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Article ; Online: Central leptin receptor action and resistance in obesity.

Bjørbaek, Christian

Journal of investigative medicine : the official publication of the American Federation for Clinical Research

2009 Volume 57, Issue 7, Page(s) 789–794

Abstract: The discovery of leptin in 1994 has led to remarkable advances in obesity research. We now know that leptin is a cytokinelike hormone that is produced in adipose tissue and plays a pivotal role in regulation of energy balance and in a variety of ... ...

Abstract	The discovery of leptin in 1994 has led to remarkable advances in obesity research. We now know that leptin is a cytokinelike hormone that is produced in adipose tissue and plays a pivotal role in regulation of energy balance and in a variety of additional processes via actions in the central nervous system. This symposium review covers current understandings of neuronal leptin receptor signaling and mechanisms of obesity-related leptin resistance in the central nervous system and provides recent insights into the regulation of peripheral glucose balance by central leptin action in rodents.
MeSH term(s)	Animals ; Brain/physiology ; Drug Resistance/genetics ; Leptin/physiology ; Obesity/genetics ; Obesity/physiopathology ; Pro-Opiomelanocortin/physiology ; Receptors, Leptin/genetics ; Receptors, Leptin/physiology ; Signal Transduction
Chemical Substances	Leptin ; Receptors, Leptin ; Pro-Opiomelanocortin (66796-54-1)
Language	English
Publishing date	2009-12-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1217870-6
ISSN	1708-8267 ; 0009-9279 ; 1081-5589
ISSN (online)	1708-8267
ISSN	0009-9279 ; 1081-5589
DOI	10.2310/JIM.0b013e3181bb0d49
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Article ; Online: Leptin revisited: its mechanism of action and potential for treating diabetes.

Coppari, Roberto / Bjørbæk, Christian

Nature reviews. Drug discovery

2012 Volume 11, Issue 9, Page(s) 692–708

Abstract: Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are ... ...

Abstract	Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are independent of its regulation of body weight and food intake. In particular, leptin can correct diabetes in animal models of type 1 and type 2 diabetes. In addition, long-term leptin replacement therapy improves glycaemic control, insulin sensitivity and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. These results have spurred enthusiasm for the use of leptin therapy to treat diabetes. Here, we review the current understanding of the glucoregulatory functions of leptin, emphasizing its central mechanisms of action and lessons learned from clinical studies, and discuss possible therapeutic applications of leptin in the treatment of type 1 and type 2 diabetes.
MeSH term(s)	Animals ; Blood Glucose/drug effects ; Blood Glucose/metabolism ; Diabetes Mellitus/drug therapy ; Diabetes Mellitus/metabolism ; Humans ; Leptin/metabolism ; Leptin/pharmacology ; Leptin/therapeutic use ; Pro-Opiomelanocortin/metabolism ; Treatment Outcome
Chemical Substances	Blood Glucose ; Leptin ; Pro-Opiomelanocortin (66796-54-1)
Language	English
Publishing date	2012-09-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/nrd3757
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Article ; Online: Role of POMC and AgRP neuronal activities on glycaemia in mice.

Üner, Aykut Göktürk / Keçik, Onur / Quaresma, Paula G F / De Araujo, Thiago M / Lee, Hyon / Li, Wenjing / Kim, Hyun Jeong / Chung, Michelle / Bjørbæk, Christian / Kim, Young-Bum

Scientific reports

2019 Volume 9, Issue 1, Page(s) 13068

Abstract: Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the ... ...

