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Pałasz A, Suszka-Świtek A, Kaśkosz A, Plewka D, Bogus K, Filipczyk Ł, Błaszczyk I, Bacopoulou F, Worthington JJ, Piwowarczyk-Nowak A, Tyszkiewicz-Nwafor M, Wiaderkiewicz R. Spexin-expressing neurons in the magnocellular nuclei of the human hypothalamus. J Chem Neuroanat 2020; 111:101883. [PMID: 33161073 DOI: 10.1016/j.jchemneu.2020.101883] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/03/2020] [Accepted: 11/03/2020] [Indexed: 12/19/2022]
Abstract
Neuropeptides are involved in numerous brain activities being responsible for a wide spectrum of higher mental functions. The purpose of this concise, structural and qualitative investigation was to map the possible immunoreactivity of the novel neuropeptide spexin (SPX) within the human magnocellular hypothalamus. SPX is a newly identified peptide, a natural ligand for the galanin receptors (GALR) 2/3, with no molecular structure similarities to currently known regulatory factors. SPX seems to have multiple physiological functions, with an involvement in reproduction and food-intake regulation recently revealed in animal studies. For the first time we describe SPX expressing neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of the human hypothalamus using immunohistochemical and fluorescent methods, key regions involved in the mechanisms of osmotic homeostasis, energy expenditure, consummatory behaviour, reproductive processes, social recognition and stress responses. The vast majority of neurons located in both examined neurosecretory nuclei show abundant SPX expression and this may indirectly implicate a potential contribution of SPX signalling to the hypothalamic physiology in the human brain.
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Affiliation(s)
- Artur Pałasz
- Department of Histology, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland.
| | - Aleksandra Suszka-Świtek
- Department of Histology, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
| | - Andrzej Kaśkosz
- Department of Anatomy, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
| | - Danuta Plewka
- Department of Cytophysiology, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
| | - Katarzyna Bogus
- Department of Histology, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
| | - Łukasz Filipczyk
- Department of Histology, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
| | - Iwona Błaszczyk
- Department of Histology, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
| | - Flora Bacopoulou
- Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece
| | - John J Worthington
- Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK
| | - Aneta Piwowarczyk-Nowak
- Department of Anatomy, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
| | - Marta Tyszkiewicz-Nwafor
- Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, ul. Szpitalna 27/33, 60-572, Poznań, Poland
| | - Ryszard Wiaderkiewicz
- Department of Histology, School of Medical Sciences in Katowice, Medical University of Silesia, ul. Medyków 18, 40-752, Katowice, Poland
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Oride A, Kanasaki H, Mijiddorj T, Sukhbaatar U, Hara T, Tumurbaatar T, Kyo S. GLP-1 increases Kiss-1 mRNA expression in kisspeptin-expressing neuronal cells†. Biol Reprod 2017; 97:240-248. [DOI: 10.1093/biolre/iox087] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 08/04/2017] [Indexed: 12/26/2022] Open
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Intrasexual Competition and Other Theories of Eating Restriction. EVOLUTIONARY PSYCHOLOGY 2014. [DOI: 10.1007/978-1-4939-0314-6_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Gonnissen HKJ, Hulshof T, Westerterp-Plantenga MS. Chronobiology, endocrinology, and energy- and food-reward homeostasis. Obes Rev 2013; 14:405-16. [PMID: 23387351 DOI: 10.1111/obr.12019] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 01/07/2013] [Accepted: 01/07/2013] [Indexed: 12/28/2022]
Abstract
Energy- and food-reward homeostasis is the essential component for maintaining energy balance and its disruption may lead to metabolic disorders, including obesity and diabetes. Circadian alignment, quality sleep and sleep architecture in relation to energy- and food-reward homeostasis are crucial. A reduced sleep duration, quality sleep and rapid-eye movement sleep affect substrate oxidation, leptin and ghrelin concentrations, sleeping metabolic rate, appetite, food reward, hypothalamic-pituitary-adrenal (HPA)-axis activity, and gut-peptide concentrations, enhancing a positive energy balance. Circadian misalignment affects sleep architecture and the glucose-insulin metabolism, substrate oxidation, homeostasis model assessment of insulin resistance (HOMA-IR) index, leptin concentrations and HPA-axis activity. Mood disorders such as depression occur; reduced dopaminergic neuronal signaling shows decreased food reward. A good sleep hygiene, together with circadian alignment of food intake, a regular meal frequency, and attention for protein intake or diets, contributes in curing sleep abnormalities and overweight/obesity features by preventing overeating; normalizing substrate oxidation, stress, insulin and glucose metabolism including HOMA-IR index, and leptin, GLP-1 concentrations, lipid metabolism, appetite, energy expenditure and substrate oxidation; and normalizing food reward. Synchrony between circadian and metabolic processes including meal patterns plays an important role in the regulation of energy balance and body-weight control. Additive effects of circadian alignment including meal patterns, sleep restoration, and protein diets in the treatment of overweight and obesity are suggested.
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Affiliation(s)
- H K J Gonnissen
- Department of Human Biology, Nutrim, Maastricht University, Maastricht, the Netherlands
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Routh VH, Horwitz BA, Gietzen DW, Stern JS. Hypothalamic Monoaminergic Activity in 11-Week-Old Cold-Exposed Female Lean(Fa/Fa)and Obese(fa/fa)Zucker Rats. ACTA ACUST UNITED AC 2012; 2:28-37. [PMID: 16355483 DOI: 10.1002/j.1550-8528.1994.tb00041.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We previously reported that serotonergic activity was reduced in the ventromedial hypothalamic nucleus (VMN) of obese vs. lean male Zucker rats. To verify that this reduction was associated with genotype rather than gender, we measured monoamines and their major metabolites in hypothalamic nuclei of 11-week-old female lean (Fa/Fa) and obese (fa/fa) Zucker rats. In addition, since the thermic response to cold is reported to differ between lean and obese rats, some rats were also exposed to 9 degrees or 22 degrees C for 2h to determine if cold exposure altered hypothalamic monoaminergic activity. As in males, levels of 5-hydroxyindoleacetic acid [5-HIAA; major metabolite of serotonin (5-HT)] and the ratio of 5-HIAA/5-HT were lower in the VMN of obese vs. lean females (P = 0.008, 0.001, respectively). 5-HIAA/5-HT was also reduced in the paraventricular (PVN) and suprachiasmatic nuclei (SCN) of the obese compared to the lean females. Cold exposure significantly stimulated brown fat mitochondrial GDP binding in lean but not obese rats. Similarly, levels of norepinephrine, dopamine (DA), 5-HIAA, and 5-HT in the PVN, and 5-HIAA in the SCN increased in cold-exposed lean but not obese rats. In contrast, VMN and preoptic 3,4-dihydroxyphenylacetic acid (DOPAC; major metabolite of DA) increased in the cold-exposed obese but not lean animals. We conclude that: (1) the blunted peripheral response to cold in obese vs. lean Zucker rats is accompanied by altered hypothalamic monoaminergic activity, the physiological role of which needs further evaluation; and 2) depressed VMN serotonergic activity is associated with the obese genotype (fa/fa) rather than gender and as such may contribute to the reduced sympathetic and enhanced parasympathetic outflow from the VMN.
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Affiliation(s)
- V H Routh
- Section of Neurobiology, Physiology, and Behavior, Division of Biological Sciences, Univ. of California, Davis, 95616, USA
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Abstract
Mammals have an endogenous timing system in the suprachiasmatic nuclei (SCN) of the hypothalamic region of the brain. This internal clock system is composed of an intracellular feedback loop that drives the expression of molecular components and their constitutive protein products to oscillate over a period of about 24 h (hence the term 'circadian'). These circadian oscillations bring about rhythmic changes in downstream molecular pathways and physiological processes such as those involved in nutrition and metabolism. It is now emerging that the molecular components of the clock system are also found within the cells of peripheral tissues, including the gastrointestinal tract, liver and pancreas. The present review examines their role in regulating nutritional and metabolic processes. In turn, metabolic status and feeding cycles are able to feed back onto the circadian clock in the SCN and in peripheral tissues. This feedback mechanism maintains the integrity and temporal coordination between various components of the circadian clock system. Thus, alterations in environmental cues could disrupt normal clock function, which may have profound effects on the health and well-being of an individual.
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Dallman MF, Bhatnagar S. Chronic Stress and Energy Balance: Role of the Hypothalamo‐Pituitary‐Adrenal Axis. Compr Physiol 2011. [DOI: 10.1002/cphy.cp070410] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Garaulet M, Madrid JA. Chronobiological aspects of nutrition, metabolic syndrome and obesity. Adv Drug Deliv Rev 2010; 62:967-78. [PMID: 20580916 DOI: 10.1016/j.addr.2010.05.005] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2009] [Revised: 05/05/2010] [Accepted: 05/19/2010] [Indexed: 10/19/2022]
Abstract
The present review starts from the classical physiological and nutritional studies related with food intake control, digestion, transport and absorption of nutrients. It continues with studies related with the metabolism of adipose tissue, and finish with modern experiments in genetics and molecular biology - all from a fresh, chronobiological point of view. Obesity will be explained as a fault in the circadian system, as pathology associated with "chronodisruption". The main gaps in chronobiological research related to obesity will be also identified and chronobiological-based therapies will be proposed in order to allow the resetting of the circadian rhythm among obese subjects.
