon monoxide (CO)). The most important neurotransmitters in the brain are glutamate and GABA. They play important roles in regulating neuronal activity in the hypothalamus and therefore contribute significantly to the central regulation of energy balance.

GABA represents the main inhibitory neurotransmitter in the central nervous system (CNS) (10 ). Intracerebroventricular injections of GABA induce feeding and positive energy balance. Intriguingly, immunoreactivity of glutamic acid decarboxylase (GAD), the enzyme that catalyzes the final step of GABA synthesis (used as marker for GABAergic neurons), co-localizes to a high percentage with orexigenic neurons (NPY/agouti-related protein (AgRP) expressing) in the ventromedial part of the arcuate nucleus (ARC) (10 ). But also one third of anorexigenic neurons (proopiomelanocortin (POMC) expressing) were shown to contain GAD mRNA and those neurons are able to release GABA. GABA receptors were detected in hypothalamic regions that are important for the regulation of feeding.

Glutamate represents the main excitory neurotransmitter in the hypothalamic neuroendocrine regulation (10 ). Released glutamate is transported into adjacent neurons or glia cells by cell membranes located high-affinity excitatory amino acid transporters (EAAT). Inside the neuron, glutamate is transported into synaptic vesicles by vesicular glutamate transport proteins (VGLUT) that serve as markers for glutamergic neurons. Among the three known VGLUTs, VGLUT2 represents the dominant hypothalamic glutamate transporter (10 , 11 ). Its co-localization with POMC/cocain-and amphetamine-related transcript (CART) neurons in the arcuate nucleus suggests that some POMC/CART neurons are glutamergic. In addition, glutamate may significantly contribute to the regulation of hypothalamic-pituitary-adrenal/thyroid axis, because 1) glutamatergic neurons (possibly of the POMC/CART type) were suggested to heavily innervate hypophysiotrophic corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus PVN (12 ) and 2) hypophysiotropic CRH and TRH neurons themselves were reported to be glutamatergic (13 ). Also hypothalamic somatostatin, vasopressin and oxytocin neurons have been reported to be of glutamatergic phenotype (14 , 15 ).

Homeostatic regulation of energy balance: connecting the hypothalamus, hindbrain and the gut.

Homeostatic regulation of energy balance requires the brain to maintain the appropriate energy levels by instantly modulating metabolites, fuel stores or hormone secretion. This demands first the ability of sensing metabolic and hormonal changes in the periphery by integrating the information from afferent signals projecting to the brain. Those signals include tissue-specific signaling molecules (e.g. leptin, ghrelin, cholecystokinin), metabolites (e.g. glucose, fatty acids), hormones (e.g. insulin, glucocorticoids, adrenaline, noradrenaline) or vegetative nerve terminals (e.g. vagal afferents). Peptides secreted by the gastrointestinal tract during eating or digestion mainly act as satiety signals, conveying information on short-term changes in nutrient and energy supply, whereas factors secreted by other peripheral organs and tissues (e.g. adipose tissue, pancreas) rather serve to signal long-term changes in metabolic state or energy stores. In addition, hormones reflecting caloric intake and acute nutritional requirements complete the information flow to the brain (see detailed description of afferent signals below).

Inside the brain, central nervous circuits coordinate a respective efferent response that modulates both behavioral patterns and peripheral metabolism according to acute and chronic requirements (1 ).

The classical endocrine axes, consisting of hypothalamic releasing hormones, pituitary hormones and peripheral endocrine signals are, without exception, involved in mediating efferent information and maintaining the balance of metabolism and energy homeostasis.