Abstract	Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the regulation of these processes. To determine this, we injected Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) viruses into the hypothalamus of normoglycaemic and diabetic AgRP-ires-cre and POMC-cre mice to chemogenetically activate or inhibit these neuronal populations. Despite robust changes in food intake, activation or inhibition of AgRP neurons did not affect glycaemia, while activation caused significant (P = 0.014) impairment in insulin sensitivity. Stimulation of AgRP neurons in diabetic mice reversed leptin's ability to inhibit feeding but did not counter leptin's ability to lower blood glucose levels. Notably, the inhibition of POMC neurons stimulated feeding while decreasing glucose levels in normoglycaemic mice. The findings suggest that leptin's effects on feeding by AgRP neurons are mediated by changes in neuronal firing, while the control of glucose balance by these cells is independent of chemogenetic activation or inhibition. The firing-dependent glucose lowering mechanism within POMC neurons is a potential target for the development of novel anti-diabetic medicines.
MeSH term(s)	Agouti-Related Protein/metabolism ; Animals ; Blood Glucose ; Diabetes Mellitus, Experimental ; Eating ; Glucose/metabolism ; Glucose Intolerance ; Insulin Resistance ; Leptin/metabolism ; Mice ; Models, Biological ; Neurons/metabolism ; Proprotein Convertases/metabolism
Chemical Substances	Agouti-Related Protein ; Blood Glucose ; Leptin ; Proprotein Convertases (EC 3.4.21.-) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2019-09-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-49295-7
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Article ; Online: Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions.

Gonçalves, Gabriel H M / Li, Wenjing / Garcia, Adriana V C-G / Figueiredo, Mariana S / Bjørbæk, Christian

Cell reports

2014 Volume 7, Issue 4, Page(s) 1093–1103

Abstract: Leptin has beneficial effects on glucose metabolism via actions in the hypothalamus, but the roles of specific subgroups of neurons responsible for these antidiabetic effects remain unresolved. We generated diabetic Lep(ob/ob) or Lepr(db/db) mice lacking ...

Abstract	Leptin has beneficial effects on glucose metabolism via actions in the hypothalamus, but the roles of specific subgroups of neurons responsible for these antidiabetic effects remain unresolved. We generated diabetic Lep(ob/ob) or Lepr(db/db) mice lacking or re-expressing leptin receptors (LepRb) in subgroups of neurons to explore their contributions to leptin's glucose-lowering actions. We show that agouti-related peptide (AgRP)-expressing neurons are both required and sufficient to correct hyperglycemia by leptin. LepRb in pro-opiomelanocortin (POMC) neurons or steroidogenic factor-1 (SF1) neurons are not required. Furthermore, normalization of blood glucose by leptin is blunted in Lep(ob/ob)/MC4R-null mice, but not in Lep(ob/ob) mice lacking neuropeptide Y (NPY) or gamma-aminobutyric acid (GABA) in AgRP neurons. Leptin's ability to improve glucose balance is accompanied by a reduction in circulating glucagon. We conclude that AgRP neurons play a crucial role in glucose-lowering actions by leptin and that this requires the melanocortin system, but not NPY and GABA.
MeSH term(s)	Agouti-Related Protein/metabolism ; Animals ; Blood Glucose/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/prevention & control ; Female ; Glucagon/metabolism ; Humans ; Hypothalamus/cytology ; Hypothalamus/metabolism ; Leptin/metabolism ; Leptin/pharmacology ; Male ; Melanocortins/metabolism ; Mice ; Mice, Transgenic ; Neurons/cytology ; Neurons/metabolism ; Receptors, Leptin/metabolism
Chemical Substances	Agouti-Related Protein ; Blood Glucose ; Leptin ; Melanocortins ; Receptors, Leptin ; Glucagon (9007-92-5)
Language	English
Publishing date	2014-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2014.04.010
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Article: Leptin signaling in the central nervous system and the periphery.

Bjørbaek, Christian / Kahn, Barbara B

Recent progress in hormone research

2004 Volume 59, Page(s) 305–331

Abstract: The discovery of leptin in 1994 has led to astonishing advances in understanding the regulation of energy balance in rodents and humans. The demonstration of leptin receptors in hypothalamic regions known to play critical roles in regulating energy ... ...

