Prokineticin Receptor Inhibition With PC1 Protects Mouse Primary Sensory Neurons From Neurotoxic Effects of Chemotherapeutic Drugs in vitro.

Neurotoxicity is a common side effect of chemotherapeutics that often leads to the development of chemotherapy-induced peripheral neuropathy (CIPN). The peptide Prokineticin 2 (PK2) has a key role in experimental models of CIPN and can be considered an insult-inducible endangering mediator. Since primary afferent sensory neurons are highly sensitive to anticancer drugs, giving rise to dysesthesias, the aim of our study was to evaluate the alterations induced by vincristine (VCR) and bortezomib (BTZ) exposure in sensory neuron cultures and the possible preventive effect of blocking PK2 signaling. Both VCR and BTZ induced a concentration-dependent reduction of total neurite length that was prevented by the PK receptor antagonist PC1. Antagonizing the PK system also reduced the upregulation of PK2, PK-R1, TLR4, IL-6, and IL-10 expression induced by chemotherapeutic drugs. In conclusion, inhibition of PK signaling with PC1 prevented the neurotoxic effects of chemotherapeutics, suggesting a promising strategy for neuroprotective therapies against the sensory neuron damage induced by exposure to these drugs.

Abundance of Probiotics and Butyrate-Production Microbiome Manages Constipation via Short-Chain Fatty Acids Production and Hormones Secretion.

SCOPE: The characteristics of gut microbiota and host metabolism are hypothesized to be associated with constipation status, but the regulation mechanism is not fully understood. Thus, the current study investigates the effect of constipation symptoms on gut functionality following the modulation of gut microbiota and metabolites via dietary fiber intervention. METHODS AND RESULTS: Constipation causes a significantly reduced short-chain fatty acids (SCFAs) production and a higher level of iso-butyrate. The feces of constipated people are characterized with inhibited Faecalibacterium, Ruminococcaceae and Roseburia abundance. Desulfovibrionaceae is identified to be an important endotoxin producer in constipated patients, and a butyrate-enriched SCFAs profile achieved by dietary fiber supplement accelerates gastrointestinal transit and increases the thickness of the mucosal layer, possibly through triggering the secretion of colonic hormones and enhancing the expression of tight junction proteins for maintaining intestinal barrier integrity. More importantly, an interacting regulatory mechanism among SCFAs, in particular butyrate and propionate, may be involved in signaling between the microbiome and host cells in the colon. CONCLUSION: Gut microbiota, characterized with enriched butyrate-producing and depressed Desulfovibrionaceae bacteria, attenuates constipation symptoms through promoting intestinal hormones secretion and maintaining gut barrier integrity.

Central and peripheral control of food intake.

The maintenance of the body weight at a stable level is a major determinant in keeping the higher animals and mammals survive. Th e body weight depends on the balance between the energy intake and energy expenditure. Increased food intake over the energy expenditure of prolonged time period results in an obesity. Th e obesity has become an important worldwide health problem, even at low levels. The obesity has an evil effect on the health and is associated with a shorter life expectancy. A complex of central and peripheral physiological signals is involved in the control of the food intake. Centrally, the food intake is controlled by the hypothalamus, the brainstem, and endocannabinoids and peripherally by the satiety and adiposity signals. Comprehension of the signals that control food intake and energy balance may open a new therapeutic approaches directed against the obesity and its associated complications, as is the insulin resistance and others. In conclusion, the present review summarizes the current knowledge about the complex system of the peripheral and central regulatory mechanisms of food intake and their potential therapeutic implications in the treatment of obesity.

Pulse Width-Dependent Effects of Intestinal Electrical Stimulation for Obesity: Role of Gastrointestinal Motility and Hormones.

