leptin and preproenkephalin

In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin. Finally, i.c.v. infusion of AC187 acutely reduced the anorectic effects of leptin. These data show that hypothalamic amylin is transcriptionally regulated by leptin, that it can act directly on ObRb neurons in concert with leptin, and that it regulates feeding. These findings provide a potential mechanism for the increased efficacy of a metreleptin/pramlintide combination therapy for obesity.

Topics: Animals; Eating; Enkephalins; Female; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Obese; Microscopy, Confocal; Neurons; Patch-Clamp Techniques; Peptide Fragments; Protein Precursors; Receptors, Leptin; RNA, Messenger

Epidemiological studies have shown a link between sleep loss and the obesity 'epidemic,' and several observations indicate that sleep curtailment engenders positive energy balance via increased palatable-food 'snacking.' These effects suggest alterations in reward-modulatory brain systems. We explored the effects of 10 days of sleep deprivation in rats on the expression of striatal opioid peptide (OP) genes that subserve food motivation and hedonic reward, and compared effects with those seen in hypothalamic energy balance-regulatory systems. Sleep-deprived (Sleep-Dep) rats were compared with yoked forced-locomotion apparatus controls (App-Controls), food-restricted rats (Food-Restrict), and unmanipulated controls (Home-Cage). Detection of mRNA levels with in situ hybridization revealed a subregion-specific upregulation of striatal preproenkephalin and prodynorhin gene expression in the Sleep-Dep group relative to all other groups. Neuropeptide Y (NPY) gene expression in the hippocampal dentate gyrus and throughout neocortex was also robustly upregulated selectively in the Sleep-Dep group. In contrast, parallel gene expression changes were observed in the Sleep-Dep and Food-Restrict groups in hypothalamic energy-sensing systems (arcuate nucleus NPY was upregulated, and cocaine- and amphetamine-regulated transcript was downregulated), in alignment with leptin suppression in both groups. Together, these results reveal a novel set of sleep deprivation-induced transcriptional changes in reward-modulatory peptide systems, which are dissociable from the energy-balance perturbations of sleep loss or the potentially stressful effects of the forced-locomotion procedure. The recruitment of telencephalic food-reward systems may provide a feeding drive highly resistant to feedback control, which could engender obesity through the enhancement of palatable feeding.

Topics: Animals; Body Weight; Eating; Enkephalins; Fasting; Insulin; Leptin; Male; Neostriatum; Nerve Tissue Proteins; Neuroimaging; Neuropeptide Y; Opioid Peptides; Protein Precursors; Rats; Rats, Sprague-Dawley; Reward; Sleep Deprivation; Up-Regulation

The prohormone preproenkephalin (ppE) and its derived peptides are involved in leukocyte functioning as well as in the regulation of hunger and satiety. Various abnormalities of the immune and endocrine systems have been described in states of malnutrition such as anorexia nervosa (AN). We hypothesized that ppE expression in AN patients may vary depending on the state of the disorder and the extent of malnutrition.. Expression of ppE mRNA was analysed in peripheral blood mononuclear cells of 29 underweight and 29 weight-recovered patients with AN and compared to that in 29 healthy control women. The extent of malnutrition was characterized by BMI and plasma leptin. Psychological distress and eating disorder specific-psychopathology was determined with the Symptom Checklist-90-Revised and the Eating Disorders Inventory-2.. ppE gene expression was similar in all 3 groups and was not related to nutritional status or eating disorder symptoms. However, a significant negative correlation was found between ppE expression and obsessive-compulsive, depressive and anxious symptoms. In addition, ppE expression was higher in smokers compared to non-smokers.. Although malnutrition and hypoleptinaemia as seen in patients with AN were not related to peripheral ppE expression, we demonstrated reduced ppE expression in patients with elevated psychological distress. Similar associations have been shown in animal models of stress. It remains speculative if psychological symptoms and/or stress may augment immune abnormalities in AN patients via a pathway that is independent of nutritional status and involves ppE.

Topics: Adolescent; Adult; Anorexia Nervosa; Anxiety; Basal Metabolism; Depression; Enkephalins; Female; Gene Expression; Humans; Leptin; Leukocytes, Mononuclear; Obsessive-Compulsive Disorder; Protein Precursors; Psychiatric Status Rating Scales; Severity of Illness Index; Stress, Psychological; Thinness

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

Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respond to leptin have not been examined comprehensively. In this study, we explored systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subsets of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was investigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of Fos-IR was observed in hypothalamic nuclei, including the paraventricular nucleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and external lateral subdivisions of the parabrachial nucleus (slPB and elPB, respectively), the supragenual nucleus, and the nucleus of the solitary tract (NTS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found that contained cocaine- and amphetamine-regulated transcript mRNA in several hypothalamic nuclei, including the RCA, Arc, DMH, and PMV. In the Arc and DMH, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Arc also expressed Fos-IR. In the brainstem, we found that cholecystokinin neurons in the slPB and glucagon-like peptide-1 neurons in the NTS were activated by leptin. We also investigated the coexpression of Fos-IR and the long form of the leptin receptor (OBRb) mRNA. We found double-labeled neurons surrounding the median eminence and in the RCA, Arc, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very few double-labeled cells. These results suggest that leptin stimulates brain pathways containing neuropeptides that are involved in the regulation of energy balance, autonomic homeostasis, and neuroendocrine status.

Topics: Animals; Brain; Brain Chemistry; Caenorhabditis elegans Proteins; Carrier Proteins; Cholecystokinin; Eating; Energy Metabolism; Enkephalins; Homeostasis; Immunohistochemistry; In Situ Hybridization; Leptin; Male; Membrane Glycoproteins; Nerve Tissue Proteins; Neurons; Neurotensin; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Receptors, Notch; RNA, Messenger; Time Factors

Effects of streptozotocin (STZ)-induced diabetes and insulin on opioid peptide gene expression were examined in rats. In experiment 1, three groups were administered STZ (75 mg/kg ip single injection). Two groups were killed at either 2 or 4 wk. In the third group, insulin treatment (7.0 IU/kg x 1 day for 3 wk) was initiated 1 wk after STZ injection. STZ induced hyperphagia and reduced weight gain. Insulin decreased food intake and increased body weight relative to diabetes. Proopiomelanocortin (POMC) mRNA in arcuate nucleus (Arc) and pituitary decreased in diabetes and normalized after insulin treatment. Prodynorphin (proDyn) mRNA increased in diabetes and normalized in the pituitary after insulin but not in the Arc. Diabetes did not alter proenkephalin (proEnk) expression in the Arc or pituitary, nor dynorphin A1-17 or beta-endorphin in paraventricular nucleus (PVN). alpha-Melanocyte-stimulating hormone (alpha-MSH) peptide levels were decreased in the PVN and normalized following insulin treatment. Diabetes increased Arc neuropeptide Y mRNA, and insulin suppressed this increase. In experiment 2, insulin (2.5 IU/kg sc) daily for 1 wk in normal rats increased Arc POMC mRNA, but not proDyn and proEnk mRNA. These results suggest that Arc POMC expression and PVN alpha-MSH peptide levels decrease in diabetes. Also, insulin may influence Arc and pituitary POMC activity in neurons that regulate energy metabolism.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Eating; Energy Metabolism; Enkephalins; Gene Expression; Hypoglycemic Agents; Insulin; Leptin; Male; Melanocytes; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pituitary Gland; Pro-Opiomelanocortin; Protein Precursors; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger