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PubMedDate not supplied

The role of endocannabinoids in the hypothalamic regulation of visceral function.

The hypothalamus plays an important role in the regulation of several visceral processes, including food intake, thermoregulation and control of anterior pituitary secretion. Endogenous cannabinoids and CB(1) cannabinoid receptors have been found in the hypothalamus. In the present review, we would like to clarify the role of the endocannabinoid system in the regulation of the above-mentioned visceral functions. There is historical support for the role of marihuana (i.e. exogenous cannabinoids) in the regulation of appetite. Endocannabinoids also stimulate food intake. Furthermore, the specific CB(1) receptor antagonist SR141716 reduces food intake. Leptin treatment decreases endocannabinoid levels in normal rats and ob/ob mice. These findings provide evidence for the role of the hypothalamic endocannabinoid system in food intake and appetite regulation. Cannabinoids can change body temperature in a dose-dependent manner. High doses cause hypothermia while low doses cause hyperthermia. Cannabinoid administration decreases heat production. It seems that the effects of can- nabinoids on thermoregulation is exerted by altering some neurochemical mediator effects at both the presynaptic and postsynaptic level.THC and endocannabinoids have mainly inhibitory effects on the regulation of reproduction. Administration of anandamide (AEA) decreases serum luteinizing hormone (LH) and prolactin (PRL) levels. AEA causes a prolongation of pregnancy in rats and temporarily inhibits the postnatal development of the hypothalamo-pituitary axis in offspring. The action of AEA on the reproductory parameters occurs at both the hypothalamic and pituitary level. CB(1) receptors have also been found in the anterior pituitary. Further, LH levels in CB(1) receptor-inactivated mice were decreased compared with wild-type mice. Taken together, all these observations suggest that the endocannabinoid system is playing an important part in the regulation of the mentioned visceral functions and it provides the bases for further applications of cannabinoid receptor agonists and/or antagonists in visceral diseases regulated by the hypothalamus.

Animals↗
PubMed2003

Long-term alteration in bodyweight and food restriction does not affect the gene expression of either preproorexin or prodynorphin in the sheep.

Various hypothalamic neuropeptides are involved in central regulation of food intake and expression of genes encoding these peptides changes with alterations in the bodyweight/metabolic status/nutritional status. Orexin(s) and dynorphin have been implicated in the regulation of appetite and neuroendocrine systems, but the function of these peptides is not well understood. We have employed in situ hybridization to examine the effects of long-term alterations in the bodyweight on expression of mRNA for preproorexin and prodynorphin in the putative feeding centers of the ovine hypothalamus. Expression of preproorexin was localized to the dorsomedial hypothalamic nucleus, perifornical area and lateral hypothalamic area. Cells expressing prodynorphin were localized to the periventricular, supraoptic, paraventricular, ventromedial hypothalamic nuclei and the thalamus. Small numbers of single scattered cells were seen in other brain areas. A few scattered prodynorphin-expressing cells were found in the lateral hypothalamic area but, in contrast to observations in the rat, there was no colocalization with preproorexin. Long-term alterations in the bodyweight did not influence the level of expression of preproorexin or prodynorphin. These findings suggest that orexin and dynorphin may not play a direct role in appetite regulation in sheep, although regulation at the level of the receptors for these peptides remains a possibility.

Animals↗
PubMed2001

Dose-dependent effects of central leptin gene therapy on genes that regulate body weight and appetite in the hypothalamus.