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Singla P, Bardoloi A, Parkash AA. Metabolic effects of obesity: A review. World J Diabetes 2010; 1:76-88. [PMID: 21537431 PMCID: PMC3083889 DOI: 10.4239/wjd.v1.i3.76] [Citation(s) in RCA: 192] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Revised: 06/22/2010] [Accepted: 06/29/2010] [Indexed: 02/05/2023] Open
Abstract
With the many recent advances in the biomedical world, vast changes are taking place in our growing knowledge of the physiological aspects of almost all the tissues and organs of the human body. One of the most prevalent topics of discussion is the question of obesity and its effect on the metabolic changes in the human body. The original classical role of adipose tissue as an energy storage organ has been greatly modified. We now know that it is an endocrine organ, producing adipokines like leptin, adiponectin, visfatin, resistin, apelin, etc, which modulate metabolic processes in the body. Since obesity is associated with an increase in the adipose tissue mass, these hormones may be expected to be produced in increased concentrations and may thus have a significant impact on the macronutrient metabolism. Further, these adipokines may interact with long term energy modulators like insulin. Even though the scientific community has started unravelling the mysteries of the close linkage between obesity, its hormones and their physiological effects, a lot still remains to be discovered. The present discussion makes an attempt to trace the basic modern day concepts of the role of obesity in various metabolic processes.
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Affiliation(s)
- Parul Singla
- Parul Singla, Animesh Bardoloi, Department of Biochemistry, Lady Hardinge Medical College, New Delhi 110001, India
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Affiliation(s)
- Marian Roman
- College of Nursing, University of Tennessee, 1200 Volunteer Blvd, Knoxville, TN 37996, USA.
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Görgülü M, Boğa M, Şahin A, Serbester U, Kutlu HR, Şahinler S. Diet selection and eating behaviour of lactating goats subjected to time restricted feeding in choice and single feeding system. Small Rumin Res 2008. [DOI: 10.1016/j.smallrumres.2008.04.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Yeh SS, Blackwood K, Schuster MW. The cytokine basis of cachexia and its treatment: are they ready for prime time? J Am Med Dir Assoc 2008; 9:219-36. [PMID: 18457797 DOI: 10.1016/j.jamda.2008.01.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2008] [Accepted: 01/04/2008] [Indexed: 01/14/2023]
Abstract
Cachexia is a hypercatabolic condition that is often associated with the terminal stages of many diseases, in which the patient's resting metabolic rate is high and loss of muscle and fat tissue mass occur at an alarming rate. The patient also usually has concurrent anorexia, amplifying the wasting syndrome that is cachexia. The greater the extent of cachexia (regardless of underlying disease), the worse the prognosis. Efforts to treat cachexia over the years have fallen short of satisfactorily reversing the wasting syndrome. This article reviews the pathophysiology of cachexia, enumerating the different pro-inflammatory cytokines that contribute to the syndrome and attempting to illustrate their interwoven pathways. We also review the different treatments that have been explored, as well as the recent literature addressing the use of anti-cytokine therapy to treat cachexia.
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Tizzano JP, Stribling DS, Perez-Tilve D, Strack A, Frassetto A, Chen RZ, Fong TM, Shearman L, Krieter PA, Tschöp MH, Skolnick P, Basile AS. The triple uptake inhibitor (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane hydrochloride (DOV 21947) reduces body weight and plasma triglycerides in rodent models of diet-induced obesity. J Pharmacol Exp Ther 2008; 324:1111-26. [PMID: 18089843 DOI: 10.1124/jpet.107.133132] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2025] Open
Abstract
Selective inhibitors of biogenic amine (e.g., serotonin, norepinephrine, and dopamine) uptake exhibit varying degrees of safety and efficacy as antiobesity agents. Moreover, preclinical findings suggest that the combined inhibition of monoamine neurotransmitter transporters synergistically enhances antiobesity activity. (1R,5S)-(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo-[3.1.0] hexane hydrochloride (DOV 21947) inhibits norepinephrine, 5-hydroxytryptamine, and dopamine uptake, and it reduces body weight in rodent models of diet-induced obesity (DIO). DIO rats treated orally with DOV 21947 for 1 to 24 days showed significantly lower body weights than vehicle-treated DIO rats. The decrease in body weight resulted specifically from a loss of retroperitoneal and mesenteric depots of white adipose tissue. DOV 21947 also reduced daily food intake in DIO rats, but consumption returned to control levels after 11 days of treatment. With the exception of a decrease in triglyceride levels, blood chemistry was unaltered after 24 days of DOV 21947 treatments. DOV 21947 had no effect on motor activity. Although DOV 21947 increased respiratory rate and decreased the tidal volume of normal rats, it did not alter the minute volume. In addition, DOV 21947 did not significantly affect blood pressure, heart rate, electrocardiographic indices or body temperature in telemeterized dogs. However, it caused a sustained, but reversible reduction in the rate of body weight gain for as long as 6 months in normal rats, and for up to 1 year in normal dogs. In summary, DOV 21947 is effective in causing a sustained and selective reduction in fat content and triglyceride levels in animal models of obesity without significantly altering vital organ function.
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Affiliation(s)
- Joseph P Tizzano
- Department of Preclinical Pharmacology, DOV Pharmaceutical, Inc., 150 Pierce St., Somerset, NJ 08873-4185, USA
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Ryabinin AE, Yoneyama N, Tanchuck MA, Mark GP, Finn DA. Urocortin 1 microinjection into the mouse lateral septum regulates the acquisition and expression of alcohol consumption. Neuroscience 2007; 151:780-90. [PMID: 18164138 DOI: 10.1016/j.neuroscience.2007.11.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2007] [Revised: 11/09/2007] [Accepted: 12/12/2007] [Indexed: 01/09/2023]
Abstract
Previous studies using genetic and lesion approaches have shown that the neuropeptide urocortin 1 (Ucn1) is involved in regulating alcohol consumption. Ucn1 is a corticotropin releasing factor (CRF) -like peptide that binds CRF1 and CRF2 receptors. Perioculomotor urocortin-containing neurons (pIIIu), also known as the non-preganglionic Edinger-Westphal nucleus, are the major source of Ucn1 in the brain and are known to innervate the lateral septum. Thus, the present study tested whether Ucn1 could regulate alcohol consumption through the lateral septum. In a series of experiments Ucn1 or CRF was bilaterally injected at various doses into the lateral septum of male C57BL/6J mice. Consumption of 20% volume/volume ethanol or water was tested immediately after the injections using a modification of a 2-h limited access sweetener-free "drinking-in-the-dark" procedure. Ucn1 significantly suppressed ethanol consumption when administered prior to the third ethanol drinking session (the expression phase of ethanol drinking) at doses as low as 6 pmol. Ethanol intake was differentially sensitive to Ucn1, as equivalent doses of this peptide did not suppress water consumption. In contrast, CRF suppressed both ethanol and water intake at 40 and 60 pmol, but not at lower doses. Repeated administration of Ucn1 during the acquisition of alcohol consumption showed that 40 pmol (but not 2 or 0.1 pmol) significantly attenuated ethanol intake. Repeated administration of Ucn1 also resulted in a decrease of ethanol intake in sham-injected animals, a finding suggesting that the suppressive effect of Ucn1 on ethanol intake can be conditioned. Taken together, these studies confirm the importance of lateral septum innervation by Ucn1 in the regulation of alcohol consumption.
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Affiliation(s)
- A E Ryabinin
- Department of Behavioral Neuroscience, Oregon Health and Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
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Abstract
Efficacy of antiepileptic drugs (AEDs) are often equivalent, hence selection of an AED is often determined by the adverse effects (AEs). The development of neurocognitive AEs is almost inevitable with use of AEDs, especially in high-risk groups. Teratogenesis with major or minor malformations is of great concern during the first trimester of pregnancy, but an increasing body of information suggests that potential neurocognitive developmental delay may also occur with use of AEDs in the latter part of pregnancy. Decreased bone mineral density has been found in adults and children receiving both enzyme-inducing AEDs and valproate, an enzyme-inhibiting drug. AEDs may influence the lipid profile, body weight, reproductive, hormonal and other endocrine functions, and sleep architecture. There are age-specific AEs related to pharmacokinetic differences that have been highlighted in this review with emphasis on the pediatric population. A classification of AEs using different parameters is also included.
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Affiliation(s)
- Sanjeev V Kothare
- St Christopher's Hospital for Children, Section of Neurology, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA 19134, USA.
