dynorphins and Obesity

Of the many factors that influence food intake, there is strong evidence that opioid and CCK peptides, which stimulate feeding and elicit satiety, respectively, are important components that may act in concert to regulate energy balance. Cholecystokinin peptides have been isolated in both the brain and gastrointestinal tract, and changes in concentration in the brain and in plasma have been shown to vary with feeding. Peripherally injected CCK has been shown to elicit satiety in many species, including humans, an effect that may be mediated in the CNS via the vagus. In several species, most notably the sheep, direct injection into the CSF potently decreases food intake. Questions remaining regarding the role of CCK peptides in eliciting satiety include the sites and mechanisms of action. It is unknown whether CCK acts directly on receptors, indirectly on some other parameter, or as a neurotransmitter. Although opioid peptides have also been localized in portions of both the periphery and brain, a specific physiological role for their presence has not yet been determined. Opioid peptides from three families--endorphins, enkephalins, and dynorphins--have been shown to stimulate feeding in various species. They have been active at several opioid receptor types in the CNS, but there is limited evidence to suggest they affect food intake when administered peripherally. In contrast, peripheral injection of opiate antagonists has effectively decreased food intake, an observation that led to the original hypothesis that opioids were involved in the hunger component in the control of food intake and that excess concentrations might be involved in the development of obesity. An increasing body of evidence supports the concept that opioid and CCK peptides may interact to control food intake, but the evidence is more suggestive than conclusive.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; beta-Endorphin; beta-Lipotropin; Brain; Ceruletide; Cholecystokinin; Digestive System Physiological Phenomena; Dynorphins; Eating; Endorphins; Enkephalins; Fasting; Food; Humans; Immunologic Techniques; Kinetics; Morphine; Nervous System; Neurons; Obesity; Peptide Fragments; Protein Precursors; Receptors, Cell Surface; Receptors, Cholecystokinin; Satiation; Sincalide; Species Specificity; Structure-Activity Relationship; Tissue Distribution

Topics: Analgesics; Animals; Appetite Depressants; Appetite Regulation; beta-Endorphin; Dynorphins; Endorphins; Humans; Narcotics; Obesity; Peptides; Stimulation, Chemical

Topics: Arcuate Nucleus of Hypothalamus; Dynorphins; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Neurokinin B; Neurons; Obesity

The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A

Topics: Analgesics, Opioid; Animals; Brain; Dynorphins; Mice; Obesity; Orexins; Paraventricular Hypothalamic Nucleus

Metabolic stress resulting from either lack or excess of nutrients often causes infertility in both sexes. Kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the arcuate nucleus (ARC) has been suggested to be a key players in reproduction via direct stimulation of the pulsatile gonadotropin-releasing hormone (GnRH) and subsequent gonadotropin release in mammalian species. In this study, we investigated the effect of high-fat diet (HFD) on hypothalamic KNDy gene expression to examine the pathogenic mechanism underlying obesity-induced infertility in male and female rats. Male and female rats at 7 weeks of age were fed with either a standard or HFD for 4 months. In the male rats, the HFD caused a significant suppression of ARC Kiss1 and Pdyn gene expressions, but did not affect the plasma luteinizing hormone (LH) levels and sizes of the morphology of the testis and epididymis. In the female rats, 58% of the HFD-fed female rats exhibited irregular estrous cycles, whereas the remaining rats showed regular cycles. Two of the 10 rats that showed HFD-induced irregular estrous cycles showed profound suppression of LH pulse frequency and the number of ARC Kiss1-expressing cells, whereas the other females showed normal LH pulses and ARC Kiss1 expression. Our finding shows that suppression of ARC Kiss1 expression might be the initial pathological change of hypogonadotropic hypogonadism in HFD-fed male rats, while the obese-related infertility in the female rats may be mainly induced by KNDy-independent pathways. Taken together, ARC kisspeptin neurons in male rats may be susceptible to HFD-induced obesity compared with those in female rats.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Dynorphins; Female; Gonadal Steroid Hormones; Hypogonadism; Kisspeptins; Luteinizing Hormone; Male; Metabolic Diseases; Neurokinin B; Neurons; Obesity; Rats; Rats, Wistar

KNDy neurons co-expressing kisspeptin (KP), neurokinin B (NKB) and dynorphin A (DYN A) in the arcuate nucleus of the hypothalamus (ARC) are key regulators of reproduction. Their activity is influenced by metabolic and hormonal signals. Previously, we have shown that orchidectomy alters the KP-, NKB-, and DYN A-immunoreactivity in the high-fat diet-induced (HFD) obesity and diabetes type 2 (DM2) models. Considering the potential sex difference in the response of KNDy neurons, we have hypothesized that ovariectomy (OVX) and post-ovariectomy replacement with estradiol (OVX+E

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus, Experimental; Dynorphins; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Kisspeptins; Male; Neurokinin B; Neurons; Obesity; Ovariectomy; Rats