Abstract	The discovery of leptin in 1994 has led to astonishing advances in understanding the regulation of energy balance in rodents and humans. The demonstration of leptin receptors in hypothalamic regions known to play critical roles in regulating energy intake and body weight has produced considerable excitement in the field. Most attention has focused on the central actions of leptin. The receptor is present in several populations of neurons that express specific appetite-regulating neuropeptides for which both expression and release are regulated by leptin. Recent advances show that central leptin action is not limited to influencing energy balance. Leptin regulates a broad variety of processes and behaviors, such as blood pressure, neuroendocrine axes, bone mass, and immune function. The cloning of leptin receptors also led to parallel studies examining their signaling capacities in mammalian cell lines. The long-form receptor regulates multiple intracellular signaling cascades, including the classic janus activating kinase-signal transducer and activator of transcription (JAK-STAT) pathway, consistent with belonging to the cytokine-receptor superfamily and the phosphoinositol-3 kinase and adenosine monophosphate kinase pathways. Progress has been made in understanding the role of individual signaling pathways in vivo and the mechanisms by which specific neuropeptides are regulated. Regulation of the pro-opiomelanocortin (pomc) and the thyrotropin-releasing hormone (trh) genes by leptin is particularly well understood. Novel players in negative regulation of central leptin receptor signaling have been identified and open the possibility that these may be important in the development of leptin resistance and obesity. While initial focus was on the central effects of leptin, important actions have been discovered in peripheral tissues. These include roles of leptin to directly regulate immune cells, pancreatic beta cells, adipocytes, and muscle cells. Recent elucidation of a new signaling pathway in skeletal muscle affecting fatty acid metabolism has implications for regulation of insulin sensitivity and glucose metabolism. Recent progress in understanding central and peripheral leptin receptor signaling provides potential new targets for anti-obesity and anti-diabetes drug development.
MeSH term(s)	AMP-Activated Protein Kinases ; Animals ; Brain/physiology ; Gene Expression ; Humans ; Leptin/physiology ; Multienzyme Complexes/physiology ; Muscle, Skeletal/physiology ; Neurons/physiology ; Neuropeptides/physiology ; Protein Serine-Threonine Kinases/physiology ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/physiology ; Receptors, Leptin ; Signal Transduction
Chemical Substances	LEPR protein, human ; Leptin ; Multienzyme Complexes ; Neuropeptides ; Receptors, Cell Surface ; Receptors, Leptin ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2004-01-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	209338-8
ISSN	0079-9963
ISSN	0079-9963
DOI	10.1210/rp.59.1.305
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Article: Leptin and melanocortin signaling in the hypothalamus.

Bjørbaek, Christian / Hollenberg, Anthony N

Vitamins and hormones

2002 Volume 65, Page(s) 281–311

Abstract: The regulation of body weight in humans is coordinated by the interplay between food intake and energy expenditure. The identification of the adipocyte-secreted hormone leptin as a key regulator on both of these processes has shed new light on the ... ...

Abstract	The regulation of body weight in humans is coordinated by the interplay between food intake and energy expenditure. The identification of the adipocyte-secreted hormone leptin as a key regulator on both of these processes has shed new light on the pathways involved in their regulation. Indeed, mutations in the gene's encoding leptin and its cognate receptor cause severe obesity in humans. Leptin's actions are mediated principally by target neurons in the hypothalamus where it acts to alter food intake, energy expenditure, and neuroendocrine-function. Recently, it has become clear that a number of critical neuropeptides are regulated by leptin in the hypothalamus. Among these is the proopiomelanocortin (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), which is produced in the arcuate nucleus and is a potent negative regulator of food intake. Like leptin, mutations in POMC or in central melanocortin receptors lead to obesity in humans. Thus, an understanding of the mechanisms by which the leptin and melanocortin pathways signal in the hypothalamus is critical in order to begin to clarify the pathways involved in regulating body weight in humans.
MeSH term(s)	Agouti-Related Protein ; Animals ; Gene Expression Regulation ; Humans ; Hypothalamus/metabolism ; Intercellular Signaling Peptides and Proteins ; Leptin/genetics ; Leptin/physiology ; Mutation ; Obesity ; Pro-Opiomelanocortin/genetics ; Pro-Opiomelanocortin/physiology ; Proteins/genetics ; Proteins/physiology ; Receptor, Melanocortin, Type 3 ; Receptor, Melanocortin, Type 4 ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/physiology ; Receptors, Corticotropin/genetics ; Receptors, Corticotropin/physiology ; Receptors, Leptin ; Receptors, Melanocortin ; Signal Transduction ; alpha-MSH/genetics ; alpha-MSH/physiology
Chemical Substances	Agouti-Related Protein ; Intercellular Signaling Peptides and Proteins ; LEPR protein, human ; Leptin ; Proteins ; Receptor, Melanocortin, Type 3 ; Receptor, Melanocortin, Type 4 ; Receptors, Cell Surface ; Receptors, Corticotropin ; Receptors, Leptin ; Receptors, Melanocortin ; alpha-MSH (581-05-5) ; Pro-Opiomelanocortin (66796-54-1)
Language	English
Publishing date	2002-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/s0083-6729(02)65068-x
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Article: The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis.