INTRODUCTION: The goals of this experiment were to study therapeutic potential of intestinal electrical stimulation (IES) for obesity, its mechanisms involving gastrointestinal motility and hormones, and role of pulse width in diet-induced obese rats. METHODS: In a 4-week study, rats equipped with one pair of electrodes at the duodenum were assigned to receive either a sham or IES of varied pulse widths in a sequential way. Food intake was measured daily and body weight measured weekly. Blood samples were collected for the measurement of glucagon-like peptide-1 (GLP-1). Solid gastric emptying (GE) and small bowel transit (SIT) tests were performed at the end of the experiment. RESULTS: The results of the study were as follows: (1) Daily food intake, not affected by IES of 0.3 ms, was pulse width-dependently reduced by 1.9 g with 1 ms and by 5.7 g with 3 ms. Accordingly, body weight was pulse width-dependently reduced by 2.4 g with 1 ms and by 12.8 g with 3 ms compared to a gain of 5.6 g in sham. (2) GLP-1 level was elevated by both 0.3 and 3 ms at 15 min, but was elevated only with 3 ms at 60 min. (3) GE was delayed to 52.3 % by IES of 3 ms but not 0.3 ms, compared to that at 64.4 % with sham IES. (4) Compared to the geometric center of 7.0 with sham IES, SIT was accelerated by 3 ms to 7.8 but not by 0.3 ms. CONCLUSION: IES pulse width-dependently reduces food intake and body weight, attributed to the delay of gastric emptying and the acceleration of small bowel transit, as well as the enhancement of GLP-1 secretion.

Activation of Nesfatin-1-Containing Neurones in the Hypothalamus and Brainstem by Peripheral Administration of Anorectic Hormones and Suppression of Feeding via Central Nesfatin-1 in Rats.

Peripheral anorectic hormones, such as glucagon-like peptide (GLP)-1, cholecystokinin (CCK)-8 and leptin, suppress food intake. The newly-identified anorectic neuropeptide, nesfatin-1, is synthesised in both peripheral tissues and the central nervous system, particularly by various nuclei in the hypothalamus and brainstem. In the present study, we examined the effects of i.p. administration of GLP-1 and CCK-8 and co-administrations of GLP-1 and leptin at subthreshold doses as confirmed by measurement of food intake, on nesfatin-1-immunoreactive (-IR) neurones in the hypothalamus and brainstem of rats by Fos immunohistochemistry. Intraperitoneal administration of GLP-1 (100 µg/kg) caused significant increases in the number of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the supraoptic nucleus (SON), the area postrema (AP) and the nucleus tractus solitarii (NTS) but not in the paraventricular nucleus (PVN), the arcuate nucleus (ARC) or the lateral hypothalamic area (LHA). On the other hand, i.p. administration of CCK-8 (50 µg/kg) resulted in marked increases in the number of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the SON, PVN, AP and NTS but not in the ARC or LHA. No differences in the percentage of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the nuclei of the hypothalamus and brainstem were observed between rats treated with saline, GLP-1 (33 µg/kg) or leptin. However, co-administration of GLP-1 (33 µg/kg) and leptin resulted in significant increases in the number of nesfatin-1-IR neurones expressing Fos-immunoreactivity in the AP and the NTS. Furthermore, decreased food intake induced by GLP-1, CCK-8 and leptin was attenuated significantly by pretreatment with i.c.v. administration of antisense nesfatin-1. These results indicate that nesfatin-1-expressing neurones in the brainstem may play an important role in sensing peripheral levels of GLP-1 and leptin in addition to CCK-8, and also suppress food intake in rats.

[Glucose homeostasis and gut-brain connection]. / Contrôle de la glycémie par l'axe nerveux intestin-cerveau.

Since the XIX(th) century, the brain has been known for its role in regulating food intake (via the control of hunger sensation) and glucose homeostasis. Further interest has come from the discovery of gut hormones, which established a clear link between the gut and the brain in regulating glucose and energy homeostasis. The brain has two particular structures, the hypothalamus and the brainstem, which are sensitive to information coming either from peripheral organs or from the gut (via circulating hormones or nutrients) about the nutritional status of the organism. However, the efforts for a better understanding of these mechanisms have allowed to unveil a new gut-brain neural axis as a key regulator of the metabolic status of the organism. Certain nutrients control the hypothalamic homeostatic function via this axis. In this review, we describe how the gut is connected to the brain via different neural pathways, and how the interplay between these two organs drives the energy balance.