Neurones expressing kisspeptin, neurokinin B and dynorphin A, located in the arcuate nucleus of the hypothalamus (ARC), are important regulators of reproduction. Their functions depend on metabolic and hormonal status. We hypothesised that male rats with high-fat diet-induced obesity (DIO) and/or streptozotocin-induced diabetes mellitus type 1 (DM1) and type 2 (DM2) will have alterations in numbers of immunoreactive (-IR) cells: kisspeptin-IR and/or neurokinin B-IR and dynorphin A-IR neurones in the ARC in the sham condition. In addition, orchidectomy alone (ORX) and with testosterone treatment (ORX+T) will unmask possible deficits in the response of these neurones in DIO, and/or DM1 and DM2 rats. Rats were assigned to four groups: a control (C) and one diabetic group (DM1) were fed a regular chow diet, whereas the obese group (DIO) and the other diabetic group (DM2) were fed a high-fat diet. To induce diabetes, streptozotocin was injected. After 6 weeks, each group was divided into three subgroups: ORX, ORX+T and sham. After another 2 weeks, metabolic and hormonal profiles were assessed and immunocytochemistry was performed. We found that: (1) under sham conditions: (i) DM1 and DM2 animals had higher numbers of kisspeptin-IR cells than controls and (ii) DM2 rats had increased numbers of neurokinin B-IR and dynorphin A-IR cells compared to C animals; (2) ORX and ORX+T treatments unmasked deficits of the studied neurones in DM1 and DM2 but not in DIO animals; and (3) DIO, DM1 and DM2 rats had altered metabolic and hormonal profiles, in particular decreased levels of testosterone. We concluded that alterations in numbers of kisspeptin-IR and neurokinin B-IR neurones in the ARC and their response to ORX and ORX+T may account for disruptions of metabolic and reproductive functions in diabetic but not in obese rats.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus, Experimental; Diet, High-Fat; Dynorphins; Kisspeptins; Male; Neurokinin B; Neurons; Obesity; Orchiectomy; Rats; Testosterone

Arcuate neurons that coexpress kisspeptin (Kiss1), neurokinin B (Tac2), and dynorphin (Pdyn) mediate negative feedback of 17β-estradiol (E2) on the HPG axis. Previous studies report that fasting and caloric restriction reduce arcuate Kiss1 expression. The objective of this study was to determine the interactions of E2 with fasting, caloric restriction, and diet-induced obesity on KNDy gene and receptor expression. Ovariectomized female mice were separated into control and estradiol benzoate (E2B)-treated groups. E2B decreased Kiss1 and the tachykinin 2 receptor, Tac3r, in ARC tissue and Tac2 in Tac2 neurons. Diet-induced obesity decreased Kiss1 in oil-treated animals and the kisspeptin receptor, Kiss1r and Tac3r in the ARC of E2B-treated animals. Chronic caloric (30%) restriction reduced all three neuropeptides in oil-treated females and Kiss1r by E2B in CR animals. Taken together, our experiments suggest that steroidal environment and energy state negatively regulate KNDy gene expression in both ARC and Tac2 neurons.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Caloric Restriction; Diet; Diet, High-Fat; Dynorphins; Estradiol; Fasting; Female; Gene Expression Profiling; Gene Expression Regulation; Ghrelin; Kisspeptins; Mice, Inbred C57BL; Models, Biological; Neurokinin B; Neurons; Neuropeptides; Obesity; Organ Size; Signal Transduction

Puberty is starting earlier than ever before and there are serious physiological and sociological implications as a result of this development. Current research has focused on the potential role of high caloric, and commensurate high adiposity, contributions to early puberty. However, girls with normal BMI also appear to be initiating puberty earlier. Westernized diets, in addition to being high in fat and sugar, are also high in salt. To date, no research has investigated a link between elevated salt and the reproductive axis. We hypothesize that a high salt diet can result in an earlier onset of puberty through three mechanisms that are not mutually exclusive. (1) High salt activates neurokinin B, a hormone that is involved in both the reproductive axis and salt regulation, and this induces kisspeptin release and ultimate activation of the reproductive axis. (2) Vasopressin released in response to high salt acts on vasopressin receptors expressed on kisspeptin neurons in the anteroventral periventricular nucleus, thereby stimulating gonadotropin releasing hormone and subsequently luteinizing hormone secretion. (3) Salt induces metabolic changes that affect the reproductive axis. Specifically, salt acts indirectly to modulate adiposity, ties in with the obesity epidemic, and further compounds the pathologic effects of obesity. Our overall hypothesis offers an additional cause behind the induction of puberty and provides testable postulates to determine the mechanism of potential salt-mediated affects on puberty.

Topics: Age Factors; Animals; Arcuate Nucleus of Hypothalamus; Body Mass Index; Child; Diet; Dynorphins; Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Male; Mice; Neurokinin B; Neurons; Obesity; Puberty; Rats; Reproduction; Sexual Maturation; Sodium Chloride, Dietary

Orexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone.. We generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts.. Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-h fast, with no effect on serum glucose levels after glucose injection.. Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.