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Gozen O, Balkan B, Yararbas G, Koylu EO, Kuhar MJ, Pogun S. Sex differences in the regulation of cocaine and amphetamine-regulated transcript expression in hypothalamic nuclei of rats by forced swim stress. Synapse 2007; 61:561-8. [PMID: 17447258 DOI: 10.1002/syn.20395] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Cocaine and amphetamine-regulated transcript (CART) peptides are suggested to play a role in several physiological processes including feeding, reward, neuroendocrine modulation, and the stress response. Although some studies implicate the modulation of CART peptide expression by glucocorticoids, direct evidence relating CART to the stress response is limited. The present study was undertaken to evaluate the possible involvement of CART peptides during acute stress in male and female rats. Forced swim was used as the stress procedure. Following stress, serum adrenocorticotropic hormone (ACTH), and corticosterone (CORT) levels were determined, and CART immunocytochemistry was performed in the paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus. Our results depict the following changes: (1) Serum ACTH and CORT levels were increased by stress and CORT levels were higher in female rats than males. (2) Stress modulated the number of CART expressing neurons. The degree and direction of this modulation varied according to the hypothalamic region and the sex of the subject. Forced swim stress increased CART peptide expression significantly in the PVN of female rats. In males, although there was a tendency for an increase in CART-immunoreactive cells by forced swim stress, the difference was not statistically significant. In the ARC nucleus, forced swim stress did not affect CART peptide expression in either sex. Our results suggest differential and sexually dimorphic modulation of CART expression in the PVN and ARC by forced swim stress.
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Affiliation(s)
- Oguz Gozen
- Center for Brain Research, Ege University,Bornova, Izmir, Turkey
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Arora S. Role of neuropeptides in appetite regulation and obesity--a review. Neuropeptides 2006; 40:375-401. [PMID: 16935329 DOI: 10.1016/j.npep.2006.07.001] [Citation(s) in RCA: 296] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2006] [Revised: 06/17/2006] [Accepted: 07/07/2006] [Indexed: 01/27/2023]
Abstract
Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.
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Affiliation(s)
- Sarika Arora
- Department of Biochemistry, Lady Hardinge Medical College, Shaheed Bhagat Singh Marg, Connaught Place, New Delhi, Delhi 110 001, India.
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Ryabinin AE, Weitemier AZ. The urocortin 1 neurocircuit: Ethanol-sensitivity and potential involvement in alcohol consumption. ACTA ACUST UNITED AC 2006; 52:368-80. [PMID: 16766036 DOI: 10.1016/j.brainresrev.2006.04.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2005] [Revised: 04/26/2006] [Accepted: 04/29/2006] [Indexed: 11/27/2022]
Abstract
One of the hallmarks of alcoholism is continued excessive consumption of alcohol-containing beverages despite the negative consequences of such behavior. The neurocircuitry regulating alcohol consumption is not well understood. Recent studies have shown that the neuropeptide urocortin 1 (Ucn1), a member of the corticotropin-releasing factor (CRF) family of peptides, could be an important player in the regulation of alcohol consumption. This evidence is accumulated along three directions of research: (1) Ucn 1-containing neurons are extremely sensitive to alcohol; (2) the Ucn1 neurocircuit may contribute to the genetic predisposition to high alcohol intake in mice and rats; (3) manipulation of the Ucn1 system alters alcohol consumption and sensitivity. This paper reviews the current knowledge of the Ucn1 neurocircuit and the evidence for its involvement in alcohol-related behaviors, and proposes a mechanism for its involvement in the regulation of alcohol consumption.
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Affiliation(s)
- Andrey E Ryabinin
- Department of Behavioral Neuroscience, Oregon Health and Science University, L470, 3181 SW Sam Jackson Park Road, Portland, 97239, USA.
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Kyrkouli SE, Strubbe JH, Scheurink AJW. Galanin in the PVN increases nutrient intake and changes peripheral hormone levels in the rat. Physiol Behav 2006; 89:103-9. [PMID: 16806319 DOI: 10.1016/j.physbeh.2006.05.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2005] [Revised: 05/12/2006] [Accepted: 05/15/2006] [Indexed: 11/21/2022]
Abstract
In self-selection feeding paradigms, rats display differential patterns of nutrient (protein, carbohydrate or fat) intake. Factors known to influence this selection include brain peptides as well as circadian parameters. In this series of experiments we investigated the role of PVN galanin in nutrient intake during the early and late dark periods in the rat. Rats were allowed to select between three isocaloric diets enriched in protein, carbohydrate or fat. Following a 2-week adaptation period, the animals' 24-h intake was monitored for 4 weeks. Galanin was injected into the PVN and food intake was measured 1, 2 and 24 h post-injection. Galanin significantly increased the 1 h total food intake but it failed to increase the intake of any particular nutrient. Galanin had no effect 2 or 24 h post-injection. Analysis of the data grouped by preference based on the rats 24 h baseline selection patterns over the 4-week period revealed that galanin seem to increase the preferred nutrient. That is, galanin preferentially increased the intake of the carbohydrate- or fat-rich diet in animals with high (over 40% of the total food intake) 24-h baselines in this particular nutrient. Finally, analysis of the plasma hormone levels after paraventricular galanin administration revealed a significant increase in noradrenaline levels, a small reduction in plasma insulin with no effects on adrenaline, glucose or corticosterone. The data revealed that galanin in the PVN influences both food intake and metabolic functioning. PVN galanin significantly increases sympathetic outflow and seems to stimulate the intake of the individual rat's preferred macronutrient.
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Affiliation(s)
- Stavroula E Kyrkouli
- Laboratory of Pharmacology, Department of Medicine, University of Crete, P.O. Box 1393, Heraklion 71110, Crete, Greece
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Koylu EO, Balkan B, Kuhar MJ, Pogun S. Cocaine and amphetamine regulated transcript (CART) and the stress response. Peptides 2006; 27:1956-69. [PMID: 16822586 DOI: 10.1016/j.peptides.2006.03.032] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2006] [Accepted: 03/25/2006] [Indexed: 01/24/2023]
Abstract
CART is expressed abundantly in the hypothalamic paraventricular nucleus and locus coeruleus, major corticotropin releasing factor (CRF) and noradrenaline sources, respectively. There is a bidirectional relation between CART and hypothalamo-pituitary-adrenal axis activity. CART stimulates CRF, adrenocorticotropic hormone and glucocorticoid secretion, whereas CRF and glucocorticoids increase the transcriptional activity of the CART gene; adrenalectomy declines CART expression in the hypothalamus. Stress exposure modulates CART expression in hypothalamus and amygdala in rat brain in a region and sex specific manner. CART may be a mediator peptide in the interaction between stress, drug abuse, and feeding. The review discusses the established role of CART as it relates to the stress response.
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Affiliation(s)
- Ersin O Koylu
- Ege University Center for Brain Research, Department of Physiology, Bornova, 35100 Izmir, Turkey.
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Chua ASB, Keeling PWN, Dinan TG. Role of cholecystokinin and central serotonergic receptors in functional dyspepsia. World J Gastroenterol 2006; 12:1329-35. [PMID: 16552797 PMCID: PMC4124306 DOI: 10.3748/wjg.v12.i9.1329] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Symptoms of functional dyspepsia are characterized by upper abdominal discomfort or pain, early satiety, postprandial fullness, bloating, nausea and vomiting. It is a chronic disorder, with symptoms more than 3 mo per year, and no evidence of organic diseases. Dysfunctional motility, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. It is believed that these pathophysiological mechanisms interact to produce the observed symptoms. Dyspepsia has been categorized into three subgroups based on dominant symptoms. Dysmotility-like dyspepsia describes a subgroup of patients whose symptom complex is usually related to a gastric sensorimotor dysfunction. The brain-gut peptide cholecystokinin (CCK) and serotonin (5-HT) share certain physiological effects. Both have been shown to decrease gastric emptying and affect satiety. Furthermore the CCK induced anorexia depended on serotonergic functions probably acting via central pathways. We believe that abnormalities of central serotonergic receptors functioning together with a hyper responsiveness to CCK or their interactions may be responsible for the genesis of symptoms in functional dyspepsia (FD).
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Antonatos S, Galanopoulou P. Effects of mu-CPP and mesulergine on dietary choices in deprived rats: possible mechanisms of their action. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:112-9. [PMID: 16242827 DOI: 10.1016/j.pnpbp.2005.08.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2005] [Indexed: 10/25/2022]
Abstract
Although it has been well established that compounds that stimulate 5-HT(2C) and/or 5-HT(1B) receptors induce hypophagia by promoting satiety process, the relative role of these receptor subtypes in dietary choices remains to be fully determined. m-CPP is considered a useful probe of 5-HT(2C) receptor function in vivo and its administration reduces food intake and appetite in humans and rats. Conversely, the non-selective 5-HT(2C) receptor antagonist mesulergine elicits feeding in rats. Food intake and dietary choices were measured in a food-deprivation experimental protocol employing male Wistar rats. Animals were given access for a 4-h period to a pair of isocaloric diets. These two diets were enriched in protein or carbohydrate proportions, respectively, but fat content was held constant. The mixed 5-HT(2C/1B) receptor agonist, m-CPP, led to a dose-dependent hypophagia, due to substantial reduction in carbohydrate consumption while protein intake was spared (0.62, 1.25 and 2.50 mg/kg i.p., respectively). The non-selective 5-HT(2C) receptor antagonist and also D2 agonist, mesulergine, on its own produced a significant dose-dependent increase in both protein and carbohydrate diets (1.0 and 3.0 mg/kg i.p., respectively). Combined treatment with m-CPP, at its maximum effective dose, and mesulergine dose-dependently reversed m-CPP-induced hypophagia, during the 4-h test period. In order to clarify the effects of mesulergine on dietary choices since it is simultaneously a dopamine agonist besides its antiserotonergic properties, the D2 agonist apomorphine was also used. Apomorphine caused a dose-dependent increase in protein intake while carbohydrate and total food intake remained nearly unchanged (0.5 and 1.0 mg/kg i.p., respectively). It is concluded that the mesulergine-induced hyperphagic response on both diets is the expression of a dual mode of action, due to its 5-HT(2C) antagonist activity together with D2 agonist properties. The results further indicate that the activation of hypothalamic 5-HT(2C) receptors may be involved in both protein sparing and carbohydrate suppressing effects of 5-HT (m-CPP-like effect), whereas an important role in increase of protein consumption seems to have the dopaminergic system probably through D2 receptors (apomorphine-like and mesulergine-like effects, respectively).