The hypothalamo-pituitary-adrenal (HPA) axis with corticotropine releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosteroids is mediating stress responses, contributes to glucose mobilization and induces a positive energy balance. The hypothalamo-pituitary-thyroid (HPT) axis with thyreotropin releasing hormone (TRH), throidea stimulating hormone (TSH) and thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) is an important stimulator of development and metabolism. In case of demand, T4 is tissue-specifically converted into the active thyroid hormone T3 mainly by type 1 and 2 deiodinase whose expression pattern and activity play an additional role in mediating thyroid hormone effects (16 ). Thyroid hormones increase metabolic rate and produce energy deficits. Their circulating level correlates directly with basal metabolic rate. The growth hormone (GH)- insulin-like growth factor 1 (IGF-1) axis (somatotropic axis) regulates growth and metabolism. GH secretion from the pituitary is induced by hypothalamus derived growth hormone releasing hormone (GHRH). GH directly promotes lipolysis and glycogenolysis, while IGF-1 stimulates protein synthesis (muscle growth), cell division and bone growth. The hypothalamo-pituitary-gonadal axis with hypothalamus-derived gonadotropin releasing hormone (GnRH), the pituitary-derived hormones luteinizing hormone (LH) and follicle stimulating hormone (FSH) and the gonadal hormones testosterone (secreted from testis) and estrogens and gestagens (e.g. estradiol and progesterone secreted from ovaries) regulates functions necessary for reproduction. Since reproduction is dependent on sufficient energy stores gonadal hormones also regulate energy balance. Testosterone mainly acts in an anabolic pattern, stimulating protein synthesis and increasing the ratio of muscle to fat mass in men. Progesterone has mainly orexigenic functions, and estradiol is anorexigenic causing a negative energy balance in women. Although classical hormones secreted by the endocrine glands are largely neglected as afferent signals that convey peripheral metabolic states, energy stores or nutritional requirements to the brain, they play an important role in the complex networks governing appetite and body weight (17 ). Central administration of corticosteroids , for example, induces appetite and increases fat mass (18 ). While the negative energy balance induced by thyroid hormones is mainly attributed to their multiple peripheral effects, T4 as well as T3 receptors are also localized in the brain, where they serve as important feedback targets (19 ). The same feedback principle exists for hormones of the somatotropic axis such as growth hormone (GH) and insulin-like growth factor I (IGF-I) (17 ).

The other effector system is the autonomous nervous system (the parasympathetic and the sympathetic nervous system) that is believed to represent the predominant efferent pathways from the brain to the periphery in the adjustment of energy balance (20 , 21 ) See also http://http://www.endotext.org/obesity/obesity4/obesityframe4.htm for more detailed information.

There has always been a trend to simplify the regional contribution of brain areas to homeostatic regulation of energy balance: It allows a relatively simple conceptualization of the involvement of different brain mechanisms. It also contributes to a rapid advancement in knowledge of the involvement of particular neuropeptides and their receptors in these processes. It is important to remember that despite ever increasing data gathered in the last century, including the discovery of leptin and the repeated revelations of "the most important" hormone or neuropeptide, an effective pharmacotherapy for obesity is still lacking. Thus, when considering the brain structures discussed below and their putative function, the reader is advised to keep in mind that this is a reflection of our current understanding and not necessarily a rigid blueprint of metabolic regulation. Our present knowledge of these circuits continues to improve, but is far less clear than the pathways for vision, hearing or basic motor functions that, for example, involve and require interaction between the cortex, basal ganglia, striatum and cerebellum.

Stepping outside the homeostatic square: extra-hypothalamic centers involved in reward, hedonism and cognition contribute to body weight regulation

There are other brain areas besides the hypothalamus and brainstem that play important roles in regulating energy balance. For example, it is critical that appropriate motor function is exerted in order to both gather food as well as to appropriately process ingested nutrients.

The homeostatic regulation of energy balance is remarkably powerful in defending the lower limits of adiposity (bias towards weight gain, (23 ), and weak in curbing appetite to prevent weight gain in the current world of abundance of highly palatable high energy foods. Non-metabolic sensory factors that lead the homeostatic system to become unbalanced and contribute to overeating and obesity include food palatability, sensory-specific satiety, fixed meal times, food salience and portion size, energy density of food, consumption rate, stress, social environment and energy output/exercise (230 , 231 ). Palatability and pleasantness of food are arguably the most powerful determinants in regulating motivation to eat.

