Hypothalamic Regulation Of Food Intake Research Articles

C75, a Fatty Acid Synthase (FAS) Inhibitor

Recent data has demonstrated that fatty acid metabolism plays a critical role in the hypothalamic regulation of food intake and the evidence is as follows. Circulating long chain fatty acids act as nutrient surplus signals in the hypothalamus. On addition, fatty acid synthesis pathway enzymes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) and its upstream regulator, AMP-activated protein kinase (AMPK) are regulated by nutritional and hormonal stimuli. Very importantly, current evidence also indicates that fatty acid metabolism pathway may be a potential target for obesity treatment. In this sense, it has been demonstrated that pharmacological inhibition of FAS results in profound decrease in food intake and body weight in rodents. These anorectic actions are mediated by the modulation of hypothalamic neuropeptide systems, through a malonyl-CoA dependent mechanism. In this review, we recapitulate what is known about hypothalamic fatty acid metabolism and the regulation of feeding, with particular interest in a specific FAS inhibitor, C75, which has been recently patented as a potential drug for adipose mass reduction. Keywords: AMP-activated protein kinase (AMPK), C75, cerulenin, fatty acid synthase (FAS), FAS inhibitors, food intake, hypothalamus, lipid sensing, tamoxifen

Neurobiologic changes in the hypothalamus associated with weight loss after gastric bypass

Effects of Roux-en-Y gastric bypass (RYGB) on hypothalamic food intake regulation have not been investigated. The hypothalamic arcuate nucleus (ARC) and the magnocellular (m) and parvocellular (p) parts of the paraventricular nucleus (PVN) regulate hunger and satiety, and are under control of the orexigenic neuropeptide Y (NPY), and the anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and serotonin (5-HT). We hypothesized that after RYGB, weight loss is associated with hypothalamic down regulation of NPY and up regulation of 5-HT and alpha-MSH. Obesity was induced in 12 Sprague Dawley rats using a high-energy diet for 7 weeks, and then the rats were divided into three groups (n = 4/group): RYGB, sham-operated pair-fed (PF), and sham-operated ad libitum (obese control). Ten days after operation, immunohistochemical quantification of NPY, alpha-MSH, and 5-HT(1B)-receptors in ARC and PVN was performed. Data were analyzed using ANOVA and Tukey's test. Body weight decreased in RYGB (417 +/- 21 g; mean +/- SE) and in PF (436 +/- 14 g) rats 10 days after operation compared with obese control rats (484 +/- 15 g; p < 0.05 for each comparison). NPY in ARC, pPVN, and mPVN decreased by 43%, 43%, and 61%, respectively in RYGB and by 55%, 42%, and 71% in PF, respectively, compared with obese controls (p < 0.05 for each pairwise comparison). RYGB versus PF did not show differences. alpha-MSH in ARC, pPVN and mPVN increased by 35%, 175%, and 67%, respectively in RYGB and by 29%, 162%, and 116% in PF, respectively, compared with obese controls (each p < 0.05). In mPVN, alpha-MSH significantly decreased by 23% in RYGB versus PF (p < 0.05). 5-HT-(1B)-receptor in pPVN increased by 58% in RYGB and by 26% in PF, compared with obese controls (p < 0.05). Compared with obese controls, 5HT-(1B)-receptor in mPVN increased by 39% in RYGB (p < 0.05) and by 9% in PF (p > 0.05). An increase of 5-HT-(1B)-receptor in pPVN and mPVN occurred in RYGB versus PF (p < 0.05). Obese rats that undergo weight loss after RYGB demonstrate changes in hypothalamic down regulation of NPY and up regulation of alpha-MSH and serotonin.