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Affiliation(s)
- Spyridon Antonatos
- Department of Experimental Pharmacology, Medical School, University of Athens, 75, M. Asias, str, Athens 11527, Goudi, Greece.
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Lin L, York DA. 5-HT1B receptors modulate the feeding inhibitory effects of enterostatin. Brain Res 2005; 1062:26-31. [PMID: 16256085 PMCID: PMC2526559 DOI: 10.1016/j.brainres.2005.09.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2005] [Revised: 09/05/2005] [Accepted: 09/24/2005] [Indexed: 11/23/2022]
Abstract
Serotonin (5-HT) is considered to play an important role in control of appetite. Enterostatin has been shown to alter 5-HT release in the brain, and non-specific 5-HT antagonists blocked the anorectic response to icv enterostatin. The aim of this study was to further identify which 5-HT receptor subtype mediates the enterostatin feeding behavior and whether this effect occurs due to action in the PVN. Wild-type and 5-HT2C receptor-/- (KO) mice and normal Sprague-Dawley rats were used in these experiments. All animals were fed a high fat diet. Enterostatin (120 nmol, i.p.) reduced the intake of high fat diet in 5-HT2C receptor mutant mice (saline 4.54 +/- 0.47 kcal vs. Ent 2.53 +/- 0.76 kcal) 1 h after injection. A selective 5-HT1B antagonist (GR55526, 40 mg/kg body weight, i.p.) blocked the enterostatin hypophagic effects in these KO mice. Rats were implanted with cannulas into the amygdala and the ipsilateral PVN. The 5-HT receptor antagonists metergoline (non-specific receptor subtypes 1 and 2), or ritanserin (selective 2C), or GR55562 (selective l B) was injected into the PVN prior to enterostatin (0.01 nmol) injection into the amygdala. Enterostatin reduced food intake (saline: 5.80 +/- 0.59 g vs. enterostatin 3.47 +/- 0.56 g, P < 0.05 at l h). Pretreatment with either metergoline (10 nmol) or GR55526 (10 nmol) but not ritanserin (10 nmol) into the PVN attenuated the anorectic response to amygdala enterostatin. The data imply that the enterostatin anorectic response may be modulated by 5-HT1B receptors and that a neuronal pathway from the amygdala to the PVN regulates the enterostatin response through activation of 5-HTlB receptors in PVN.
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Affiliation(s)
- Ling Lin
- Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA
| | - David A. York
- Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA
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24
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Hsieh YS, Yang SF, Kuo DY. Amphetamine, an appetite suppressant, decreases neuropeptide Y immunoreactivity in rat hypothalamic paraventriculum. ACTA ACUST UNITED AC 2005; 127:169-76. [PMID: 15680483 DOI: 10.1016/j.regpep.2004.11.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2004] [Revised: 11/10/2004] [Accepted: 11/18/2004] [Indexed: 11/17/2022]
Abstract
Amphetamine (AMPH) is a well-known anorectic agent. The mechanism underlying the anorectic response of AMPH has been attributed to its inhibitory effect on hypothalamic neuropeptide Y (NPY), an orexigenic peptide in the brain. However, there is still lack of genomic or in situ immunohistochemical evidence to prove it. The present study was aimed to assess the molecular mechanism of AMPH anorexia by immunostaining of hypothalamic NPY protein in the area of paraventricular nucleus (PVN) and by detecting the change of hypothalamic NPY mRNA level using RT-PCR. Results revealed that an AMPH treatment might reduce the expression of NPY at both transcriptional and posttranslational levels. Comparatively, a treatment of clomipramine, a serotonin transporter inhibitor, was unable to reduce NPY mRNA level, revealing the noninvolvement of hypothalamic NPY gene in serotonin anorexia. Our results provided genomic and in situ immunohistochemical evidence to confirm the mediation of hypothalamic NPY neurons in the anorectic action of AMPH.
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Affiliation(s)
- Yih-Shou Hsieh
- Institute of Biochemistry, Chung Shan Medical University, Taichung 40201, Taiwan
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25
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Leonhardt M, Langhans W. Fatty acid oxidation and control of food intake. Physiol Behav 2005; 83:645-51. [PMID: 15621070 DOI: 10.1016/j.physbeh.2004.07.033] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2004] [Accepted: 07/28/2004] [Indexed: 10/26/2022]
Abstract
Fatty acid oxidation is thought to play a role in the control of food intake, and a low postprandial oxidation of ingested fat may contribute to the overeating on a high-fat diet. Evidence for a role of fatty acid oxidation in control of food intake is mainly derived from the stimulation of feeding in response to administration of the acyl-CoA-dehydrogenase inhibitor mercaptoacetate (MA) and other inhibitors of fatty acid oxidation in different species (rat, mouse, man). Denervation studies suggest that this "lipoprivic feeding" is related to changes in hepatic fatty acid oxidation. In contrast to the strong case for a feeding stimulatory effect of an inhibition of fatty acid oxidation, the evidence for a feeding suppressive effect of a stimulation of fatty acid oxidation is inconsistent and comparatively weak. Ingestion of medium-chain fatty acids (MCFA) and peripheral administration of substances known to increase fatty acid oxidation, such as the fatty acid synthase inhibitor C75 and beta3-adrenergic agonists, decrease feeding. Yet, these substances also reduce the rats' usual preference for saccharin solution, indicating that the feeding suppressive effect is not only due to a stimulation of fatty acid oxidation. A possible approach to answer the question of whether a stimulation of hepatic fatty acid oxidation enhances satiety is to selectively increase expression and activity of the enzyme CPT 1alpha in the liver. CPT 1alpha transfers long-chain fatty acids in the cytosol from CoA to carnitine, which is the precondition for the entry of long-chain fatty acids into mitochondria and the rate-controlling step in mitochondrial fatty acid oxidation. The generation of rats with inducible, liver-specific overexpression of CPT 1alpha should permit to critically examine the putative contribution of hepatic fatty acid oxidation to the control of food intake.
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Affiliation(s)
- Monika Leonhardt
- Institute of Animal Sciences, Swiss Federal Institute of Technology, Schorenstr. 16, CH-8603 Schwerzenbach, Switzerland.
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Shimbara T, Mondal MS, Kawagoe T, Toshinai K, Koda S, Yamaguchi H, Date Y, Nakazato M. Central administration of ghrelin preferentially enhances fat ingestion. Neurosci Lett 2004; 369:75-9. [PMID: 15380311 DOI: 10.1016/j.neulet.2004.07.060] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2004] [Revised: 07/15/2004] [Accepted: 07/28/2004] [Indexed: 11/18/2022]
Abstract
Ghrelin, a brain-gut peptide discovered from the stomach, stimulates growth hormone release, food intake, adiposity, and weight gain. Circulating ghrelin levels are modulated under conditions of positive and negative energy balance, however its effect on macronutrient selection is not known. The present experiment investigates the effect of ghrelin on single and two-diet feeding paradigms in high-carbohydrate (HC) and high-fat (HF) preferring rats. In the macronutrient selection test in which rats were given free access to either high-carbohydrate or high-fat diet, an intracerebroventricular (i.c.v.) administration of ghrelin potently enhanced fat intake over carbohydrate intake in both HC- and HF-preferring rats. In the diet preference test in which rats were given free access to both high-carbohydrate and high-fat diets simultaneously, an i.c.v. administration of ghrelin also preferentially enhanced fat consumption over carbohydrate in both HF- and HC-preferring rats. Intracerebroventricular administrations of galanin and neuropeptide Y enhanced fat and carbohydrate ingestion, respectively. Centrally administered ghrelin enhanced fat ingestion. These results provide further insights for the role of ghrelin in feeding behavior and the development of obesity.