We have examined the dose-dependent effects and central action of intraventricular administration of a recombinant adeno-associated virus encoding rat leptin (rAAV-leptin) in suppressing body weight (BW) gain in adult female rats. A low dose of rAAV-leptin (5x10(10) particles) suppressed weight gain (15%) without changing daily food intake (FI), but a twofold higher dose decreased BW by 30% along with a reduction in daily FI. Reduced BW was due to a loss in body adiposity because serum leptin was reduced. Serum insulin levels were decreased (96%) by only the high dose along with a slight reduction in glucose. Uncoupling protein-1 (UCP-1) mRNA expression in brown adipose tissue (BAT), reflecting energy expenditure through thermogenesis, was upregulated to the same magnitude by the two rAAV-leptin doses. We analyzed by in situ hybridization the expression in the hypothalamus of genes encoding the appetite-regulating neuropeptides. Only the high dose decreased expression of neuropeptide Y (NPY), the orexigenic peptide, and increased proopiomelanocortin (POMC), precursor of the an orexigenic peptide, alpha-MSH. Our studies show for the first time that increased availability of leptin within the hypothalamus through central leptin gene therapy dose-dependently decreases weight gain, adiposity, and serum insulin by increasing energy expenditure and decreasing FI. The decrease in FI occurs only when NPY is reduced and alpha-MSH is increased in the hypothalamus by the high dose of rAAV-leptin. Delivery of the leptin gene centrally through rAAV vectors is a viable therapeutic modality for long-term control of weight and metabolic hormones.

Agouti-Related Protein↗
PubMed1998

Hormonal regulation of appetite and food intake.

Several clinical disorders are strongly influenced by hormones involved in appetite and weight regulation. Obesity and eating disorders are of major importance, because they are associated with severe morbidity and considered to be among the greatest health problems in the Western world today. This review describes recent findings in hormonal regulation of food intake by substances acting both centrally, such as corticotropin-releasing factor, neuropeptide Y and leptin, and peripherally, such as cholecystokinin and somatostatin. Sex hormones and glucocorticoids play an important role in long-term regulation of metabolism. The role of these hormones in appetite and weight changes during life as well as during pregnancy and lactation is discussed. Furthermore, the development of obesity and eating disorders is influenced, in particular, by steroid hormones. Treatment with sex hormones, as in hormone replacement therapy, affects appetite and weight and may have beneficial effects in preventing android obesity. Currently, there is great effort in developing endogenous neurohumoral substances into effective drugs for the treatment of obesity and eating disorders. Leptin and neuropeptide Y analogues are of interest as potential antiobesity agents.

Appetite↗
PubMed2001

Regulation of appetite: role of leptin in signalling systems for drive and satiety.

BACKGROUND: The healthy regulation of appetite involves a balance between excitatory (drive) and inhibitory (satiety) processes. For many years research has concentrated on the identification of signalling systems that mediate satiety to the relative exclusion of drive-inducing biological events. However, the so-called long-term regulation of body weight has recently been given substance by the identification of a chemical signal believed to link the brain with adipose tissue stores. ANALYSIS: This signal, leptin, is in position to modulate the expression of a drive to eat. Studies on the relationship between leptin and perceived hunger, and on the eating behaviour of leptin-deficient individuals, are consistent with the intervention of leptin in a drive system. The contrast between the roles of leptin and serotonin in appetite regulation reflects the difference between drive-signalling and satiety signalling processes. CONCLUSION: It is proposed that leptin modulates the drive signals arising from the metabolic demand for energy but also shows some properties of a post-prandial satiety signal.

Animals↗
PubMed2001

[Regulation of appetite by melanocortin and its receptors].

alpha, beta, gamma-MSH and ACTH are derived from the same precursor, POMC(proopiomelanocortin), and are classified as melanocortin. alpha-MSH plays an important role in the regulation of appetite and energy expenditure via central melanocortin receptor, melanocortin 4 receptor(MC4R), which is expressed mainly in hypothalamus. alpha-MSH or its analogue shows inhibitory effect on appetite and inversely MC4R antagonist stimulates appetite. MC4R knock-out mice has adult-onset obesity and decreased energy expenditure. POMC gene expression in hypothalamus is partially regulated by leptin. Agouti-related peptide(AgRP), a homologue of agouti peptide and antagonist of MC3R and MC4R, is expressed in human brain and may act as a inhibitor of alpha-MSH. From the genetical aspect, the region near POMC gene, 2p23, is one of the susceptibility loci of human obesity. POMC gene mutations are found in two families, where mutations in both alleles cause human obesity, red hair, adrenal dysfunction, due to alpha-MSH and ACTH deficiencies. In morbidity obese patients, heterozygous MC4R gene mutations are found among 4% of them. These results suggest the importance of melanocortin and its receptors on appetite regulation in human.