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

On the Role of Neuropeptides in the Hypothalamic Regulation of Food Intake

Neuropeptides are molecules of outstanding importance in the regulation of most different physiological and biochemical processes. They act as signal transducting molecules that makes them an ideal target for pharmacological treatment. Because of their possibility to act via different receptor subtypes within a whole receptor family, the peptides are able to selectively induce physiological processes. Therefore, peptide research provides important contributions to a detailed understanding of physiological processes. The hypothalamic regulation of food intake reveals a redundant system of neuropeptides, acting and interacting with each other in order to control energy homeostasis and body weight. Leptin and insulin are peripheral adiposity signals, inducing first order neuronal signalling in the arcuate nucleus of the hypothalamus. There, they inhibit anabolic peptides, whereas they stimulate catabolic peptides. Neurons from the arcuate nucleus project to candidate second-order neurons involved in hypothalamic response to leptin and insulin, located in the paraventricular nucleus and the lateral hypothalamic and perifornical area. However, anomalies in body weight, especially overweight and obesity, are not only genetically determined, but also by the environment. Cultural, socioeconomic and psychosocial factors, physical activity and other environmental factors are known for sustained influence of body weight. Medicinal chemistry importantly contributes to the molecular understanding of anomalies and diseases, which likely culminates in the development of appropriate medical treatments. Hereby, the development of receptor subtype selective agonists and antagonists is a key step. This is exemplified on a set of hypothalamic neuropeptides which are involved in the regulation of food intake. Keywords: Neuropeptides, hypothalamic Regulation, Neuropeptide Y, Insulin, Leptin, Neuronal Signalling, Obesity, Pomc, Msh, Pro-opiomelanocotin Pomc

Leptin physiology: a second look

It is widely believed that the primary physiologic role of leptin is to prevent obesity by regulating food intake and thermogenesis through actions on hypothalamic centers. Here we sugest that the first premise, the anti-obesity role, is untenable, and present evidence for an alternative physiologic role, namely antisteatotic activity in which fatty acid overaccumulation in nonadipose tissues is prevented by leptin-mediated regulation of β-oxidation. The second premise, namely that leptin acts exclusively on the hypothalamus, is confirmed in normal lean animals with plasma leptin concentrations below 5 ng/ml; their correlation with cerebrospinal fluid levels supports the classical concept of leptin-mediated hypothalamic regulation of food intake. However, when chronic hyperleptinemia exceeds 15 ng/ml, as in obesity, a further rise in plasma leptin does not raise cerebrospinal leptin levels or reduce food intake. Nevertheless, the peripheral antisteatotic action of leptin in acquired obesity continues, suggesting that at chronically hyperleptinemic levels the hormone acts primarily on peripheral tissues and that its hypothalamic action has reached a plateau.

Neuropeptide Y polymorphism and alcohol consumption in middle-aged men.

Neuropeptide Y (NPY) plays an important role in the hypothalamic regulation of food intake and energy balance. According to recent findings in animals, NPY also seems to be a potent regulator of alcohol consumption. We used the recently identified Leu(7) to Pro(7) polymorphism in the signal peptide part of NPY to investigate whether the NPY system is associated with alcohol consumption in humans. The subjects (N = 889) were an ethnically homogeneous, nonselected population sample of middle-aged men from Eastern Finland. The gene variant producing Pro(7) substitution was associated with a 34% higher average alcohol consumption, even after adjustment for a number of covariates (P = 0.03). The proportion of heavy drinkers (over 230 g of ethanol/week) was also somewhat higher in this group (13.1% vs. 8.2%, P = 0.10). Our study provides the first evidence that alcohol preference in humans is likely to be regulated by the NPY system.

Nicotine administration enhances NPY expression in the rat hypothalamus

Epidemiological studies have shown an inverse relationship between cigarette smoking and body weight. In rodents, a negative correlation between nicotine and body weight has been reported, but this observation was largely derived from studies where relatively high doses of nicotine (∼12 mg/kg/day) were used. In the current study, we showed that a negative relationship also holds for low doses of nicotine that are comparable to that consumed by average human smokers (<6 mg/kg/day). We also demonstrated that 14 days of nicotine administration (4 mg/kg/day) reduced average daily food intake by 19.5% ( P<0.01) in the free-feeding nicotine-treated group compared to saline controls. No significant differences in body weight were detected between the nicotine-treated and pair-fed groups. To determine whether the effects of nicotine on food intake and body weight were related to neuropeptide Y (NPY) expression, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and radioimmunoassay were utilized to measure NPY mRNA and peptide levels in various regions of the hypothalamus. Significantly higher levels of NPY mRNA (ca. 20–50%) and peptide (ca. 24–69%) were only detected in the nicotine-treated groups. In addition, significantly higher NPY contents were also obtained in two hypothalamic areas of pair-fed control animals. In summary, our data suggest that the pharmacological effects of nicotine on food intake and body weight may be mediated by changes in hypothalamic NPY levels, a neuropeptide that is pivotal to the hypothalamic regulation of food intake.