Gastrointestinal hormones and gut motility.

PURPOSE OF REVIEW: To summarize the recent findings. RECENT FINDINGS: Studies of changes in the plasma levels confirm the earlier concepts, but offer little proof of causal effect. It is increasingly realized that peptides produced in the gut have a paracrine role or an indirect effect via the gut-brain axis. Interest in prokinetic peptide agonists remains high despite the failure of two candidate drugs, but relamorelin and camicinal offer new hope. SUMMARY: We review the original studies published since January 2013 on peptides produced in the gut and with an effect on gastrointestinal motility.

[Food intake regulation -  1st part]. / Regulace príjmu potravy -  I. cást.

The review article summarizes a very complex process of appetite regulation: the part focused on homeostatic regulation of food intake. The aim of homeostatic regulation is to achieve energy balance, stabile weight and optimal nutrient intake, in contrast to hedonic regulation of food intake, in which emotional and motivational factors are involved. Homeostatic regulation could be divided into shortterm and longterm regulation and comprises mainly gastrointestinal peptides, fat tissue hormones and central mechanisms localized in hypothalamus. It is a resultant of the action of orexigenic factors (increasing appetite and food intake) and anorexigenic factors (decreasing appetite and thus food intake), respectively. The anorexigenic factors include gastrointestinal peptides (e.g. cholecystokinin, glucagonlike peptide 1, bombesin, peptide YY and others), hormone of fat tissue leptin and centrally acting melanocortin system. On the contrary, orexigenic factors comprise of gastric ghrelin and centrally acting system of neuropeptide Y/ Agoutirelated peptide. Understanding the principles of the regulation of food intake is essential for comprehension of pathogenesis of eating disorders and obesity, whose prevalence has been recently increasing, and it provides potential targets for pharmacological interventions.

Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system.

Although Berberine (BER) is popular in treating gastrointestinal (GI) disorders, its mechanisms are not clear yet. In order to investigate the effects and possible mechanism of BER on GI motility in rodents, we first explored GI motility by recording the myoelectrical activity of jejunum and colon in rats, and upper GI transit with a charcoal marker in mice. Then, the plasma levels of gastrin, motilin, somatostatin and glucagon-like-peptide-1 (Glp-1) were measured by ELISA or radioimmunoassay (RIA). Furthermore, endogenous opioid-peptides (ß-endorphin, dynorphin-A, met-enkephalin) were detected by RIA after treatment with BER. Our results showed that BER concentration-dependently inhibited myoelectrical activity and GI transit, which can be antagonized by opioid-receptor antagonists to different extents. The elevated somatostatin and Glp-1, and decreased gastrin and motilin in plasma, which were caused by BER application, also could be antagonized by the opioid-receptor antagonists. Additionally, plasma level of ß-endorphin, but not dynorphin-A and met-enkephalin, was increased by applying BER. Taken together, these studies show that BER plays inhibiting roles on GI motility and up-regulating roles on somatostatin, Glp-1 and down-regulating roles on gastrin, motilin. The pharmacological mechanisms of BER on GI motility and plasma levels of GI hormones were discovered to be closely related to endogenous opioid system.

Gastric stimulation for weight loss.

The prevalence of obesity is growing to epidemic proportions, and there is clearly a need for minimally invasive therapies with few adverse effects that allow for sustained weight loss. Behavior and lifestyle therapy are safe treatments for obesity in the short term, but the durability of the weight loss is limited. Although promising obesity drugs are in development, the currently available drugs lack efficacy or have unacceptable side effects. Surgery leads to long-term weight loss, but it is associated with morbidity and mortality. Gastric electrical stimulation (GES) has received increasing attention as a potential tool for treating obesity and gastrointestinal dysmotility disorders. GES is a promising, minimally invasive, safe, and effective method for treating obesity. External gastric pacing is aimed at alteration of the motility of the gastrointestinal tract in a way that will alter absorption due to alteration of transit time. In addition, data from animal models and preliminary data from human trials suggest a role for the gut-brain axis in the mechanism of GES. This may involve alteration of secretion of hormones associated with hunger or satiety. Patient selection for gastric stimulation therapy seems to be an important determinant of the treatment's outcome. Here, we review the current status, potential mechanisms of action, and possible future applications of gastric stimulation for obesity.