Üner, Aykut / Gonçalves, Gabriel H M / Li, Wenjing / Porceban, Matheus / Caron, Nicole / Schönke, Milena / Delpire, Eric / Sakimura, Kenji / Bjørbæk, Christian

Molecular metabolism

2015 Volume 4, Issue 10, Page(s) 678–691

Abstract: Objective: Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of ... ...

Abstract	Objective: Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown. Methods: We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies. Results: We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lep (ob/ob) mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lep (ob/ob) mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions. Conclusions: GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action.
Language	English
Publishing date	2015-07-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2708735-9
ISSN	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2015.06.010
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Article ; Online: Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity.

Gamber, Kevin M / Huo, Lihong / Ha, Sangdeuk / Hairston, Joyce E / Greeley, Sarah / Bjørbæk, Christian

PloS one

2012 Volume 7, Issue 1, Page(s) e30485

Abstract: Diet-induced obesity (DIO) in rodents is characterized by impaired activation of signal-transducer and activator of transcription 3 (STAT3) by leptin receptors (LepRb) within the hypothalamic arcuate nucleus. This signaling defect likely plays an ... ...

Abstract	Diet-induced obesity (DIO) in rodents is characterized by impaired activation of signal-transducer and activator of transcription 3 (STAT3) by leptin receptors (LepRb) within the hypothalamic arcuate nucleus. This signaling defect likely plays an important role in development of DIO. However, the neuro-chemical identity of the leptin-STAT3 resistant arcuate neurons has not been determined and the underlying mechanisms responsible for development of cellular leptin resistance remain unclear. To investigate this, we first measured arcuate gene expression of known key signaling components of the LepRb signaling pathway and tested whether specifically the critical arcuate pro-opiomelanocortin (POMC) neurons are resistant to LepRb-STAT3 signaling in mice given a high-fat-diet (HFD) compared to mice provided a low-fat control diet (LFD). We found that leptin-dependent STAT3 phosphorylation was decreased within POMC neurons of HFD mice. In addition, Leprb mRNA and suppressor of cytokine signaling 3 (Socs3) mRNA were elevated in the arcuate of HFD mice. To investigate whether increased LepRb expression per se in POMC neurons can influence development of DIO and Socs3 expression, we created mice that over-express LepRb selectively in POMC neurons (POMC-LepRb). No differences in body weight, fat mass or food intake were found between LFD POMC-LepRb mice and LFD controls. Surprisingly, body weight, fat mass and caloric intake of HFD POMC-LepRb mice was markedly higher than HFD control mice. In addition, arcuate Socs3 mRNA was increased in HFD POMC-LepRb mice compared to HFD controls. These data show that specifically POMC neurons of DIO mice are resistant to STAT3 activation by leptin, indicating that those cells might play a role in development of DIO. Furthermore, over-expression of LepRb selectively in POMC neurons increases susceptibility to the development of DIO. We propose a model where over-reactivity of the leptin-LepRb signaling system in arcuate neurons may play causal a role in development of diet-induced obesity.
MeSH term(s)	Animals ; Body Composition ; Diet, Fat-Restricted/adverse effects ; Diet, High-Fat/adverse effects ; Hypothalamus/cytology ; Immunohistochemistry ; In Situ Hybridization ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/metabolism ; Obesity/chemically induced ; Phosphorylation ; Pro-Opiomelanocortin/metabolism ; Receptors, Leptin/genetics ; Receptors, Leptin/metabolism ; STAT3 Transcription Factor/metabolism ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins/genetics
Chemical Substances	Receptors, Leptin ; STAT3 Transcription Factor ; Socs3 protein, mouse ; Stat3 protein, mouse ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Pro-Opiomelanocortin (66796-54-1)
Language	English
Publishing date	2012-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0030485
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Article: Divergent regulation of proopiomelanocortin neurons by leptin in the nucleus of the solitary tract and in the arcuate hypothalamic nucleus.

