INTRODUCTION:

Obesity is a major health disorder whose prevalence is increasing dramatically worldwide^1–6. This epidemic, accompanied by metabolic and behavioral disorders^7,8, is the result of genetic and particularly environmental factors. Despite advanced research in this field, the rate of obesity and related disorders is dramatically increasing due to a change in the quality of foods consumed and the dietary behavior whose maintenance is an essential condition for the survival of organisms. Food intake is a complex act that results from the integration of many signals of different natures and duration in the central nervous system (CNS)⁹.

Signals of hunger and satiety of hormonal or nervous nature are permanently integrated by various structures of the CNS such as the hypothalamus or the brainstem to modify feeding behavior and the interaction between the different structures, which are undoubtedly very complex¹⁰. The choice of hypothalamic structures in this review is due to their intervention in the regulation of hunger and satiety (PVN, AN, HL, VMN)¹¹. Thus, eating behavior also depends on the individual's emotion towards food¹² and the motivation that comes primarily from activating the reward system that initiates this behavior which incites the individuals to consume mostly palatable food¹³. This system is also referred to as the hedonic system (Nacc, VTA, and VP), and is associated with activation of the neuronal reward system in response to any highly palatable food, i.e., any food which independently of its nutritional value produces a pleasurable sensation¹⁴. Indeed, recent studies have shown that obesity is not only influenced by lifestyle changes and the underlying homeostatic mechanisms but also by cognitive, social, and emotional factors^15,16.

Homeostatic Regulation of Food Intake:

Peripherally-derived Satiety, Hunger and Adiposity signals:

The involvement of dietary protein and circulating amino acid concentrations in the regulation of food intake has been suggested as early as the 1990s¹⁷. These proteins exert a satietogenic role in the short term¹⁸. Conversely, a diet low in protein induces a stimulating effect on food intake¹⁹. Also, some neurons in the hypothalamus exert their modulated activities according to glucose concentration. Indeed, these neurons are named GR (Glucose Responsive) neurons whose activity increases when blood sugar levels increase, and GS (Glucose Sensitive) neurons whose activity is inhibited by high concentrations of glucose. These neurons were first identified in VMH and LH²⁰, however, it is now recognized that AN and PVN also present such neurons²¹. The cellular and molecular mechanisms thereby these neurons detect variations in glycemia would involve actors common to those described in the pancreas, in particular the transporter Glut-2²², glucokinase²³, or the ATP-dependent potassium channels²⁴. It is noteworthy that hormones synthesized by the gastrointestinal tract also regulate food intake. These peptide hormones are produced in response to the activation of baro- and chemoreceptors signaling to the gastrointestinal tract depending on the presence and the energy density of the food ingested. The information is then relayed to the CNS, which then helps to regulate the food intake²⁵.

Among the gastrointestinal signals, the anorectic signals play a crucial role in the regulation of food intake, notably the peptide YY3-36, cholecystokinin (CCK), and leptin^26–28. In contrast, ghrelin is the only peripheral orexigenic known signal to date²⁹. Indeed, ghrelin, which was isolated from rat stomach, plays an important role in regulating energy balance³⁰. Ghrelin has been thought to be viewed as the product of a "thrifty" gene, promoting food consumption and fat storage and thus allowing the body to adapt to different periods of famine ²⁹. By binding to its GHS-R receptor (growth hormone secretagogue receptor), ghrelin stimulates the secretion of growth hormone from the pituitary gland as well as many peptides such as prolactin³¹. While at the AN level, it activates orexigenic neurons, stimulates the production of NPY and AgRP, and inhibits anorectic neurons, opposing therefore the action of leptin and thus inducing an increase in food intake and body weight^32,33. Leptin, the product of the obese gene (ob), which was first cloned from the adipose tissue of genetically obese mice (ob/ob mice) is secreted into the bloodstream in proportion to the adipose tissue mass and acts as a factor of satiety to reduce food intake³⁴. This hormone has six receptors called Ob-Ra to Ob-Rf, while the Ob-Rb receptor is the most functional. The activation of the Ob-Rb receptor at the AN level causes the production of anorectic peptides with a similar effect as observed under the action of insulin³⁵.