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Affiliation(s)
- Takuya Shimbara
- Third Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan
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27
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Hsieh YS, Hsu JD, Yang SF, Kuo DY. Immunohistochemical and genomic evidence for the involvement of hypothalamic neuropeptide Y (NPY) in phenylpropranolamine-mediated appetite suppression. Peptides 2004; 25:2155-61. [PMID: 15572205 DOI: 10.1016/j.peptides.2004.08.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2004] [Revised: 08/14/2004] [Accepted: 08/20/2004] [Indexed: 11/29/2022]
Abstract
Phenylpropanolamine (PPA) is an appetite suppressant. The mechanism for the anorectic effect of PPA has been attributed to its action on the site of hypothalamic paraventriculum. Neuropeptide Y (NPY) is an appetite stimulant that is widely distributed in the site of hypothalamus. It is not clear whether hypothalamic NPY is involved in the anorectic action of PPA. This study was aimed to investigate the mechanism underlying the involvement of NPY gene in the anorectic action of PPA. Results revealed that PPA treatment in rats could decrease both NPY content and mRNA level in the hypothalamus. In addition, the expression of NPY immunoreactivity following PPA treatment was decreased in areas of hypothalamic arcuate nucleus, paraventricular nucleus and periventricular area using immunohistochemical staining, suggesting an involvement of NPYergic pathway in the action of PPA anorexia. Our results provided immunohistochemical and genomic evidence to suggest that PPA might reduce feeding by altering NPY gene expression.
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Affiliation(s)
- Yih-Shou Hsieh
- Institute of Biochemistry, Chung Shan Medical University, Taichung City 402, Taiwan, ROC
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28
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Abstract
Esta revisão aborda alguns aspectos psicobiológicos ligados à manifestação do comportamento alimentar, e tem como objetivo evidenciar a relação entre os principais processos neuropsicológicos e a neurociência nutricional. Algumas estruturas neurais estão associadas ao controle alimentar por mecanismos distintos e correlatos que ocorrem no hipotálamo, hipocampo e em outras áreas como no cerebelo, bulbo olfatório, glândulas pituitária e pineal que exercem funções distintas, porém influênciam o comportamento alimentar, intermediadas geralmente por neurotransmissores comuns. Os precursores dos neuroquímicos apresentam funções específicas, sendo a influência na alimentação relevante no contexto comportamental da escolha de alimentos. Os processos sensoriais na alimentação como paladar, olfato, visão e audição interagem entre si e com outras estruturas e vias neurais, participando também do controle do apetite e da saciedade, que culminam na iniciação e no término da alimentação. A interação entre aspectos neurais no processo de consumo de alimento promove a manifestação do comportamento alimentar específico para cada espécie em seu ambiente.
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29
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Eikelis N, Lambert G, Wiesner G, Kaye D, Schlaich M, Morris M, Hastings J, Socratous F, Esler M. Extra-adipocyte leptin release in human obesity and its relation to sympathoadrenal function. Am J Physiol Endocrinol Metab 2004; 286:E744-52. [PMID: 14722031 DOI: 10.1152/ajpendo.00489.2003] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The link between the human sympathoadrenalmedullary system and the adipocyte hormone leptin is controversial. We measured total and regional norepinephrine spillover, epinephrine secretion rate, and extra-adipocyte leptin release in 22 lean [body mass index (BMI) < 26] and 20 obese (BMI > 28) normotensive men who underwent arterial and central venous catheterization. Because plasma clearance of leptin is primarily by renal removal, for men at steady state we could estimate whole body leptin release to plasma from renal plasma leptin extraction. Whole body leptin release was 1,950 +/- 643 (means +/- SE) ng/min in obese men and 382 +/- 124 ng/min in lean men (P < 0.05). Total and renal norepinephrine spillover rates correlated directly with whole body leptin secretion rate. Leptin is released from multiple nonadipocyte sites, which we tested by use of simultaneous arteriovenous blood sampling. We found a surprisingly large contribution of brain leptin release to the plasma leptin pool, 529 +/- 175 ng/min (> 40% whole body leptin release), with greater leptin release in obese than in lean men, 935 +/- 321 vs. 160 +/- 59 ng/min (P = 0.045). In parallel with leptin measurements, we also quantified brain serotonin turnover and jugular overflow of neuropeptide Y (NPY). Brain serotonin turnover was higher in obese than in lean men, 227 +/- 112 vs. 21 +/- 14 ng/min (P = 0.019), as was overflow of NPY from the brain, 12.9 +/- 1.4 vs. 5.3 +/- 2.2 ng/min (P = 0.042). These results suggest that leptin is released within the brain and at an increased rate in obese humans, in whom activation of brain serotonergic and NPY mechanisms also exists.
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Affiliation(s)
- Nina Eikelis
- Baker Heart Research Institute, Melbourne University, Melbourne, Victoria 8008, Australia
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Abstract
In most individuals, food intake occurs as discrete bouts or meals, and little attention has been paid to the factors that normally determine when meals will occur when food is freely available. On the basis of experiments using rats, the authors suggest that when there are no constraints on obtaining food and few competing activities, 3 levels of interacting controls normally dictate when meals will start. The first is the genetically determined circadian activity pattern on which nocturnal animals tend to initiate most meals in the dark. The second is the regularly occurring changing of the light cycle: These changes provide temporal anchors. The third relates to the size of the preceding meal, such that larger meals cause a longer delay until the onset of the next meal. Superimposed on these 3 are factors related to learning, convenience, and opportunity.
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Affiliation(s)
- Jan H Strubbe
- Department of Neuroendocrinology, University of Groningen, Haren, The Netherlands.
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31
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Abstract
A few examples of hypothalamic, peptidergic disorders leading to clinical signs and symptoms are presented in this review. Increased activity of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) and decreased activity of the vasopressin neurons in the biological clock and of the thyroxine-releasing hormone (TRH) neurons in the PVN contribute to the signs and symptoms of depression. In men, the central nucleus of the bed nucleus of the stria terminalis (BSTc) is about twice as large and contains twice as many somatostatin neurons as in women. In transsexuals this sex difference is reversed, pointing to a role of this structure in gender. Luteinizing hormone-releasing hormone (LHRH) neurons are formed in the fetal olfactory placade and migrate along the terminal nerve fibers into the hypothalamus. In Kallmann's syndrome the migration process of the LHRH (gonadotropin-releasing hormone) neurons is aborted, which explains the joint occurrence of hypogonadotropic hypogonadism and anosmia in this syndrome. In postmenopausal women, the neurons of the infundibular nucleus hypertrophy and become hyperactive because of the disappearance of the estrogen feedback and contain hyperactive peptidergic neurons. Climacteric flushes may be caused by hyperactivity of the neurokinin-B or LHRH neurons in this nucleus. The hypocretin (orexin) neurons in the perifornical area are involved in sleep. In narcolepsy with cataplexy, a loss of these neurons, probably due to an autoimmune process, is found. Obese subjects with a mutation in the gene that encodes for leptin, the preproghrelin gene, or the alpha-melanocyte-stimulating hormone (alpha-MSH) gene have been described. Decreased numbers and activity of the oxytocin neurons in the PVN may be responsible for the absence of satiety in Prader-Willi syndrome. Moreover, a glucocorticoid receptor polymorphism is associated with obesitas and dysregulation of the hypothalamus-pituitary-adrenal axis. In contrast, two single nucleotide polymorphisms (SNPs) of the AGRP gene have been associated with anorexia nervosa.
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Affiliation(s)
- Dick F Swaab
- Netherlands Institute for Brain Research, 1105 AZ, Amsterdam, The Netherlands
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32
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Abstract
Anorexia nervosa (AN) is commonly attributed to psychological conflicts, attempts to be fashionably slender, neuroendocrine dysfunction, or some combination of these factors. Considerable research reveals these theories to be incomplete. Psychological and societal factors account for the decision to diet but not for the phenomenology of the disorder; theories of biological defects fail to explain neuroendocrine findings that suggest coordinated physiological mechanisms. This article presents evidence that AN's distinctive symptoms of restricting food, denial of starvation, and hyperactivity are likely to be evolved adaptive mechanisms that facilitated ancestral nomadic foragers leaving depleted environments; genetically susceptible individuals who lose too much weight may trigger these archaic adaptations. This hypothesis accounts for the occurrence of AN-like syndromes in both humans and animals and is consistent with changes observed in the physiology, cognitions, and behavior of patients with AN.
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Abstract
The potential of specific antiepileptic drugs (AEDs) to cause clinically significant changes in bodyweight is a key consideration in the management of epilepsy; changes in weight can pose health hazards, impair body image and self-esteem, and lead to noncompliance with therapy. This article reviews the data regarding the effects of conventional and newer AEDs on weight and discusses the clinical implications of these effects for the management of patients with epilepsy. The data demonstrate that AEDs can differ substantially in their effects on weight. Some, such as valproate and carbamazepine, increase weight; others, such as topiramate and felbamate, decrease it. Still others, such as lamotrigine, levetiracetam and phenytoin, are weight neutral. Because most data regarding the effects of AEDs on weight are circumstantial, the incidence, magnitude and determinants of weight changes with AEDs remain poorly elucidated. Furthermore, little is known about the mechanisms of AED-induced changes in weight. The importance of effects on weight in selecting an AED depends largely upon the individual patient's needs and the risks and benefits of therapy for that patient. The most appropriate therapeutic choice is a weight-neutral medication unless circumstances dictate otherwise.
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Affiliation(s)
- Victor Biton
- Arkansas Epilepsy Program, 2 Lile Court, Suite 100, Little Rock, AR 72205, USA.