Huo, Lihong / Grill, Harvey J / Bjørbaek, Christian

Diabetes

2006 Volume 55, Issue 3, Page(s) 567–573

Abstract: Proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus are activated by leptin and mediate part of leptin's central actions to influence energy balance. However, little is known about potential leptin signaling in POMC ... ...

Abstract	Proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus are activated by leptin and mediate part of leptin's central actions to influence energy balance. However, little is known about potential leptin signaling in POMC neurons located in the nucleus of the solitary tract (NTS), the only other known population of POMC neurons. Leptin-responsive neurons do exist in the NTS, but their neurochemical phenotype is largely unknown. The contribution of NTS POMC neurons versus ARC POMC neurons in leptin action is thus undetermined. We show here that in contrast to POMC neurons in the ARC, leptin does not stimulate phosphorylation of signal-transducer and activator of transcription 3 in NTS POMC neurons of POMC-EGFP reporter mice. In addition, leptin does not induce c-Fos expression in NTS POMC neurons unlike ARC POMC neurons. Fasting induces a fall in POMC mRNA in both the ARC and the NTS, but different from the ARC, the reduction in NTS POMC mRNA is not reversed by leptin. We conclude that POMC neurons in the NTS do not respond to leptin unlike ARC POMC neurons. POMC neurons in the hypothalamus may therefore mediate all of leptin's signaling via POMC-derived peptides in the central nervous system.
MeSH term(s)	Animals ; Arcuate Nucleus of Hypothalamus/chemistry ; Arcuate Nucleus of Hypothalamus/drug effects ; Immunohistochemistry ; Leptin/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/chemistry ; Phosphorylation ; Pro-Opiomelanocortin/analysis ; Proto-Oncogene Proteins c-fos/analysis ; STAT3 Transcription Factor/analysis ; Solitary Nucleus/chemistry ; Solitary Nucleus/drug effects
Chemical Substances	Leptin ; Proto-Oncogene Proteins c-fos ; STAT3 Transcription Factor ; Pro-Opiomelanocortin (66796-54-1)
Language	English
Publishing date	2006-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/diabetes.55.03.06.db05-1143
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Article ; Online: Role of POMC and AgRP neuronal activities on glycaemia in mice

Aykut Göktürk Üner / Onur Keçik / Paula G. F. Quaresma / Thiago M. De Araujo / Hyon Lee / Wenjing Li / Hyun Jeong Kim / Michelle Chung / Christian Bjørbæk / Young-Bum Kim

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 14

Abstract: Abstract Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations ... ...

Abstract	Abstract Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the regulation of these processes. To determine this, we injected Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) viruses into the hypothalamus of normoglycaemic and diabetic AgRP-ires-cre and POMC-cre mice to chemogenetically activate or inhibit these neuronal populations. Despite robust changes in food intake, activation or inhibition of AgRP neurons did not affect glycaemia, while activation caused significant (P = 0.014) impairment in insulin sensitivity. Stimulation of AgRP neurons in diabetic mice reversed leptin’s ability to inhibit feeding but did not counter leptin’s ability to lower blood glucose levels. Notably, the inhibition of POMC neurons stimulated feeding while decreasing glucose levels in normoglycaemic mice. The findings suggest that leptin’s effects on feeding by AgRP neurons are mediated by changes in neuronal firing, while the control of glucose balance by these cells is independent of chemogenetic activation or inhibition. The firing-dependent glucose lowering mechanism within POMC neurons is a potential target for the development of novel anti-diabetic medicines.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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