Hypothalamic Neuronal circuits:

Several studies performed on the hypothalamus, brainstem, and intestinal-brain axis, have demonstrated the presence of food intake regulators. The hypothalamus is the seat of the regulation of food intake¹⁶. This structure is composed of several nuclei controlling hunger and satiety. The arcuate nucleus (AN) is considered a metabolic relay in reason of its location at the median eminence³⁶ structure which is devoided of the blood-brain barrier. This nucleus constitutes the mid-basal hypothalamus with the ventromedial nucleus (VMN), which receives signals from the periphery. The AN has two neuronal populations notably POMC neurons (pro-opio melanocortin), which produce POMC and CART (Cocaine and amphetamine Regulate transcript) and NPY / AgRP neurons (neuropeptide Y) (agouti-related protein) whose production is hormone-dependent³⁷. Excessive activation of neurons at NPY / AgRP is the main feature of people with obesity. The lateral hypothalamus (LH) is considered a center of hunger comprising a wide variety of neurons that express orexigenic peptides: Orixen A and B also called hypocretins³⁸. The activation of this nucleus depends on the stimulation of the neuronal population at NPY of AN by the ghrelin hormone. The LH expresses Melanin Concentrating Hormone (MCH) neurons which are inhibited by leptin³⁹. Any destruction of this nucleus leads to hypophagia⁴⁰, and the individual is indifferent to food. The VMN and the paraventricular nucleus (PVN) are considered the center of satiety⁴¹. The destruction of one of these nuclei leads to morbid obesity following increased food intake. The VMN expresses Neurons that produce the steroidogenic factor (SF1) that decreases food intake. Indeed, studies have shown that SF-1 KO mice represent a genetic model of obesity⁴². Some neurons of the VMN express the Brain-Derived Neurotrophic Factor (BDNF)^43,44. An injection of this factor in the VMN nucleus of normal rats induces a drop in weight caused by the decrease in food intake⁴⁵. Any lesion of the anterior part of the hypothalamus, notably at the PVN nucleus is accompanied by the development of obesity and hyperphagia⁴⁶. The hypothalamus controls food intake through metabolic signals particularly leptin and insulin which stimulate POMC neurons of the AN that project to the PVN to inhibit food intake while ghrelin acts on NPY / AgRP neurons that stimulate LH and inhibit PVN⁴⁷. The STN (Solitary tract nucleus) controls food intake by metabolic signals that pass through the Area postrema (AP) or through peripheral stimulation of the vagus nerve that transmits the nerve impulse to the STN that projects to the nuclei of the hypothalamus⁴⁸ (figure 1).

Figure 1. Schematic representation of the metabolic regulation of food intake: LH (lateral hypothalamus), CRF (corticotropic factor), ME (median eminence), NPY (neuropeptide Y), AgRP (agouti-related protein), GABA (Gamma-Amino Butyric acid), AN (Arcuate nucleus) POMC (pro-opio-melano-cortin), VMH (ventromedial nucleus of hypothalamus), SF1 (steroidogenic factor), BDNF (Brain-derived neurotrophic factor), PVN (the paraventricular nucleus) MCH ( melanocortin hormone), AP (area postrema), STN (Solitary tract nucleus), GLP ( glucagon like-protein). The hypothalamus controls food intake through metabolic signals, leptin and insulin stimulate POMC neurons of the AN that will project to the PVN to inhibit food intake while ghrelin acts on NPY / AgRP neurons that will stimulate LH and inhibit PVN. The STN controls food intake by metabolic signals that pass through the AP or through peripheral stimulation of the vagus nerve that transmits the nerve impulse to the STN that will project to the nuclei of the hypothalamus.

Brainstem mechanisms:

The regulation of energetic homeostasis is complex and involves several cerebral structures depending on the nature of the signals⁴⁹. The STN, considered a visceral-sensory relay, constitutes a privileged center for the short-term regulation of food intake due to strong connections with the Area postrema (AP) and the dorsal motor nucleus of the vagus nerve (DMNV)⁵⁰. Studies have shown that the destruction of the STN induces hyperphagia⁵¹. The STN integrates pre- and post-absorptive signals via the vagus nerve or hormones by responding to signals from digestion⁵². The STN contains noradrenergic neurons activated by mechanical stimulation (distortion of the stomach or intestine that activates vagus nerve mechanoreceptors that transmit the signal to noradrenergic neurons in STN)⁵³. The STN also contains GLP-1 (glucagon-like peptide-1) neurons which project to the PVN (paraventricular nucleus) with an anorectic role⁵⁴. It should be noted that the POMC neurons located in the brainstem secrete POMCs which are precursors of α-MSH (α-Melanocyte-stimulating hormone), acting on the neurons of the PVN to induce an anorexigenic effect⁵⁵.