Animals↗
PubMed2001

[Role of leptin and its receptor in the regulation of appetite and body fat].

The role of leptin and its receptor on the regulation of appetite and body fat was summarized. Leptin directly exerts its anorexigenic effects on arcuate nucleus via proopiomelanocortin and neuropeptide Y neurons. The anorexia and sympathetic nerve activation result in the reduction of body fat. But physiological concentrations of leptin could not reduce body fat in obese people, while genetic loss of central leptin effects induces obesity in children. Melanin concentrating hormone, orexin, and corticotropin-releasing hormone may be directly regulated by leptin. Serotonergic neurons may be separate from leptin effects. Phosphorylation of 985- and 1138-tyrosine of long-form leptin receptor activates SHP-2 and STAT3, respectively. Soluble leptin receptor concentrations in serum are negatively correlated with BMI. Clinical usefulness of leptin is now in progress.

Adipose Tissue↗
PubMed1999

Two important systems in energy homeostasis: melanocortins and melanin-concentrating hormone.

Our understanding of the regulation of appetite and energy balance has advanced significantly over the past decade as several peptides, centrally or peripherally expressed, have been characterized and shown to profoundly influence food intake and energy expenditure. (1)The growing number of putative appetite-regulating neuropeptides includes peptides that are orexigenic (appetite-stimulating) signals and anorectic peptides. Neuropeptide Y (NPY), melanin concentrating hormone (MCH), orexins A and B, galanin, and agouti -related peptide (AgRP) all act to stimulate feeding while alpha-melanocyte stimulating hormone (alphaMSH), corticotropin releasing hormone (CRH), cholecystokinin (CCK), cocaine and amphetamine regulated transcript (CART), neurotensin, glucagon-like peptide 1 (GLP 1), and bombesin have anorectic actions.(1) Leptin, expressed in the periphery in white adipose tissue, acts in the CNS to modulate the expression of several of these hypothalamic peptides.(1) This creates a functional link between the adipose tissue and the brain that translates the information on body fat provided by leptin to input into energy balance regulating processes. In the current review we examine the significant role of the melanocortin system (alphaMSH, agouti and AgRP peptides, and their receptors and mahogany protein) and melanin concentrating hormone in the regulation of energy balance.

Animals↗
PubMed2006

Obesity, voracity, and short stature: the impact of glutamate on the regulation of appetite.

BACKGROUND: World-wide obesity has risen to alarming levels. We present experimental support for a new and very challenging hypothesis linking obesity, voracity, and growth hormone (GH) deficiency, to the consumption of elevated amounts of the amino-acid glutamate (GLU). Supraphysiological doses of GLU are toxic for neuronal cells. METHODS: Human data were obtained from 807,592 German conscripts born between 1974 and 1978, and from 1,432,368 women of the German birth statistics (deutsche Perinatalerhebung) 1995-1997. The effects of orally administered monosodium glutamate (MSG) were investigated in 30 pregnant Wistar rats and their offspring. Pregnant animals either received no extra MSG, or 2.5 g MSG, or 5 g MSG per day, up to the end of the weaning period. In all, 2.5 g, respectively 5 g, MSG accounted for some 10%, respectively 20%, of dry weight of the average daily food ration. After weaning, MSG feeding was continued in the offspring. FINDINGS: Morbid obesity associates with short stature. Average stature of conscripts progressively declines when body mass index increases above 38 kg/m2. Also morbidly obese young women are shorter than average though to a lesser extent than conscripts. Oral administration of MSG to pregnant rats affects birth weight of the offspring. Maternal feeding with 5 g MSG per day results in severe birth weight reduction (P<0.01). Weight increments remain subnormal when MSG feeding to the mothers is maintained during weaning (P < 0.01). GH serum levels are affected in animals that received MSG during prenatal life via maternal feeding. Animals that are kept on high MSG diet (5 g MSG per day) continue to show serum GH levels that are as low or even lower than those of MSG injected animals (P < 0.05), both at day 30 and at day 90 of life. Animals that were kept on medium MSG diet (2.5 g MSG per day) showed low serum GH levels at day 30 of life (P < 0.01), but seemed to partially recover before day 90. Almost identical results were observed in IGF-1 serum levels. Oral MSG resulted in dose dependent voracity. The animals fed 5 g MSG per day increased water uptake by threefold (P < 0.01), and food uptake by almost two-fold (P < 0.01). The influence of MSG is in general more marked in males than in females. INTERPRETATION: GLU is a widely used nutritional substance that potentially exhibits significant neuronal toxicity. Voracity, and impaired GH secretion are the two major characteristics of parenterally administered GLU-induced neuronal damage. GLU maintains its toxicity in animals even when administered orally. Males appear to be more sensitive than females. The present study for the first time demonstrates, that a widely used nutritional monosubstance--the flavouring agent MSG--at concentrations that only slightly surpass those found in everyday human food, exhibits significant potential for damaging the hypothalamic regulation of appetite, and thereby determines the propensity of world-wide obesity. We suggest to reconsider the recommended daily allowances of amino acids and nutritional protein, and to abstain from the popular protein-rich diets, and particularly from adding the flavouring agents MSG.