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Laugero KD, Gomez F, Manalo S, Dallman MF. Corticosterone infused intracerebroventricularly inhibits energy storage and stimulates the hypothalamo-pituitary axis in adrenalectomized rats drinking sucrose. Endocrinology 2002; 143:4552-62. [PMID: 12446582 DOI: 10.1210/en.2002-220613] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
When allowed to drink sucrose, bilaterally adrenalectomized (ADX) rats exhibit normal weight gain, food intake, sympathetic neural activity, and ACTH compared with sham-ADX rats. Furthermore, ADX rats drinking sucrose have normal corticotropin-releasing factor (CRF) mRNA throughout brain. In ADX rats without sucrose, all of these variables are abnormal. Systemic corticosterone (B) replacement also restores these variables in ADX rats to normal. To test whether B acts centrally, we infused B or saline intracerebroventricularly into ADX rats under basal conditions and after repeated restraint. Rats were exposed to no stress or 3 h/d restraint for 3 d. Body weights and food and fluid intakes were measured. Brains were analyzed using immunocytochemistry against glucocorticoid receptors (GR) and CRF. Intracerebroventricular B blocked the positive effects of sucrose on metabolism, increased basal ACTH concentrations, and augmented ACTH responses to restraint on d 3. B-infused rats exhibited nuclear GR staining in perirhinal cortex, hippocampus, and hypothalamic paraventricular nuclei, showing that infused B spreads effectively. CRF staining in the paraventricular nucleus of the hypothalamus was higher in B- than in saline-infused rats. We conclude that under basal conditions B acts systemically, but not in the brain, to restore metabolism and neuropeptides after adrenalectomy. By contrast, tonic GR occupancy in brain initiates metabolic and ACTH responses characteristic of stress.
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Affiliation(s)
- Kevin D Laugero
- Department of Physiology and Program in Neuroscience, University of California, San Francisco, California 94143-0444, USA
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35
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Nandi J, Meguid MM, Inui A, Xu Y, Makarenko IG, Tada T, Chen C. Central mechanisms involved with catabolism. Curr Opin Clin Nutr Metab Care 2002; 5:407-18. [PMID: 12107377 DOI: 10.1097/00075197-200207000-00010] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Catabolism conjures up an end-metabolic process in which muscle and fat tissue are broken down into their constituent parts to provide nutrients for the body, secondary to a noxious stimulus that prevents the organism from adequately nourishing itself. However, catabolism is a primary event, initiated in the brain in response to perceived or real stresses or noxious stimuli, which has a secondary effect of inhibiting food intake and consequently the break down of skeletal muscle and adipose tissues to provide nutrients for the body to survive. RECENT FINDINGS This is achieved via a cascade of neurohormonal monoaminergic and peptidergic mediators in the central nervous system, invoking the cortex, the limbic system and the hypothalamus. Among the most detailed mediators studied are corticotropin-releasing factor and serotonin which, via the hypothalamic-pituitary-adrenal axis and the sympathetic and parasympathetic nervous system, stimulate catecholamines and cortisol and inhibit anabolic hormones, insulin, leptin, ghrelin, including neuropeptide Y and other neuropeptides, among them the paracrine-acting cytokines. Simultaneously, there occurs stimulation of the counter-regulatory hormones cortisol, glucagon and the melanocortin family of neuropeptides. SUMMARY The net effect is anorexia, with the inhibition of food intake, body weight loss, delayed gastric emptying and functions, the stimulation of gluconeogenesis, glycogenolysis and ketogenesis as sources of metabolic fuel, which if unabated leads ultimately to cachexia. The use of antagonists and the removal of stress or noxious stimuli experimentally test different pathways of this dynamic metabolic picture. Several studies have demonstrated important progress towards our understanding of the central mechanisms involved in anorexia and weight loss, which we summarize in this review.
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Affiliation(s)
- Jyotirmoy Nandi
- Department of Medicine, Gastroenterology Division, University Hospital, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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Shi Y, Schlenker EH. Neonatal sex steroids affect ventilatory responses to aspartic acid and NMDA receptor subunit 1 in rats. J Appl Physiol (1985) 2002; 92:2457-66. [PMID: 12015360 DOI: 10.1152/japplphysiol.01236.2001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We hypothesized that administration of estradiol benzoate to males and testosterone propionate to female neonatal rat pups alters sex-specific ventilatory responses to aspartic acid with correspondent changes in N-methyl-D-aspartate receptor subunit 1 (NR1) expression determined by Western blot in specific brain regions. One-day-old rat pups received estradiol benzoate, testosterone propionate, or vehicle and were studied at weanling and adulthood. Different groups had distinct patterns of changes in tidal volume and frequency of breathing after aspartic acid administration. NR1 expression in hypothalamus was altered by age, sex, and treatment. Medullary and pontine NR1 expression correlated with baseline ventilation and magnitude of the ventilatory response to aspartic acid in some groups. Thus 1) tidal volume and breathing frequency patterns in response to aspartic acid are gender, age, and treatment dependent; 2) sex, age, and exogenous steroid hormones affect NR1 expression primarily in the hypothalamus; and 3) there is correlation between NR1 expression in pons and medulla with ventilatory parameters.
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Affiliation(s)
- Yijiang Shi
- Division of Basic Biomedical Sciences, School of Medicine, University of South Dakota, Vermillion, South Dakota 57069, USA
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37
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Baillie-Hamilton PF. Chemical toxins: a hypothesis to explain the global obesity epidemic. J Altern Complement Med 2002; 8:185-92. [PMID: 12006126 DOI: 10.1089/107555302317371479] [Citation(s) in RCA: 364] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The number of obese people worldwide has escalated recently, revealing a complex picture of significant variations among nations and different profiles among adults and children, regions, and occupations. The commonly held causes of obesity-overeating and inactivity-do not explain the current obesity epidemic. There is evidence of a general decrease in food consumption by humans and a significant decline in their overall levels of physical activity. There is also more evidence to indicate that the body's natural weight-control mechanisms are not functioning properly in obesity. Because the obesity epidemic occurred relatively quickly, it has been suggested that environmental causes instead of genetic factors maybe largely responsible. What has, up to now, been overlooked is that the earth's environment has changed significantly during the last few decades because of the exponential production and usage of synthetic organic and inorganic chemicals. Many of these chemicals are better known for causing weight loss at high levels of exposure but much lower concentrations of these same chemicals have powerful weight-promoting actions. This property has already been widely exploited commercially to produce growth hormones that fatten livestock and pharmaceuticals that induce weight gain in grossly underweight patients. This paper presents a hypothesis that the current level of human exposure to these chemicals may have damaged many of the body's natural weight-control mechanisms. Furthermore, it is posited here that these effects, together with a wide range of additional, possibly synergistic, factors may play a significant role in the worldwide obesity epidemic.
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Affiliation(s)
- Paula F Baillie-Hamilton
- Occupational and Environmental Health Research Group at Stirling, Stirling University, Scotland.
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38
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Abstract
Bodyweight gain is a common and frequent undesirable effect associated with the use of anticonvulsant drugs. This has been observed for many years with valproic acid (sodium valproate) and carbamazepine, and also, more recently, with some of the newer anticonvulsants such as vigabatrin and gabapentin. Very often bodyweight gain in children, adolescents and adults with epilepsy taking such anticonvulsants results in cosmetic adverse effects. On the other hand, bodyweight gain is disturbing to general health, with a possible increase in the risk of diabetes mellitus or heart disease. Other potential adverse effects, such as the association of obesity with polycystic ovaries, have been reported with the use of valproic acid. Potential mechanisms of anticonvulsant-associated bodyweight gain are not yet clear and differ between drugs used. The involvement of lowered blood glucose level, which may stimulate eating through an effect on the hypothalamus, constitutes one of the possible mechanisms. Lowered blood glucose levels may result from a competition between the binding of the drug and long chain fatty acids. An increased availability of the latter stimulates insulin production and lowers the serum glucose levels. Another possible explanation for lowered blood glucose may be a deficiency in carnitine directly caused by the drug, that would result in a reduction of fatty acid metabolism and an increase in glucose consumption. An enhancing effect of gamma-aminobutyric acid-mediated neurotransmission may increase appetite for carbohydrates and reduce energy expenditure. An antidiuretic hormone-like effect or effects on norepinephrine (noradrenaline) or serotonin-mediated neurotransmission are more rarely considered. Many studies on anticonvulsant-associated bodyweight gain illustrate how we could better define the risk factors for the development of anticonvulsant-induced bodyweight gain and uncover the mechanisms behind it.
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Affiliation(s)
- P Jallon
- Epilepsy Unit, Hôpital Cantonal, Geneva, Switzerland.