Neuropeptide Y polymorphism and alcohol consumption in middle-aged men

Neuropeptide Y (NPY) plays an important role in the hypothalamic regulation of food intake and energy balance. According to recent findings in animals, NPY also seems to be a potent regulator of alcohol consumption. We used the recently identified Leu(7) to Pro(7) polymorphism in the signal peptide part of NPY to investigate whether the NPY system is associated with alcohol consumption in humans. The subjects (N = 889) were an ethnically homogeneous, nonselected population sample of middle-aged men from Eastern Finland. The gene variant producing Pro(7) substitution was associated with a 34% higher average alcohol consumption, even after adjustment for a number of covariates (P = 0.03). The proportion of heavy drinkers (over 230 g of ethanol/week) was also somewhat higher in this group (13.1% vs. 8.2%, P = 0.10). Our study provides the first evidence that alcohol preference in humans is likely to be regulated by the NPY system.

Molecular insights into the regulation of energy intake and expenditure.

The maintenance of a precise caloric equilibrium is one of the most closely regulated parameters, as illustrated by the calculation that a positive energy balance of only ˛0.3% over 30 years would lead to an increase in body weight of over 20 kg. Hence, the caloric input (i.e. appetite) and energy expenditure must be tightly regulated processes. The recent elucidation of the role of the melanocortin-4 receptor (MC4-R) and the cloning of the uncoupling protein 2 (UCP-2) gene have broadened our molecular understanding of the regulation of energy intake and dissipation respectively. I. The role of the melanocortin-4 receptor in regulating food intake The list of peptides involved in the hypothalamic regulation of food intake comprises leptin, neuropeptide Y (NPY), corticotropin-releasing hormone, urocortin, and melanin-concentrating hormone. Melanocortinergic peptides (such as a-melanocyte-stimulating hormone, a-MSH), and their hypothalamic MC4-R in particular, have now to be added to this list. The concept of a potential link between the melanocortinergic system and body weight is derived from the agouti mouse model of genetic obesity. The agouti allele results in the ectopic expression of agouti, a 131 amino acid peptide, which is normally only expressed in the hair follicle where it acts in a paracrine manner. These mutant agouti animals are not only of yellow fur color, but they also develop hyperphagia and maturity-onset obesity due to adipocyte hyperplasia. While the absence of black hair color could be attributed to the antagonistic effect of agouti on a-MSH at the level of the melanocortin-1 receptor (MC1-R) controlling melanin synthesis in hair follicles, the obesity phenotype remained unexplained. Notably, lack of functional MC1-R does not result in obesity, suggesting that the ectopically expressed agouti protein must have other sites of action. In vitro studies have demonstrated that agouti can act as an a-MSH antagonist not only on the MC1-R, but also on the MC4-R, a G-protein coupled receptor primarily expressed in the brain, and particularly in the hypothalamic nuclei implicated in the regulation of food intake (1). In order to test whether the MC4-R is involved in the pathophysiology of the agouti phenotype, and hence in the regulation of appetite, Huszar et al. created a mouse knock-out model for the MC4-R gene (2). Interestingly, these mice lacking MC4-R exhibit maturity-onset obesity with hyperphagia, hyperinsulinemia and hyperglycemia, closely resembling the agouti phenotype. While it is formally possible that the observed phenotype results from abnormal brain development rather than from a role of the MC4-R in regulating feeding, the results of Fan et al. strongly argue against this possibility (3). These investigators identified pharmacological agonistic (MTII) and antagonistic (SHU9119) analogs of a-MSH. In keeping with the hypothesis that melanocortinergic neurons are involved in the inhibition of feeding behavior, the MTII analog not only decreased normal nocturnal food intake in mice, but it also acutely reduced food consumption in several models of hyperphagic obesity, such as the leptin-deficient ob/ob mouse, the obese yellow agouti mouse, and NPY-induced hyperphagia. Conversely, the a-MSH antagonist (and agouti-mimetic) SHU9119 not only blocked the effects of MTII, but it also enhanced nocturnal feeding when given alone. In summary, these observations suggest that the MC4-R and its agonist(s) are involved in the regulation of body weight and that the obesity phenotype in the agouti mice results from the inhibition of this pathway. At a clinical level, a phase II clinical study with MC4-R agonists is currently being conducted in obese type II diabetics, but no data regarding their efficiency are yet available.