Adult↗
PubMed1984

The role of the endogenous opiates in zinc deficiency anorexia.

Anorexia is a major symptom of zinc deficiency, but the mechanism(s) for this anorexia are poorly defined. Recent studies have suggested an integral role for endogenous opiate peptides in appetite regulation. Dynorphin, a leucine-enkephalin containing opiate peptide, is a potent inducer of spontaneous feeding. In this study we showed that zinc deficient animals were relatively resistant to dynorphin-induced feeding. Measurement of dynorphin levels using a highly sensitive radioimmunoassay showed that zinc deficient animals had lower levels of dynorphin in the hypothalamus than did ad lib fed animals, with weight restricted animals having intermediate values. [3H]-naloxone binding was significantly increased to isolated brain membranes from zinc deficient animals using 1 nM unlabeled naloxone when compared to ad lib fed controls with the weight restricted animals again having intermediate values. These data suggest that abnormalities in endogenous opiate regulation of appetite may well play a role in the anorexia of zinc deficiency. The effects of zinc deficiency on endogenous opiate action appear to include alterations in receptor affinity, a post-receptor defect and alterations in the synthesis and/or release of dynorphin.

Animals↗
PubMed1998

Zinc may regulate serum leptin concentrations in humans.

OBJECTIVE: Leptin, the product of the ob gene, plays a key role in a feedback loop that maintains energy balance by signaling the state of energy stores to the brain and by influencing the regulation of appetite and energy metabolism. Zinc also plays an important role in appetite regulation. Thus, we evaluated the relationship between zinc status and the leptin system in humans. METHODS: We studied nine healthy men with marginal zinc deficiency, induced by dietary means, before and after zinc supplementation. RESULTS: Zinc restriction decreased leptin levels while zinc supplementation of zinc-depleted subjects increased circulating leptin levels. In addition, zinc supplementation increased IL-2 and TNF-alpha production that could be responsible for the observed increase in leptin concentrations. CONCLUSIONS: Zinc may influence serum leptin levels, possibly by increasing the production of IL-2 and TNF-alpha.

Adult↗
PubMed1994

The role of serotonin and melatonin in gastrointestinal physiology: ontogeny, regulation of food intake, and mutual serotonin-melatonin feedback.