HEDONIC ASPECT AND FOOD INTAKE:

Dopamine mediated Regulation of Reward circuits:

Recent studies have shown that control of food intake has exceeded metabolic signals¹⁷. In the majority of humans, food consumption depends on their mood state, suggesting the intervention of structures responsible for hedonism: Nacc, VP, VTA, prefrontal cortex, and the amygdala which are part of the reward system⁵⁶. These structures of hedonism are responsible for learning, emotion, motivation, and liking⁵⁷.

During food intake, the natural processes related to obtaining a reward involve the ventral striatum structure in the regulation of motivated behaviors⁵⁸. These processes are similar to those of addiction⁵⁹. The deregulation of food intake in people with obesity may be associated with emotion, which requires subsequent recognition of food at the central amygdala (CeA), a small area of the amygdala that is involved in the integration of emotional signals⁹. Following this learned emotion, the CeA transmits the message to the Accumbens Shell Nucleus (Nacc) (pleasure and reward center) which is responsible for the motivational aspect related to hedonism (Wanting)⁶⁰. The Nacc inhibits VTA activity by direct projection via GABAergic neurons called Medium Spiny neurons (MSN) while it causes VTA activation by indirect projection via the ventral pallidum (VP)⁶¹. The MSN expressing D1-like receptors project directly to VTA while D2-like receptors project to VP. They are the mechanisms by which Nacc controls the activity of VTA which produces the well-known molecule with a motivational aspect, dopamine⁶² (Figure 2).

Figure 2. Regulation of dopamine production: The presence of a palatable food activates the MSN neurons of the Nacc which project towards the PV to lift the inhibition that has been exerted on the VTA, which activates this nucleus. Whereas the absence of this food activates MSNs, which project directly onto the VTA to inhibit it. MSN: medium spiny neurons. VTA: ventral tegmental area. GABA : γ-aminobutyrique acid. PV : ventral pallidum. – Inhibition. + Stimulation.

In people with obesity characterized by a loss of control over food intake^63,64, the motivational aspect may be unconscious, which corresponds to a state called (incentive salience) involving dopaminergic connections between Nacc and VTA⁶⁵. The CeA is responsible for the learning process while the mechanisms involving the Nacc and the CeA are responsible for the affective component linked to positive reinforcement (figure 3). In addition, the mechanisms that involve Nacc, PV, and VTA are responsible for the process of motivation through dopamine production⁶². Nacc neurons receive direct afferents notably dopaminergic from VTA, and glutamatergic from CPF and CeA, and indirect afferents from VTA and CPF via GABAergic and cholinergic interneurons⁶². Studies have shown that injection of Nacc with a cholinergic antagonist caused a decrease in the levels of opioid peptide mRNA expression and food intake⁶². CeA is responsible for the learning of the emotions to food and projects towards the Nacc to control the production of dopamine by the VTA which is responsible for the pleasure of consuming palatable foods. This phenomenon is also controlled by indirect projections of the VP which increases the production of dopamine, and PFC inhibits all the pleasure in consuming these foods^63,66.

Figure 3. Scheme showing dopamine production during positive or negative reinforcement. A: Dopamine production during positive reinforcement. B: Dopamine production during negative reinforcement. The presence of a positive reinforcer activates the central nucleus of the amygdala, which projects to the Nacc, stimulating the VTA to produce dopamine, which promotes motivation and the search for pleasure. PFCm, which generally inhibits Nacc activation, will in turn be inhibited by dopaminergic projections following the presence of G2 dopaminergic receptors, resulting in excessive Nacc activation. During negative reinforcement, these mechanisms are reversed. – Inhibition. + Stimulation.

Opioid and Endocannabinoid mediated Regulation of Reward circuits:

In people with obesity, the emotion created about food and the motivation to consume it are translated in the form of “liking” which involves the GABAergic and opioidergic system⁶⁷ of Nacc and VTA whose stimulation leads to the development of conscious and unconscious pleasure associated with a stimulus of a visual, odor or taste nature⁶⁸. The overconsumption of palatable foods is considered to be an addiction caused by an overproduction of endocannabinoids and opioid peptides⁶⁹. The dysfunction of such a system is accompanied by deregulation of dopamine production which is the cause of overconsumption of palatable foods. The production of anandamide, an endocannabinoid molecule highly expressed in the brain, increases the consumption of sugary foods following the action of this molecule on the CB1 receptor located in the interneurons of the Nacc⁷⁰. As for drug use, repeated ingestion of palatable foods activates centers of hedonism including Nacc, CeA, and VTA or the opioid and endocannabinoid systems. Animal investigations have shown that consumption of palatable foods leads to an increase in the expression of CB1 mRNA⁷¹. Many studies have demonstrated the presence of μ receptors (opioid receptors) at the level of the caudal part of the Nacc and the rostral part of the VP, and their stimulation by opioid peptides is responsible for “liking”⁷².