The role of pharmacotherapy in anorexia nervosa and bulimia

The purpose of this article is to review the basic pharmacology and the role of drugs that are used to treat anorexia nervosa and bulimia. The pharmacological treatment of eating disorders is based upon theoretical principles. The theoretical models include: (a) an illness secondary to other psychiatric disorders, (b) a disorder in the hypothalamic control of food intake, (c) a disorder of hypothalamic endocrine regulation, (d) a syndrome secondary to depressive illness, and (e) a disorder in the hypothalamic regulation of food intake. Theoretical models a, b, and c govern the choice of drug therapy for anorexia nervosa, and models d and e govern the choice of drug therapy for bulimia. Drugs used to treat anorexia nervosa and bulimia include tricyclic antidepressants and lithium carbonate. Chlorpromazine, metoclopramide, cyproheptadine, and clomiphene citrate have also been prescribed for the treatment of anorexia nervosa. Monoamine oxidase inhibitors are commonly prescribed to treat bulimia. Fenfluramine has the potential to be of therapeutic value in patients with bulimia. Although drug therapy plays a limited role in the treatment of eating disorders, drugs are commonly prescribed. Therefore, the nutritionist should be familiar with the basic pharmacology and the side effects related to drug therapy.

The role of GABA in the ventromedial hypothalamic regulation of food intake

The rat hypothalamus was mapped for sites in which metabolic substrates (D-glucose, beta-hydroxybutyrate), amino acids (GABA, glutamate, glutamine, gamma-hydroxybutyric acid) and pharmacological GABA manipulations (amino-oxyacetic acid (AOAA), bicuculline) altered feeding behavior in ad lib fed male Long-Evans rats. In a region along the base of the brain lateral to the ventromedial nucleus in which D-glucose injections decreased daily food intake, both GABA and AOAA produced immediate decreases in food intake, which after AOAA continued for 24 hr. Blockade of GABA receptors with bicuculline increased 24 hr intakes. Food consumption was relatively unaffected following 155mM saline, L-glucose, beta-hydroxybutyrate, and glutamine injections into this area. GABA manipulations also affected feeding following administration into the ventromedial nucleus proper and into the perifornical area in the anterior hypothalamus, but the effects were not as consistent as injections into the basolateral Ventromedial hypothalamus (BVMH). The data support the existence of cells within the BVMH which are sensitive to glucose metabolism and which may encode metabolic information through the formation of glutamate and GABA via substrate entry into the GABA shunt. Since flow through GABA shunt parallels the flow of energy through the tricarboxylic acid cycle, a direct link between energy metabolism and functional neural activity could be maintained.

GABA and glutamate: Possible metabolic intermediaries involved in the hypothalamic regulation of food intake

Pharmacologically-induced increases and decreases in GABA activity in the ventromedial hypothalamus cause reciprocal changes in food intake in the rat. Conditions which augment GABA reduce ad lib feeding whereas a decrease in GABA activity is associated with an increase in food intake. These changes are most prominent within a discrete region of the hypothalamus which has low basal metabolic activity but a relatively high yield of 14C-GABA from a (U- 14C) glucose precursor. Both GABA and glutamate are released into push-pull perfusates collected from this circumscribed region as the rat consumes food. Thus far, the release of GABA appears to be triggered by nutrients arriving at the gut and does not specifically parallel the entry of intraduodenally infused glucose into the brain. Sites which release GABA appear to be neuroanatomically distinct from sites which release norepinephrine during feeding. The data support the existence of an independent and metabolically distinct GABA-nergic system within the basal hypothalamus which exerts inhibitory control over feeding behavior.

GABA and glutamate: Possible metabolic intermediaries involved in the hypothalamic regulation of food intake

GABA and glutamate: Possible metabolic intermediaries involved in the hypothalamic regulation of food intake

AN IRRITATIVE HYPOTHESIS CONCERNING THE HYPOTHALAMIC REGULATION OF FOOD INTAKE.

AN IRRITATIVE HYPOTHESIS CONCERNING THE HYPOTHALAMIC REGULATION OF FOOD INTAKE.