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Odorizzi M, Fernette B, Angel E, Burlet C, Tankosic P, Burlet A. Galanin receptor antagonists decrease fat preference in Brattleboro rat. Neuropharmacology 2002; 42:134-41. [PMID: 11750923 DOI: 10.1016/s0028-3908(01)00115-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The Brattleboro rat eats spontaneously 46% of its diet per day in fat when given a choice of carbohydrate, protein and fat. An overexpression of galanin (GAL) has been also observed in the hypothalamic paraventricular nuclei (PVN). This associative correlation has led to a hypothesis of a functional relation between central galanin expression and the preference for a lipid diet. In the present experiments, the effects of two GAL receptor antagonists, C7 and galantide, on fat consumption and central overexpression of GAL were investigated. Both antagonists were injected into either the cerebral ventricles or directly above the PVN, and the diet consumption followed for the subsequent 24h. C7 decreased significantly fat consumption when injected into the ventricles or directly above the PVN. In contrast, galantide must be injected above the PVN to show the same effect. However, the two antagonists did not modify GAL mRNA expression in the PVN when they were injected 2h before sacrifice. These experiments confirm a functional link between the preferential consumption of fat and hypothalamic Galanin; different subtypes of the GAL receptor are probably involved, since both Galanin antagonists were differently efficient in decreasing spontaneous fat selection of the Brattleboro rat.
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40
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Abstract
A plethora of data from experimental animals provide strong support for the concept that reduced dopaminergic neuronal activity and enhanced noradrenergic tone in specific hypothalamic nuclei are involved in the pathogenesis of the metabolic syndrome. The available information on these neurotransmitter systems in insulin-resistant humans with obesity is in keeping with the postulate that analogous mechanisms may underlie their adverse metabolic profile. Treatment with bromocriptine, which has dopaminergic (D2 receptor agonist) and sympatholytic (alpha2-adrenoceptor agonistic and an alpha1-adrenoceptor antagonistic) actions, can reverse the metabolic anomalies in a variety of obese mammalian species. Combined D1/D2 receptor activation appears to exert even more powerful effects on fuel metabolism in various animal models of the metabolic syndrome. The currently available data on the metabolic effects of bromocriptine in humans with obesity and type 2 diabetes mellitus point in the same direction. Bromocriptine favorably affects glucose metabolism and various other components of the metabolic syndrome simultaneously to ameliorate the risk of damage to eyes, neural tissue, kidneys and the cardiovascular system in patients with type 2 diabetes mellitus. Moreover, a substantial number of studies indicate that bromocriptine lowers blood pressure in animals and humans with hypertension via its sympatholytic capacities. However, the effects of bromocriptine alone are relatively modest, the metabolic mechanism of action in humans remains uncertain, and the long-term efficacy and safety profiles of this compound are unknown. It seems important to seek for ways to boost the action of bromocriptine, by combining dopaminergic D2 and D1 receptor activation, for example. Notably, there is no antidiabetic drug that acts through central (dopaminergic) mechanisms. This novel approach may, therefore, result in synergistic actions with other available agents to favorably impact the risk of tissue damage in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Hanno Pijl
- Leiden University Medical Center, Department of Internal Medicine, Leiden, The Netherlands.
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41
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Hellström PM, Näslund E. Interactions between gastric emptying and satiety, with special reference to glucagon-like peptide-1. Physiol Behav 2001; 74:735-41. [PMID: 11790437 DOI: 10.1016/s0031-9384(01)00618-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The slowing of gastric emptying is an important mechanism for the satiating effect of gut peptide signaling. After food intake, cholecystokinin (CCK), as well as glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2), are released from the gastrointestinal tract to mediate satiety. In humans, CCK and the GLP-1 have been found to cause satiety in both normal and obese subjects. This satiating effect may be caused by the peptides circulating as hormones with direct effects in the central nervous system, or indirect effects through signals mediated either via the vagus nerve or by activation of vagal afferent fibers due to slow gastric emptying. These peptides also cause gastric relaxation, considered an additional component in the satiating effect of the peptides. To conclude, after food intake, gut peptides may act in concert as neurohormonal satiety signals acting directly in the brain or indirectly via the vagus nerve, as well as through gastric sensory mechanisms to limit food intake.
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Affiliation(s)
- P M Hellström
- Department of Internal Medicine, Unit of Gastroenterology Karolinska Hospital, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
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42
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Abstract
Catecholamine, dopamine, serotonine (5HT) and neuronal histamine are anorectic monoamines and act as anorectic neurotransmitters. The anorectic agents as modulators of these monoamines inhibit appetite by activating release together with suppressing reuptake of those monoamines. The anorectic agents were classified in clinical use into either alpha 1, beta-adrenergic receptor agonists or 5HT-receptor agonist. Dexfenfluramine, a 5HT-receptor agonist, was inhibited in clinical use because of its cardiac complications including pulmonary hypertension and valvelar disease. Mazindol is an adrenergic agonist and the solitary anti-obesity drug used clinically in Japan. Sibutramine shows the effects of both beta-adrenergic and serotonergic receptor agonists. Sibutramine induces not only appetite suppression but also acceleration of peripheral energy expenditure. No histaminergic anorectics have been employed in the clinical situation to date. L-Histizine, precursor amino acid of endogenous neuronal histamine, is useful for suppression of food intake, lipolytic acceleration of peripheral adipose tissues and enhanced energy expenditure in both animals and humans. L-Histizine thus inspires development of more effective and safer anorectics that can be used without suffering from the rebound phenomenon of body weight.
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Affiliation(s)
- K Fukagawa
- 1st Department of Internal Medicine, Oita Medical University, Idaiga-oka, Hazama-cho, Hazama-gun, Oita 879-5593, Japan.
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43
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Abstract
Food intake is the simplest and most obvious measure of gastrointestinal function, yet it rarely receives more than cursory attention from surgeons. In this review we cover recent findings on relationships between gut function and appetite regulation mediated via neuropeptides influenced by afferent and efferent vagal activity. Evidence from the new discipline known as neurogastroenterology elucidates gastric and intestinal signals involved in the elicitation of hunger, satiety, and aversion. Discovery of the adipose-tissue-derived hormone, leptin, has energized the field of metabolism spawning increasing numbers of publications related to interactions between leptin and insulin release and glucose disposal, as well as appetitive behavior. Peptides such as cholecystokinin (CCK), the proglucagon-derived peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), and the recently identified powerful intake-stimulating molecule, orexin, are examples of potential targets for drug development and studies of surgical pathophysiology. A major conclusion of this work is that the considerable redundancy and overlap between mediators of caloric intake subserving survival of the species, while beneficial after foregut surgery, contribute to the complexity of treating the global epidemic of obesity. Possibly knowledge derived from basic research in neurogastroenterology can translate into advances in surgical treatment of obesity.
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Affiliation(s)
- E Näslund
- Division of Surgery, Karolinska Institutet Danderyd Hospital, SE-182 88 Danderyd, Sweden.
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44
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Cambraia RP, Vannucchi H, Almeida SS, De-Oliveira LM. Effects of malnutrition during early lactation on development and feeding behavior under the self-selection paradigm. Nutrition 2001; 17:455-61. [PMID: 11399403 DOI: 10.1016/s0899-9007(01)00515-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Selection of food can be affected by several factors, and with the method of self-selection, qualitative changes in nutritional balance may be detected. The goal of the present study was to evaluate feeding preferences in weaning rats using three macronutrients (protein, carbohydrate, and fat), through a free-choice method, evaluating the alteration in their feeding patterns as compared with the previous nutritional status during the early lactation period. We analyzed the effects of protein restriction during lactation over the nitrogen balance after the weaning. The dams were assigned to one of two diet conditions (nourished or malnourished). At weaning, two pups from each litter were housed individually in metabolic cages, and they were maintained on self-selection under a free-choice paradigm and were provided with separate sources of macronutrients. The parameter for evaluating the nutritional effectiveness of the diets was nitrogen balance. We observed that protein intake tended to increase and consumption of carbohydrate and fat tended to decrease progressively during the 3 wk of experiment. In selecting their own food, growing rats and malnourished rats consumed a larger amount of protein than the other rats. Nourished rats selecting their diet had a larger nitrogen balance than nourished rats receiving a composed diet; no nitrogen balance difference was found between the self-selecting groups. Rats can choose an adaptive form when recovering from protein malnutrition.
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Affiliation(s)
- R P Cambraia
- Departamento de Psicologia e Educação, Faculdade de Filosofia Ciências e Letras, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
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45
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Siega-Riz AM, Herrmann TS, Savitz DA, Thorp JM. Frequency of eating during pregnancy and its effect on preterm delivery. Am J Epidemiol 2001; 153:647-52. [PMID: 11282791 DOI: 10.1093/aje/153.7.647] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Frequency of eating or meal patterns during pregnancy may be a component of maternal nutrition relevant to pregnancy outcome. To identify meal patterns of pregnant women and investigate the relation between these meal patterns and preterm delivery, the authors performed an analysis using data from the Pregnancy, Infection, and Nutrition Study (n = 2,065). Women recruited from August 1995 to December 1998 were categorized by meal patterns on the basis of their reported number of meals (breakfast, lunch, and dinner) and snacks consumed per day during the second trimester. An optimal pattern was defined according to the Institute of Medicine recommendation of three meals and two or more snacks per day. In this population, 72 percent of the women met this recommendation, and 235 delivered preterm. Women who consumed meals/snacks less frequently were slightly heavier prior to pregnancy, were older, and had a lower total energy intake. In addition, these women had a higher risk of delivering preterm (adjusted odds ratio = 1.30, 95 percent confidence interval: 0.96, 1.76). There was no meaningful difference in the risk by early versus late preterm delivery, but those who delivered after premature rupture of the membranes (adjusted odds ratio = 1.87, 95 percent confidence interval: 1.02, 3.43) had a higher risk than those who delivered after preterm labor (adjusted odds ratio = 1.11, 95 percent confidence interval: 0.64, 1.89). This study supports previous animal model work of an association between decreased frequency of eating and preterm delivery.