Repeated stimulation of the hedonism pathways by palatable foods could induce neurobiological adaptations increasing therefore the frequency of food urges. Actual data state that the hedonic component of food intake is selectively established by a Nacc neural network and relies on modulation performed by the opioid system while the motivational component relies on the action of dopamine from the Nacc-VTA axis of the mesocorticolimbic system. The Nacc-VTA connections are controlled by highly hierarchical structures of the PFC⁷³. The orbitofrontal cortex is involved in food choice and decision making as food preference is controlled by CeA which is modulated by opioids. However, the cognitive side is provided by the dorsolateral CPF⁷⁴. All of these structures involved in the hedonic process are controlled by metabolic signals. The reward induced by food intake is also under the control of the hypothalamic LH structure which projects towards the Nacc and the PV which contain receptors for orexigenes molecules⁷³.

INTERACTIONS BETWEEN THE HOMEOSTATIC AND THE NON-HOMEOSTATIC HEDONIC MECHANISMS:

At the AN level, leptin and insulin modulate the activity of orexigenic and anorectic neurons⁷⁵. Indeed, they inhibit the expression of the orexigenic neuropeptides notably NPY and AgRP⁷⁶, and activate the expression of the anorectic neuropeptides particularly POMC and CART⁷⁷.

The binding of leptin to its ObRb receptor is capable of recruiting the PI3K (Phosphatidyl-Inositol-3-Kinase) signaling pathway, either directly or via JAK tyrosine kinases (Janus kinases) which are phosphorylating proteins linked to the intramembrane domain of the ObRb⁷⁸. It is well known that insulin activates the IRS / PI3K signaling pathway (insulin receptor substrate /PI3K), however, leptin was also found to play with insulin synergistic role in this pathway⁷⁹. Indeed, studies have demonstrated accordance in leptin and insulin signaling pathways at the level of IRSs‐PI 3‐kinase and divergence at the level of Akt. However, the direct and positive cross‐talk between insulin and leptin at the level of Janus kinase 2 and signal transducer and activator of transcription 3 tyrosine phosphorylation constitute a potential mechanism thereby both insulin and leptin control food intake and body weight⁸⁰.

Under certain conditions, the homeostatic control of food intake can be exceeded by these signals since non-homeostatic factors linked to hedonism could interfere⁸¹. In fact, the conscious or unconscious purpose of hedonism is the search for reward that generates pleasure^52,81. This component depends on the subsequent recognition of the food (which creates an emotion vis-à-vis this food at the level of the central amygdala), the motivational aspect of hedonism, or "wanting" at the level of the Nacc and VTA and the aspect of hedonism "liking,"⁸² which illustrates the conscious or unconscious pleasure associated with a stimulus. Indeed, the Nacc receives afferents from STN⁸³ situated in the brainstem relaying the signals from the intestinal tract, but also afferents related to the taste⁸⁴, texture, and palatability of food emanating from the oropharyngeal sphere, which passes through the parabrachial nucleus (PBN) to the Nacc^71,85. The same information from visceral and gustatory sources passes through highly hierarchical structures of the PFC or orbitofrontal cortex (OFC) which in turn project onto the Nacc^14,72. The amygdala, a key structure of the limbic system associated with affective reactions, is the target of both PFC and Nacc⁸⁶. These structures integrate several afferents from central structures involved in the different affective, cognitive, and emotional facets, as well as hypothalamic afferents directly reflecting the metabolic status of the organism⁸⁷. The attribution of a hedonic value to food implies the release and the action of dopamine in these regions in order to participate in the establishment, in a more or less lasting way in obtaining a "reward"⁸⁸. Indeed during positive reinforcement, the nucleus accumbens is activated following the reception of signals from the CeA. The activated projections of the nucleus accumbens inhibit the VP which reverses the inhibition exerted on VTA. This connecting loop triggers the activation of VTA and thus the release of dopamine⁸⁹ (figure 4). As for the hedonic value of food relative to liking, it involves GABA neurons and the Nacc opioid system: µ opioid receptors and GABAergic Nacc neurons are also activated and in turn activate orexin neurons in LH. The orexin neurons of LH project towards other nuclei involved in the regulation of food intake, such as AN or PVN, which induce an orexigenic response leading to overeating and promoting the onset of obesity^90,91.