As discussed in the previous section, hardwired homeostatic brain mechanisms contribute to the control of appetite, however, a number of sensory and environmental factors of the “external world” contribute to over-stimulation of the sensory systems, producing sensory reward signals that sometimes overwhelm satiety signals. While satiety signals (gut-hormones i.e. CCK) presumably represent a physiological constant of meal termination regulation over the last centuries, changes on the sensory side (produced by taste, smell, texture, appearance of food, availability) have increased and changed dramatically during the last decades. In other words, satiety signals are simply being overridden by cognitive and reward stimuli, contributing to the increasing incidence of obesity. This inequality pushes the energy balance equation towards weight gain and eventually obesity. Brain areas that were evolutionarily occupied with procuring and ingesting food not only involved the hypothalamus but also corticolimbic structures such as the amygdala, nucleus accumbens and prefrontal cortex. These structures are more involved in the rewarding aspect of food ingestion and are simply overwhelmed in today’s society which has both an abundance of food and food cues and freedom from famine. It is now increasingly recognized that humans and animals are unlikely to be driven to obesity by failure of homeostatic mechanisms alone and the role of non-homeostatic reward/hedonistic pathways and the way in which they interact with cognitive and homeostatic pathways has moved closer to center stage (232 , 233 ).

Decades of research on cortical and basal ganglia function have led to the development of models of higher-order (corticolimbic) executive control of voluntary motor behavior, including that of feeding where critical aspects of motivational feeding are controlled (234 ). The hedonic impact of preferred foods is now thought to be mediated by networks linking the amygdala, prefrontal cortex and ventral striatum (including the core and shell of the nucleus accumbens).

The increase in obesity worldwide supports the idea that, particularly in humans, the initiation of a meal often starts as a purely cognitive/executive decision from the cortex in the absence of any depletion signal. Thus, even in the presence of satiation and repleted energy stores, it is possible for the cortex and limbic system to overpower the hypothalamus into an ingestive mode. The brain areas involved in the hedonistic and reward control of energy balance include the nucleus accumbens, which provides an interface with its afferent and efferent connections between motivational aspects and behavioral motor responses (235 , 236 ), the ventral tegmental area (VTA) in the midbrain, the orbitofrontal cortex, the amygdala and the thalamus which acts as an integrator for homeostatic and hedonistic signals (237 ).

The mesolimbic pathways (dopaminergic projections between the VTA and the nucleus accumbens) subserve reward based feeding (236 , 238 , 239 ) but how they are incorporated into the greater scheme of the CNS control of energy balance remains to be elucidated. Dopamine has been shown to potently augment the drive to obtain a rewarding stimulus. One mechanism that may promote consumption of a palatable food through activation of the VTA-nucleus accumbens pathway involves the projections to the LHA which is known to contain orexigenic peptides. Various tracer studies have shown projections from mainly the shell of the nucleus accumbens to the LHA/PeF (240-243 ). These pathways support the anatomical and functional view of the LHA as an integrative point for not only homeostatic but also reward-related inputs that can collectively stimulate feeding behavior and might be an important pathway for the “cognitive” brain to override homeostatic regulation. Supporting data show that orexin neurons in the LHA and NPY neurons in the ARC were activated while POMC/CART neurons were deactivated by manipulation of the nucleus accumbens with muscimol (selective GABA agonist) (244 ). Additionally, current data suggests that also the adiposity signals insulin and leptin play a role in modulating reward function. This hypothesis is supported by the expression of both insulin and leptin receptors throughout the limbic forebrain including the nucleus accumbens and VTA (245-248 ). Emerging evidence now supports the idea that the VTA is sensitive to insulin, leptin and also ghrelin and that these signals can modulate the activity of dopaminergic neurons within the VTA (248-251 ). One possible mechanism suggests that low circulating levels of insulin and leptin, indicating energy restriction, is able to increase sensitivity of reward circuits (252 , 253 ). This hypothesis is supported by data from animal studies where the administration of insulin or leptin diminishes sucrose preference which is a measure for food reward (253 ).

The cortical loci of the motivation to eat have proven difficult to isolate but evidence supporting the involvement of cortical regions including the prefrontal/orbitofrontal, anterior cingulate and insular cortex has been derived from both imaging (254-258 ) and electrophysiological studies (259-261 ). Recent imaging studies have also highlighted the anatomical correlates of mesolimbic reward pathways (262 ) and their underpinning of the phenomena of “wanting” and “liking” as proposed by Berridge and colleagues in relation to food intake (263 ). Interestingly, the adipocyte derived hormone leptin and the gut derived hormones ghrelin and PYY are likely to act locally to influence the activity of this pathway.