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Affiliation(s)
- A M Siega-Riz
- Department of Nutrition, University of North Carolina, Carolina Population Center, Schools of Public Health and Medicine, Chapel Hill, NC 27516-3997, USA.
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46
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Choi YH, Fletcher PJ, Anderson GH. Extracellular amino acid profiles in the paraventricular nucleus of the rat hypothalamus are influenced by diet composition. Brain Res 2001; 892:320-8. [PMID: 11172779 DOI: 10.1016/s0006-8993(00)03267-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
One possible mechanism by which food consumption signals feeding centers is through the resulting changes in amino acid profiles in the brain. In this study we examined the effect of voluntary consumption of a 50% protein diet or a 0% protein (carbohydrate) diet on extracellular amino acid profiles in the hypothalamic paraventricular nucleus (PVN) of freely moving rats from 1800 to 2100 h. Dialysates were continuously collected via microdialysis probes inserted in the PVN at 1500 h. Extracellular concentrations of isoleucine, leucine, methionine, tyrosine and valine were elevated within the first or second 20 min following the start of the 50% protein diet (P<0.05). The ratio of tryptophan to the total branched-chain amino acids (BCAA) in extracellular fluid increased following consumption of the carbohydrate diet (P<0.05), but decreased after the protein diet. An elevated ratio of tyrosine to BCAA was observed at the end of the measurement following the protein-free meal. It is concluded that amino acid concentrations in extracellular fluid of the PVN change rapidly after food consumption and that the changes are influenced by dietary composition.
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Affiliation(s)
- Y H Choi
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 3E2, Canada
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47
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Yeh SS, Wu SY, Levine DM, Parker TS, Olson JS, Stevens MR, Schuster MW. The correlation of cytokine levels with body weight after megestrol acetate treatment in geriatric patients. J Gerontol A Biol Sci Med Sci 2001; 56:M48-54. [PMID: 11193233 DOI: 10.1093/gerona/56.1.m48] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Cachexia is associated with elevated levels of cytokines in cancer and human immunodeficiency virus patients. Studies in cancer and acquired immunodeficiency syndrome patients showed that treatment with megestrol acetate (MA) is associated with improvement in appetite and weight gain. Reduction in the levels of cytokines is associated with weight gain in laboratory animals with cancer. This study evaluates the correlation between changes in cytokine (or their receptor) levels and weight following MA treatment in geriatric weight-loss patients. METHODS Veterans Administration Medical Center nursing home patients (N = 69) with a weight loss of > or =5% of usual body weight over the past 3 months or body weight 20% below their ideal body weight participated in a 12-week, randomized, double-blind, placebo-controlled trial, with an additional 13-week follow-up period. Patients were randomly assigned to receive a placebo or MA oral suspension of 800 mg/d for 12 weeks. Levels of the following cytokines (or their receptors) were measured at baseline and after 12 weeks of treatment: tumor necrosis factor soluble receptor (TNFR) subunits. TNFR-p55 and TNFR-p75: interleukin 6 (IL-6); and the soluble interleukin-2 receptor (sIL-2R). The subjects' weight and body composition were measured at the start of the study. Weight and mortality were followed up for another 13 weeks after discontinuing the MA study drug. RESULTS Elevated levels of IL-6 in almost all geriatric cachexic patients, compared with normal volunteers (mean, <4.6 pg/ml). were noted at baseline. At 12 weeks after the study drug treatment, there was a decrease in cytokine levels (or their receptors) in the MA group (mean change in IL-6, 3.63+/-6.62 pg/ml; TNFR-p55, -0.06+/-0.11 ng/ml; TNFR-p75. -0.01+/-0.29 ng/ml; and sIL-2R, 0.08+/-0.07 ng/ml) and the placebo group (mean change in IL-6, -2.08+/-3.92 pg/ml; TNFR-p55, -0.02+/-0.08 ng/ml; TNFR-p75, -0.20+/-0.18 ng/ml; and sIL-2R, 0.02+/-0.03 ng/ml). Although the change in cytokine levels was not statistically significant between the two groups, significant negative correlation (p < .05) was found. For example, increased weight correlated with decreased sIL-2R levels (r = .36) and TNFR-p75 (r = -.31; fat-free mass (FFM) gain and reduction of sIL-2R (r = -.39), TNFR-p75 (r = -.30). There was a significant correlation between weight gain and reduction of TNFR-p75 (r = .54), TNFR-p55 (r- = .47), and sIL-2R (r = -.53); FFM gain and reduction of sIL-2R (r = -.59), TNFR-p75 (r = -.41), TNFR-p55 (r = -.42); and fat gain and reduction of TNFR-p75 (r = -.41) in the MA group (p < .05), but not in the placebo group. CONCLUSIONS Although there was no significant change in cytokine levels between the two groups, the reduction in cytokine levels after MA treatment correlated with improvement in weight, fat mass, and FFM at 12 weeks.
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Affiliation(s)
- S S Yeh
- Department of Medicine, VA Medical Center at Northport, New York 11768, USA.
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48
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Abstract
The goals of this article are to suggest a basic wiring diagram for the motor neural network that controls motivated behavior, and to provide a model for the organization of cerebral hemisphere inputs to this network. Cerebral projections mediate voluntary regulation of a behavior control column in the ventromedial upper brainstem that includes (from rostral to caudal) the medial preoptic, anterior hypothalamic, descending paraventricular, ventromedial, and premammillary nuclei, the mammillary body, and finally the substantia nigra and ventral tegmental area. The rostral segment of this column is involved in controlling ingestive (eating and drinking) and social (defensive and reproductive) behaviors, whereas the caudal segment is involved in controlling general exploratory or foraging behaviors (with locomotor and orienting components) that are required for obtaining any particular goal object. Virtually all parts of the cerebral hemispheres contribute to a triple descending projection - with cortical excitatory, striatal inhibitory, and pallidal disinhibitory components - to specific parts of the behavior control column. The functional dynamics of this circuitry remain to be established.
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Affiliation(s)
- L W Swanson
- The Neuroscience Program, Hedco Neuroscience Building, Rm. 428, University of Southern California, 3614 Watt Way, 90089-2520, Los Angeles, CA, USA.
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49
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Jang M, Mistry A, Swick AG, Romsos DR. Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice. J Nutr 2000; 130:2813-20. [PMID: 11053526 DOI: 10.1093/jn/130.11.2813] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Leptin may rapidly inhibit food intake by altering the secretion of hypothalamic neuropeptides such as neuropeptide Y (NPY), a stimulator of food intake, and/or corticotropin-releasing hormone (CRH), an inhibitor of food intake. We measured concentrations of NPY and CRH in specific hypothalamic regions [i.e., arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial nucleus and dorsomedial nucleus] of 7- to 8-wk-old lean and ob/ob mice at 1 or 3 h after intracerebroventricular leptin administration. No rapid-onset effects of leptin on hypothalamic NPY or CRH concentrations were observed in intact mice. The addition of leptin to hypothalamic preparations from intact mice also did not alter NPY or CRH secretion. Glucocorticoids may oppose leptin actions. Consistent with this, leptin administration to adrenalectomized mice markedly reduced CRH concentrations in the ARC within 3 h after injection. This rapid reduction in CRH concentration in the ARC after leptin administration is more likely due to stimulated CRH release from this region than to decreased synthesis/transport from the PVN because leptin stimulates CRH synthesis in the PVN. Within 20 min after exposure to leptin, NPY secretion from hypothalamic preparations obtained from adrenalectomized mice was lowered by 27% and CRH secretion was elevated by 51%. The current study demonstrates that leptin rapidly influences the secretion of hypothalamic NPY and CRH and that these actions of leptin within the hypothalamus are restrained by the presence of endogenous corticosterone.
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Affiliation(s)
- M Jang
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824-1224 and. Pfizer Central Research, Groton, CT 06340, USA
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50
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Abstract
Recently novel molecular mediators and regulatory pathways for feeding and body weight regulation have been identified in the brain and the periphery. Mice lacking or overexpressing these mediators or receptors have been produced by molecular genetic techniques, and observations on mutant mice have shed new light on the role of each element in the homeostatic loop of body weight regulation. However, the interpretation of the phenotype is under the potential influence of developmental compensation and other genetic and environmental confounds. Specific alterations of the mediators and the consequences of the altered expression patterns are reviewed here and discussed in the context of their functions as suggested from conventional pharmacological studies. Advanced gene targeting strategies in which genes can be turned on or off at desired tissues and times would undoubtedly lead to a better understanding of the highly integrated and redundant systems for energy homeostasis equation.
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Affiliation(s)
- A Inui
- Second Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.
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