Figure 4. Schematic representation of the hedonic aspect of food intake: CeA (central amygdala), Nacc (nucleus accumbens), VP (ventral pallidum), LH (lateral hypothalamus, VTA (ventral tegmental area, PFC (Prefrontal cortex), GABA (gamma-Aminobutyric acid). CeA is responsible for the learning of the emotions to food projects towards the Nacc in order to control the production of dopamine by the VTA which is responsible for the pleasure of consuming palatable foods, this phenomenon is also controlled by indirect projections of the VP which increases the production of dopamine and PFC which inhibits all the pleasure to consume these foods.

CONCLUSION:

Maintaining energy homeostasis requires controlling energy intake from food intake and energy expenditure. The regulation of this physiological process is complex and involves environmental (stress, olfaction, taste), nervous (via the vagus nerve), endocrine (leptin, insulin, ghrelin, etc.), or metabolic (glucose, free fatty acids, amino acids) signals. These peripheral signals (especially from the liver, muscles, adipose tissue, and pancreas) all converge to the CNS through the blood and/or nerves which provide information on the energy status of the body. In response to this information, the CNS delivers adapted signals to the periphery via the autonomic nervous system and the hypothalamic-pituitary complex. In addition, there is the hedonic component which involves the reward system in order to choose the food consumed, taking into account the emotion towards this food and the motivation to obtain it. There is therefore a regulatory loop between the CNS and the periphery allowing precise adaptation of energy inputs to the needs of the body.

Future Research Directions:

The review underscores the intricate regulation of energy homeostasis, highlighting the roles of environmental, nervous, endocrine, and metabolic signals. To further our understanding and improve interventions, future research should focus on several key areas.

First, the integration of environmental and sensory influences requires deeper exploration. Studies should investigate how factors like stress and sensory stimuli (olfaction and taste) interact with physiological signals to affect eating behavior and energy balance. Understanding the long-term effects of chronic stress and environmental changes on energy homeostasis and metabolic health is particularly important.

Second, the role of the vagus nerve in energy regulation warrants further investigation. Research should aim to elucidate the specific mechanisms by which the vagus nerve transmits energy status signals from peripheral organs to the CNS. Additionally, the therapeutic potential of vagus nerve stimulation for treating metabolic disorders should be assessed.

Third, the endocrine and metabolic signaling pathways need more comprehensive study. Future research should delve into the roles of key hormones (leptin, insulin, ghrelin) and metabolic substrates (glucose, free fatty acids, amino acids) in energy regulation. It is also crucial to examine how these signals interact and collectively influence the CNS's response to the body's energy status.

Fourth, understanding CNS responses to energy signals is essential. Mapping the specific regions and circuits within the CNS responsible for integrating peripheral signals and coordinating energy homeostasis will provide valuable insights. Investigating the molecular and cellular mechanisms underlying CNS responses to changes in energy status can further clarify this process.

Finally, the hedonic component and the reward system's involvement in food intake regulation should be a focus. Research should study the neural pathways involved in the hedonic regulation of food intake, with particular attention to the reward system and its role in food choice, emotional response to food, and motivation to obtain it. This understanding could inform strategies to manage overeating and obesity. By addressing these areas, future research can significantly advance our knowledge of energy homeostasis and contribute to more effective interventions for metabolic disorders.

ABBREVIATIONS:

AN : arcuate nucleus; PVN : paraventricular nucleus; LH : lateral hypothalamus; STN : solitary tract nucleus; CeA : central amygdala ; Nacc : nucleus accumbens; VTA : ventral tegmental area; PFC : prefrontal cortex; GR : Glucose Responsive; GS : Glucose Sensitive; VMH : ventro-medial nucleus of hypothalamus; CCK : cholecystokinin; GHS-R : growth hormone secretagogue; POMC : pro-opio melanocortin; CART : Cocaine and amphetamine Regulate transcript; NPY / AgRP : neuropeptide Y / agouti-related protein; AP : Area postrema; GLP-1 : glucagon-like peptide-1; α-MSH : α-Melanocyte-stimulating hormone.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors are very thankful for the technical assistance provided by the Biology Department staff of Ibn Tofail University's Faculty of Science.

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Received on 23.05.2024 Revised on 17.08.2024

Accepted on 21.10.2024 Published on 24.12.2024

Available online from December 27, 2024

Research J. Pharmacy and Technology. 2024;17(12):6150-6157.

DOI: 10.52711/0974-360X.2024.00933