Neuroendocrine control of metabolism.

Metabolism is controlled through homeostatic system consisting of central centers, gut hormones, hormones from adipose tissue and the other hormonal axes. This cooperation is based on cross-talk between central and peripheral signals. Among them the hypothalamus plays a crucial role, with interconnected nuclei forming neuronal circuits. Other regions in the brain, such as the brain stem, the endocannabinoid system, the vagal afferents, are also involved in energy balance. The second component is peripheral source of signals--the gastrointestinal tract hormones. Additionally, adipokines from adipose tissue, thyrotropic, gonadotropic and somatotropic axes play a role in energy homeostasis. Knowledge about all components of this neuroendocrine circuit will be helpful in developing novel therapeutic approaches against the metabolic syndrome and its components.

Murine guanylate cyclase C regulates colonic injury and inflammation.

Guanylate cyclase C (GUCY2C or GC-C) and its ligands, guanylin (GUCA2A or Gn) and uroguanylin (GUCA2B or Ugn), are expressed in intestinal epithelial cells and regulate ion secretion, intestinal barrier function, and epithelial monolayer homeostasis via cGMP-dependent signaling pathways. The aim of this study was to determine whether GC-C and its ligands direct the course of intestinal inflammation. In this article, we show that dextran sodium sulfate (DSS)-induced clinical disease and histological damage to the colonic mucosa were significantly less severe in GC-C(-/-) mice and moderately reduced in Gn(-/-) animals. Relative to wild-type controls, GC-C(-/-) and Gn(-/-) mice had reduced apoptosis and increased proliferation of intestinal epithelial cells during DSS colitis. Basal and DSS-induced production of resistin-like molecule ß (RELMß) was substantially diminished in GC-C(-/-) mice. RELMß is thought to stimulate cytokine production in macrophages in this disease model and, consistent with this, TNF-α and IFN-γ production was minimal in GC-C(-/-) animals. RELMß and cytokine levels were similar to wild-type in Gn(-/-) mice, however. Colonic instillation of recombinant RELMß by enema into GC-C(-/-) mice restores sensitivity to DSS-mediated mucosal injury. These findings demonstrate a novel role for GC-C signaling in facilitating mucosal wounding and inflammation, and further suggest that this may be mediated, in part, through control of RELMß production.

Obesity, metabolic syndrome, adipocytes and vascular function: A holistic viewpoint.

1. Obesity is a metabolic disease of pandemic proportions largely arising from positive energy balance, a consequence of sedentary lifestyle, conditioned by environmental and genetic factors. Several central and peripheral neurohumoral factors (the major ones being the anorectic adipokines leptin and adiponecin and the orexigenic gut hormone ghrelin) acting on the anorectic (pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript) and orexigenic (neuropeptide Y and agouti gene-related protein) neurons regulate energy balance. These neurons, mainly in the arcuate nucleus of the hypothalamus, project to parts of the brain modulating functions such as wakefulness, autonomic function and learning. A tilt in the anorectic-orexigenic balance, perhaps determined genetically, leads to obesity. 2. Excess fat deposition requires space, created by adipocyte (hypertrophy and hyperplasia) and extracellular matrix (ECM) remodelling. This process is regulated by several factors, including several adipocyte-derived Matrix metalloproteinases and the adipokine cathepsin, which degrades fibronectin, a key ECM protein. Excess fat, also deposited in visceral organs, generates chronic low-grade inflammation that eventually triggers insulin resistance and the associated comorbidities of metabolic syndrome (hypertension, atherosclerosis, dyslipidaemia and diabetes mellitus). 3. The perivascular adipose tissue (PVAT) has conventionally been considered non-physiological structural tissue, but has recently been shown to serve a paracrine function, including the release of adipose-derived relaxant and contractile factors, akin to the role of the vascular endothelium. Thus, PVAT regulates vascular function in vivo and in vitro, contributing to the cardiovascular pathophysiology of the metabolic syndrome. Defining the mechanism of PVAT regulation of vascular reactivity requires more and better controlled investigations than currently seen in the literature.

Vagus nerve stimulation as a strategy to prevent and manage metabolic syndrome.

An increase in pro-inflammatory cytokines, decrease in endothelial nitric oxide (eNO) and adiponectin levels and an alteration in hypothalamic peptides and gastrointestinal hormones such as incretins and cholecystokinin that regulate satiety, hunger, and food intake occur in metabolic syndrome. Thus, metabolic syndrome is a low-grade systemic inflammatory condition and could be due to inappropriate cross-talk between the peripheral tissues and the hypothalamic centers implying that methods designed to restore these two abnormalities to normal could be of significant benefit in metabolic syndrome. Vagus nerve stimulation has been shown to suppress inflammation and acetylcholine, the principal vagal neurotransmitter, modulates the actions of several hypothalamic peptides and incretins and cholecystokinin. Based on these evidences, it is proposed that vagus nerve stimulation could be of significant benefit in the management of the metabolic syndrome.

Gastrointestinal regulation of food intake: do gut motility, enteric nerves and entero-hormones play together?

The gastrointestinal system can be considered the gateway for food entry in our body. Rather than being a passive player, it is now clear that gut strongly influence the feeding behavior and contribute to maintain energy balance with different signals. The aim of this review is to summarize the current knowledge about the role of gastrointestinal tract in the control of food intake, by focusing on the interplay existing between the enteric nervous system and gastrointestinal hormones and their ability to modulate digestive motility and sensitivity. Also the latest advances about the contribution of gut microbiota and gastrointestinal taste receptors are described. From the reported data it clearly emerges that gut hormones together with nervous signals likely contribute to the regulation of energy balance and modulate food intake through the control of digestive motility and sensations. The close linkage among gastrointestinal hormones, the gut and the central nervous systems appears very intriguing and has induced the development of a new field of research: the gastroendocrinology.

Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety.

Recently, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) have received much attention regarding possible roles in aetiology and treatment of type 2 diabetes. However, peptides co-secreted from the same enteroendocrine cells are less well studied. The present investigation was designed to characterise the in vitro and in vivo effects of xenin, a peptide co-secreted with GIP from intestinal K-cells. We examined the enzymatic stability, insulin-releasing activity and associated cAMP production capability of xenin in vitro. In addition, the effects of xenin on satiety, glucose homoeostasis and insulin secretion were examined in vivo. Xenin was time dependently degraded (t(1/2)=162±6 min) in plasma in vitro. In clonal BRIN-BD11 cells, xenin stimulated insulin secretion at 5.6 mM (P<0.05) and 16.7 mM (P<0.05 to P<0.001) glucose levels compared to respective controls. Xenin also exerted an additive effect on GIP, GLP1 and neurotensin-mediated insulin secretion. In clonal ß-cells, xenin did not stimulate cellular cAMP production, alter membrane potential or elevate intra-cellular Ca(2)(+). In normal mice, xenin exhibited a short-acting (P<0.01) satiety effect at high dosage (500 nmol/kg). In overnight fasted mice, acute injection of xenin enhanced glucose-lowering and elevated insulin secretion when injected concomitantly or 30 min before glucose. These effects were not observed when xenin was administered 60 min before the glucose challenge, reflecting the short half-life of the native peptide in vivo. Overall, these data demonstrate that xenin may have significant metabolic effects on glucose control, which merit further study.

The role of gut hormones and the hypothalamus in appetite regulation.