“Primary taste neurons” are located in the insular cortex that are responsive to sweet, salt, bitter, sour and umami taste. They are supplied by NTS neurons by way of the thalamus. These neurons provide representations of food in the mouth independently of hunger and thus of reward value and pleasantness. These cells project in turn to “secondary taste neurons” in the orbitofrontal cortex that integrate taste information with olfactory and visual inputs. The orbitofrontal cortex is responsible for forming learned associations and is a crucial site for interactions between sensory inputs produced by food and hunger/satiety signals. This system determines how pleasant a food is and whether we have an appetite for it or; in other words, the reward value is explicitly represented in the area where satiety signals modulate the response of the taste and flavor neurons. The orbitofrontal cortex is known to be a site where pleasantness and palatability of food are represented. It has connections to adjoining areas, including the cingulate cortex and nucleus accumbens, through which it can drive eating behavior.

In light of the above, the challenge is to identify and understand the nature of the integration of three key pathways: 1) the homeostatic regulation directed primarily from the ARC and brain stem, 2) the hedonistic/motivational regulation seated in mesolimbic pathways and 3) the afferent pathways that convey this information to “higher” cortical brain regions.

Food intake is thus controlled by building a multimodal representation of the sensory properties of food in the orbitofrontal cortex, which is then gated by satiety signals to produce a construct of the pleasantness and reward value of food which subsequently drives food intake. Therefore, body weight regulation not only depends on homeostatic signals emerging from nutrient supply and energy stores but it is also influenced by hedonistic and reward stimuli that may shift energy balance toward food intakes higher than energy expended leading in the long-term to body weight gain and possibly obesity. This implies that pharmacologic treatment of obesity may not only include medication targeting homeostatic signals but also compounds with combined targeting of homeostatic and hedonistic/reward signals.

SUMMARY

This chapter attempts to provide an overview of the known physiological processes that occur in the brain to integrate and analyze a large variety of afferent signals reflecting energy requirements and that respond with the appropriate compensatory changes in appetite, metabolism and behavior. Immediate conditions instantly induce hormonal and neuronal messages from the periphery that communicate to distinct areas of the brain the need for regulatory changes in order to maintain energy balance. It is within these brain areas that not only sensations such as hunger and satiety are created, but also outgoing impulses for food seeking behavior, changes in locomotor activity or appropriate modulations of peripheral metabolic drive are triggered. The localization and precise action of these brain centers, as well as the exact mapping of their interactive signal transduction pathways, remain largely unknown despite great scientific progress in this field during the last two decade. A finely tuned balance of action potentials, synaptic neurotransmitters, feedback loops and neuropeptide expression levels between regulatory centers in the brainstem, hypothalamic nuclei, basal ganglia, nucleus accumbens and even the cortex underlies the constant adjustments that take place. The redundant multiplicity of factors governing energy balance, that have been generated due to the evolutionary need to ensure sufficient caloric intake, is regarded as one reason for the continued failure to generate an effective pharmacotherapy for obesity.

Neuropeptides in hypothalamic circuits involved in metabolism regulation

The past decades have provided overwhelming evidence that the principle signaling modality within brain centers of energy balance regulation is via chemical synapses. As eluded earlier, chemical neurotransmission occurs by the release of neurotransmitters and neuropeptides from synaptic vesicles of axon terminals onto their respective receptors located at the postsynaptic membrane or membranes of adjacent axon terminals. Studies indicate that the central regulation of feeding behavior and energy expenditure relies on the appropriate interaction between particular neuropeptides. In this regard, those key hypothalamic neuropeptide systems that have been most closely associated with metabolism regulation are summarized below. However, some other peptides that are involved to a lesser extent will not be discussed. A detailed and thorough description of these peptides and their functions can be found in elaborate reviews (1 , 19 , 22-33 , 199 , 264 , 265 ).

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