Average levels of melatonin in the brain and the gastrointestinal (GIT) tissues of newborn mice declined dramatically during the first week postnatally. Food consumption increased considerably in mice bearing subcutaneous serotonin (5-HT) implants (2 mg). Melatonin implants (2 mg) also increased overall consumption but to a lesser degree. Both 5-HT and melatonin implants (2 mg) increased water content of mice fecal pellets, albeit the melatonin effect was less pronounced. Serotonin implants (2,4,6 mg/mouse) increased melatonin levels in brain, jejunum, ileum, and colon, but the effect was not dose-dependent. Intraperitoneally administered melatonin (5, 20 and 200 ug/mouse) elevated melatonin levels in brain and GIT tissues more than 100 times that of the controls, but the effect was not dose-dependent. In contrast, intraperitoneal administration of melatonin (5, 50, and 200 ug) in mice bearing a 5-HT implant (2 mg) resulted in only 3-7 times higher melatonin levels in the GIT as compared to controls, and the brain levels of melatonin were actually lower. A feedback system between 5-HT and melatonin is proposed that regulates appetite and digestive processes by endocrine as well as paracrine effects in both the brain and the GIT.

Animals↗
PubMed2006

Insulin resistance and improvements in signal transduction.

Type 2 diabetes and obesity are common metabolic disorders characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. One approach to increase muscle glucose disposal is to reverse/improve these insulin-signaling defects. Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. In contrast, physical training and metformin improve whole-body glucose disposal but have minimal effects on proximal insulin-signaling steps. A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). A different strategy to increase muscle glucose disposal is by stimulating insulin-independent glucose transport. AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge and becomes activated in situations of energy consumption, such as muscle contraction. Several studies have shown that pharmacologic activation of AMPK increases glucose transport in muscle, independent of the actions of insulin. AMPK activation is also involved in the mechanism of action of metformin and adiponectin. Moreover, in the hypothalamus, AMPK regulates appetite and body weight. The effect of AMPK to stimulate muscle glucose disposal and to control appetite makes it an important pharmacologic target for the treatment of type 2 diabetes and obesity.

AMP-Activated Protein Kinases↗
PubMedDate not supplied

Regulation of appetite during total parenteral nutrition.

To study effects of total parenteral nutrition (TPN) on appetite, in an effort to obtain an objective assessment of hunger separated from underlying pathology, caloric intake and levels of TPN were measured in two male rhesus monkeys. TPN was found to affect appetite by reducing voluntary food intake. One monkey showed precise regulation of daily oral caloric intake and maintained stable body weight during this period. The other monkey did not show such precise regulation. When TPN was stopped, both continued suppression of oral intake for a time. Implications are discussed.

Animals↗
PubMed1998

Regulation of appetite and body weight in seasonal mammals.

As models of physiological regulation of body weight, adiposity and appetite, seasonal mammals offer unique opportunities for manipulating fundamental regulatory processes that may not be available in the more frequently-studied laboratory rodents. Seasonal weight and intake cycles are anticipatory rather than reactive in nature, being manifest despite the availability of adlibitum supplies of food. They are exhibited despite all other environmental variables being held constant, and are reversible. Appropriate body weight appears to be a sliding set point in many seasonal mammals, which can move in either direction, largely independently of age. While few data are available other than from rats and mice, there appears to be a strong commonality of central neuroendocrine and peripheral signalling systems between seasonal and non-seasonal mammals, although the conditions under which endogenous regulatory pathways are activated may differ significantly between species. Peripheral and central signalling systems implicated in the regulation of appetite and body weight may be modulated during seasonal transitions. Discussion will concentrate on hypothalamic neuropeptides, gastrointestinal satiety peptides, the recently-described peptide, leptin, that is secreted by adipose tissue, and the interactions between these regulatory components.

Animals↗
PubMed2006

Anticatabolic properties of melanocortin-4 receptor antagonists.