Topics: Adipose Tissue; Animals; Appetite Regulation; Body Weight; Dynorphins; Energy Metabolism; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity

The intracerebroventricular (i.c.v.) infusion of beta-endorphin can cause either a decrease in blood pressure in normal rats or an increase in obese rats. Diet-induced obesity is associated with an increase of hypothalamic mu opioid receptors. Since beta-endorphins act by opioid receptors, we investigated the effect of CNS mu as well as kappa opioid receptor agonist and antagonist on mean blood pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male Wistar rats fed either a high fat (HF) (40% fat by weight) or a regular low fat (control) (4% fat by weight) diet. After a 12-week-feeding period the animals were implanted with i.c.v. cannulas and 3-5 days later they were anesthetized and instrumented to record MAP, HR and RSNA. HF rats have higher MAP and the i.c.v. injection of a mu opioid agonist (DAMGO) initially decreased the MAP and then increased MAP, HR and RSNA in the normal animals. The increase was greater in HF animals. The i.c.v. injection of the mu antagonist (beta-FNA) resulted in a significantly greater decrease in MAP in HF animals. beta-FNA increased the RSNA in the HF rats but decreased it in the normal rats. The kappa agonist (dynorphin) decreased MAP in normal rats followed by a return to baseline, but not in HF rats. The kappa antagonist, nor-binaltorphimine (N-BP), increased MAP and RSNA in normal rats and to a lesser extent in HF rats. These findings suggest that rats given a high fat diet have higher blood pressures and a greater mu opioid-mediated responsiveness with a greater mu opioid-mediated autonomic tone. Additionally there is a decreased kappa responsiveness and tone in the HF rats. Both these changes, increased mu and decreased kappa responsiveness could strongly contribute to the increased blood pressure in obese animals.

Topics: Animals; Blood Pressure; Body Weight; Central Nervous System; Diet; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Male; Obesity; Rats; Rats, Wistar; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

Sprague-Dawley rats selectively bred for diet-induced obesity (DIO) or diet resistance (DR) were characterized on diets of differing energy content and palatability. Over 10 wk, DR rats on a high-energy (HE) diet (31% fat) gained weight similarly to DR rats fed chow (4.5% fat), but they became obese on a palatable liquid diet (Ensure). DIO rats gained 22% more weight on an HE diet and 50% more on Ensure than chow-fed DIO rats. DIO body weight gains plateaued when switched from HE diet to chow. But, Ensure-fed DIO rats switched to chow spontaneously reduced their intake and weight to that of rats switched from HE diet to chow. They also reduced their hypothalamic proopiomelanocortin and dynorphin but not neuropeptide Y mRNA expression by 17-40%. When reexposed to Ensure after 7 wk, they again overate and matched their body weights to rats maintained on Ensure throughout. All Ensure-fed rats had a selective reduction in dynorphin mRNA in the ventromedial hypothalamic nucleus. Thus genetic background, diet composition, and palatability interact to produce disparate levels of defended body weight and central neuropeptide expression.

Topics: Adipose Tissue; Animal Feed; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet; Dietary Sucrose; Dynorphins; Eating; Food, Formulated; Gene Expression; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger

Effects of obesity on gene expression for opioid peptides and neuropeptide-Y (NPY) in the arcuate nucleus (ARC), and on opioid peptides and alpha-melanocyte stimulating hormone (alpha-MSH) in the paraventricular nucleus (PVN) were examined in obese Zucker rats (18 weeks old). Obese Zucker rats are insulin-resistant, diabetic and hyperleptinemic as indicated by high serum glucose, insulin and leptin levels. ARC proOpiomelanocortin (POMC) mRNA levels were significantly lower in the obese relative to lean Zucker rats and ARC proNeuropeptide Y (proNPY) mRNA levels were higher (P<0.05). There were no differences in proDynorphin and proEnkephalin mRNA levels in the ARC (0.05). Obese Zucker rats had lower alpha-MSH and dynorphin A(1-17) peptide levels in the paraventricular nucleus (PVN) (P<0.05), but did not have lower PVN beta-endorphin peptide levels (0.05). The decrease in POMC in the ARC and decrease in alpha-MSH in the PVN seen in the obese Zucker rat in the present study suggest that reduced activity of the melanocortin system in the ARC to PVN pathway may contribute to the related hyperphagia. Reduced activity of the melanocortin system in the ARC to PVN pathway may be due to a disturbance of leptin signaling coupling to POMC.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Blood Glucose; Dynorphins; Energy Metabolism; Enkephalins; Feeding Behavior; Gene Expression; Insulin; Leptin; Male; Melanocytes; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; Protein Precursors; Rats; Rats, Zucker; RNA, Messenger

The effect of food deprivation on opioid receptor binding was studied in 6 brain regions of lean and fatty Zucker rats; using [3H]dynorphin A. There was no significant difference between lean and fatty rats fed ad libitum in binding parameters for any regions studied. Food deprivation increased Bmax and/or Kd for cortex, midbrain and striatum of lean rats, and the former two regions of fatty rats. These results suggest that food deprivation may influence opioid receptor binding in lean and fatty Zucker rats.

Topics: Animals; Brain; Dynorphins; Food Deprivation; Kinetics; Male; Obesity; Peptide Fragments; Rats; Rats, Zucker