The World Health Organisation has estimated that by 2015 approximately 2.3 billion adults will be overweight and more than 700 million obese. Obesity is associated with an increased risk of diabetes, cardiovascular events, stroke and cancer. The hypothalamus is a crucial region for integrating signals from central and peripheral pathways and plays a major role in appetite regulation. In addition, there are reciprocal connections with the brainstem and higher cortical centres. In the arcuate nucleus of the hypothalamus, there are two major neuronal populations which stimulate or inhibit food intake and influence energy homeostasis. Within the brainstem, the dorsal vagal complex plays a role in the interpretation and relaying of peripheral signals. Gut hormones act peripherally to modulate digestion and absorption of nutrients. However, they also act as neurotransmitters within the central nervous system to control food intake. Peptide YY, pancreatic polypeptide, glucagon-like peptide-1 and oxyntomodulin suppress appetite, whilst ghrelin increases appetite through afferent vagal fibres to the caudal brainstem or directly to the hypothalamus. A better understanding of the role of these gut hormones may offer the opportunity to develop successful treatments for obesity. Here we review the current understanding of the role of gut hormones and the hypothalamus on food intake and body weight control.

Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake.

OBJECTIVE: Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis. RESEARCH DESIGN AND METHODS: We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanism of action by determining sites of neuronal activation after ICV injection of PK2, the hypothalamic site of action of PK2, and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2's potential as a therapeutic target, we investigated the effect of chronic administration in lean and obese mice. RESULTS: Hypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake, whereas anti-PK2 antibody increased food intake, suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of alpha-melanocyte-stimulating hormone (alpha-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the alpha-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight in lean and obese mice. CONCLUSIONS: This is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is mediated partly via the melanocortin system.

Hypothalamic regulation of food intake and clinical therapeutic applications.

Current estimates suggest that over 1 billion people are overweight and over 300 million people are obese. Weight gain is due to an imbalance between energy expenditure and dietary intake. This review discusses the hypothalamic control of appetite and highlights key developments in research that have furthered our understanding of the complex pathways involved. Nuclei within the hypothalamus integrate peripheral signals such as adiposity and caloric intake to regulate important pathways within the central nervous system controlling food intake and energy expenditure. Firmly established pathways involve the orexigenic NPY/AgRP and the anorexigenic POMC/CART neurons in the arcuate nucleus (ARC) of the hypothalamus. These project from the ARC to other important hypothalamic nuclei, including the paraventricular, dorsomedial, ventromedial and lateral hypothalamic nuclei. In addition there are many projections to and from the brainstem, cortical areas and reward pathways, which modulate food intake.

Hypothalamic regulation of food intake and clinical therapeutic applications: [review] / Regulação hipotalâmica da ingestão alimentar e suas aplicações terapêuticas clínicas: [revisão]

Current estimates suggest that over 1 billion people are overweight and over 300 million people are obese. Weight gain is due to an imbalance between energy expenditure and dietary intake. This review discusses the hypothalamic control of appetite and highlights key developments in research that have furthered our understanding of the complex pathways involved. Nuclei within the hypothalamus integrate peripheral signals such as adiposity and caloric intake to regulate important pathways within the central nervous system controlling food intake and energy expenditure. Firmly established pathways involve the orexigenic NPY/AgRP and the anorexigenic POMC/CART neurons in the arcuate nucleus (ARC) of the hypothalamus. These project from the ARC to other important hypothalamic nuclei, including the paraventricular, dorsomedial, ventromedial and lateral hypothalamic nuclei. In addition there are many projections to and from the brainstem, cortical areas and reward pathways, which modulate food intake.

As estimativas atuais sugerem que mais de 1 bilhão de pessoas apresentam sobrepeso e 300 milhões são obesas. O ganho de peso representa um desequilíbrio entre o gasto energético e o consumo alimentar. Esta revisão discute o controle hipotalâmico do apetite e destaca os pontos-chave no desenvolvimento de pesquisas para ampliar o nosso entendimento dos complexos mecanismos envolvidos nesta regulação. Núcleos situados no hipotálamo integram uma série de sinais com o sistema nervoso central controlando a ingestão alimentar e o gasto energético. As vias mais estabelecidas envolvem os neurônios orexigênicos NPY/AgRP e os neurônios anorexigênicos POMC/CART no núcleo arqueado (ARC) do hipotálamo. Esses neurônios se projetam do ARC para outros importantes núcleos hipotalâmicos, tais quais: paraventricular, dorsomedial, ventromedial e lateral. Além disso, existem várias projeções que vão e vem do tronco cerebral, das áreas corticais e das vias de retroalimentação que modulam o consumo alimentar.