PURPOSE OF REVIEW: Health problems related to weight regulation are increasingly common in the USA and around the world. Although obesity and associated complications garner the most attention in the media, clinical problems at the opposite end of the spectrum, such as involuntary disease-associated weight loss or cachexia, are equally devastating. This review focuses on the role of the central melanocortin system in body weight regulation, and specifically on the anticatabolic properties of antagonists of the melanocortin-4 receptor. RECENT FINDINGS: Over the past several years, the central melanocortin system has emerged as a major contributor to the body weight regulatory system in both animals and humans. In particular, the melanocortin-4 receptor, its endogenous agonist alpha-melanocyte stimulating hormone, and its endogenous antagonist agouti-related protein have been shown to be vital to the maintenance of normal body weight in both genetic and physiologic experiments. This system is now the target of multiple drug discovery endeavors, as the search continues for effective treatments for both obesity and cachexia. Several investigators have recently shown that selective synthetic antagonists of the melanocortin-4 receptor can prevent or attenuate the development of cachexia in animal models of acute and chronic disease. SUMMARY: An understanding of the biology of weight regulation, including both appetite regulation and energy metabolism, is vital if we are to unravel the etiology of and develop effective treatment for obesity and cachexia. The data reviewed here supporting a role for melanocortin-4 receptor antagonists in the treatment of catabolism represent an important advance in this field.

Animals↗
PubMed2001

Actions of cocaine- and amphetamine-regulated transcript (CART) peptide on regulation of appetite and hypothalamo-pituitary axes in vitro and in vivo in male rats.

Cocaine- and amphetamine-regulated transcript (CART) and CART peptide are abundant in hypothalamic nuclei controlling anterior pituitary function. Intracerebroventricular (ICV) injection of CART peptide results in neuronal activation in the paraventricular nucleus (PVN), rich in corticotrophin-releasing factor (CRH) and thyrotrophin-releasing factor (TRH) immunoreactive neurons. The aims of this study were three-fold. Firstly, to examine the effects of CART peptide on hypothalamic releasing factors in vitro, secondly, to examine the effect of ICV injection of CART peptide on plasma pituitary hormones and finally to examine the effect of PVN injection of CART peptide on food intake and circulating pituitary hormones. CART(55-102) (100 nM) peptide significantly stimulated the release of CRH, TRH and neuropeptide Y from hypothalamic explants but significantly reduced alpha melanocyte stimulating hormone release in vitro. Following ICV injection of 0.2 nmol CART(55-102), a dose which significantly reduces food intake, plasma prolactin (PRL), growth hormone (GH) and adrenocorticotrophin hormone (ACTH) and corticosterone increased significantly. Following PVN injection of CART(55-102), food intake was significantly reduced only at 0.2 and 0.6 nmol. However, PVN injection of 0.02 nmol CART(55-102) produced a significant increase in plasma ACTH. ICV injection of CART peptide significantly reduces food intake. Unlike many anorexigenic peptides, there is no increased sensitivity to PVN injection of CART(55-102). In contrast, both ICV and PVN injection of CART(55-102) significantly increased plasma ACTH and release of hypothalamic CRH is significantly increased by CART peptide in vitro. This suggests that CART peptide may play a role in the control of pituitary function and in particular the hypothalamo-pituitary adrenal axis.

Animals↗
PubMed2005

Endocannabinoids in the regulation of appetite and body weight.

The discovery of cannabinoid receptors, together with the development of selective cannabinoid receptor antagonists, has encouraged a resurgence of cannabinoid pharmacology. With the identification of endogenous agonists, such as anandamide, scientists have sought to uncover the biological role of endocannabinoid systems; initially guided by the long-established actions of cannabis and exogenous cannabinoids such as delta9-tetrahydrocannabinol (THC). In particular, considerable research has examined endocannabinoid involvement in appetite, eating behaviour and body weight regulation. It is now confirmed that endocannabinoids, acting at brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours, partly through interactions with more established orexigenic and anorexigenic signals. Key structures such as the nucleus accumbens and hypothalamic nuclei are sensitive sites for the hyperphagic actions of these substances, and endocannabinoid activity in these regions varies in relation to nutritional status and feeding expression. Behavioural studies indicate that endocannabinoids increase eating motivation by enhancing the incentive salience and hedonic evaluation of ingesta. Moreover, there is strong evidence of an endocannabinoid role in energy metabolism and fuel storage. Recent developments point to potential clinical benefits of cannabinoid receptor antagonists in the management of obesity, and of agonists in the treatment of other disorders of eating and body weight regulation.

Animals↗