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Biomedical subjects

B Meister

Publications and source records attributed to B Meister.

At least 19 recordsLinked to original sources
PubMed2006

FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells.

Protein kinase-B (PKB) and its target, the forkhead transcription factor like 1 (FKHRL1)/FoxO3a, have been suggested as regulators of neurotrophin-mediated cell survival in neuronal cells. We analyzed human neuroblastoma cells and found that FKHRL1 was phosphorylated, suggesting its inactivation. To study FKHRL1 function, we infected SH-EP and NB15 cells with a 4OH-tamoxifen-regulated FKHRL1(A3)ER(tm) transgene. Activation of FKHRL1 promoted cytochrome-c release and caspase-dependent apoptosis. FKHRL1 induced TRAIL and the BH3-only proteins Noxa and Bim, implicating both extrinsic and intrinsic death pathways. However, expression of dnFADD did not inhibit FKHRL1-induced cell death, whereas Bcl2 protected against apoptosis. This excluded the death-receptor pathway and suggested that cell death decision is regulated by Bcl2-rheostat. Importantly, RNAi knockdown of Noxa or Bim decreased apoptosis, indicating that Noxa and Bim cooperate to mediate FKHRL1-induced cell death. We conclude that Noxa and Bim establish a connection between FKHRL1 and mitochondria, and that both BH3-only proteins are critically involved in FKHRL1-induced apoptosis in neuroblastoma.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2005

5-HT1A receptor mRNA and immunoreactivity in the rat medial septum/diagonal band of Broca-relationships to GABAergic and cholinergic neurons.

Activation of 5-HT1A receptors results in a variety of physiological responses, depending on their localization on neurons with different phenotypes in the brain. This study investigated the localization of 5-HT1A receptor mRNA and 5-HT1A receptor immunoreactivity in cell bodies of the rat septal complex using in situ hybridization and immunohistochemistry. In adjacent sections of the medial septum/diagonal band of Broca (MSDB), the distribution of cell bodies expressing 5-HT1A receptor mRNA was closely related to cells labeled with oligonucleotide probes to GAD (glutamic acid decarboxylase), VAChT (vesicular acetylcholine transporter) or parvalbumin mRNA. Using antiserum to GAD and antibodies to GABA, 5-HT1A receptor immunoreactivity was demonstrated in a majority of GABAergic cells in the MSDB. 5-HT1A receptor-immunoreactive GABAergic cells in the MSDB were also demonstrated to contain the calcium-binding protein parvalbumin, a marker for septohippocampal projecting GABAergic neurons. In the lateral septum, 5-HT1A receptor immunoreactivity was colocalized with the calcium-binding protein calbindin D-28k, a marker for septal GABAergic somatospiny neurons. 5-HT1A receptor immunoreactivity was also detected in a subpopulation of VAChT-containing cholinergic neurons of the MSDB. In MSDB neurons, colocalization of 5-HT1A and 5-HT2A receptor immunoreactivities was demonstrated. These observations suggest that serotonin via 5-HT1A receptors may represent an important modulator of hippocampal transmission important for cognitive and emotional functions through actions on both GABAergic and cholinergic neurons of the rat septal complex. In addition, 5-HT may exert its effects in the MSDB via cells expressing both 5-HT1A and 5-HT2A receptors.

Acetylcholine↗
PubMed2004

Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice.

A mutation in the mouse tub gene causes a phenotype characterized by maturity-onset obesity, blindness and deafness. The role of the intact tubby protein and the pathogenesis resulting in the phenotype of tub/tub mice remain largely unknown. In this study, we have investigated whether obese tub/tub mice exhibit altered expression levels for agouti-related protein (AGRP) or glutamic acid decarboxylase-65 (GAD65) in body weight-regulating neurons of the hypothalamic arcuate nucleus. In situ hybridization revealed that AGRP, but not GAD65 mRNA levels, were significantly lower in obese tub/tub mice as compared to tub/+ mice. The lower levels of AGRP mRNA in the arcuate nucleus of tub/tub mice were paralleled by lower fluorescence intensity and numbers of AGRP- and neuropeptide Y (NPY)-immunoreactive (ir) nerve fibers and terminals in the arcuate, ventromedial, dorsomedial hypothalamic nuclei and perifornical and lateral hypothalamic areas. No obvious differences in GAD65-ir nerve fibers and terminals could be detected. Measurements of daily food intake revealed that tub/tub mice displayed progressively higher food consumption as compared to lean tub/+ littermates over a 15-day observation period. When moved to an unfamiliar environment, e.g. a novel cage, daily food intake was initially lower in tub/tub mice than in tub/+ mice suggesting that tub/tub mice may be more sensitive to psychogenic stress. The results together show that tub/tub mice are hyperphagic and exhibit, within the hypothalamic arcuate nucleus, a depressed expression of neuropeptides involved in the regulation of feeding behavior.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Cellular localization of GABA receptor alpha subunit immunoreactivity in the rat hypothalamus: relationship with neurones containing orexigenic or anorexigenic peptides.

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, acts via two different type of GABA receptors. GABA(A) receptors are composed of five subunits that belong to eight different classes. Depending on their subunit composition, distinct pharmacological and electrophysiological properties are obtained. GABA is produced in certain hypothalamic neurones known to be involved in control of feeding behaviour. We report the detailed immunohistochemical localization of four GABA(A)R alpha subunits in hypothalamic regions associated with the regulation of feeding behaviour. Immunoreactive structures for all studied GABA(A)R alpha subunits were observed in the hypothalamus, but with subunit-specific staining patterns. GABA(A)R alpha(1) immunoreactivity was most prominent in the dorsomedial hypothalamic nucleus and in the lateral hypothalamic area (LHA), whereas GABA(A)R alpha(2), alpha(3) and alpha(5) subunits exhibited particularly strong immunoreactivity in the ventromedial hypothalamic nucleus. In comparison, GABA(A)R alpha subunit immunoreactivities were generally weak in the arcuate nucleus. In the ventromedial part of the arcuate nucleus, neuropeptide Y- and agouti-related peptide-containing cell bodies, which also are known to be GABAergic, were immunoreactive for only the GABA(A)R alpha(3) subunit, whereas pro-opiomelanocortin- and cocaine- and amphetamine-regulated transcript- containing cell bodies located in the ventrolateral subdivision of the arcuate nucleus, showed GABA(A)R alpha(1), alpha(2) and alpha(3) subunit immunoreactivity. In the LHA, GABA(A)R alpha(3) subunit immunoreactivity was demonstrated in both melanin-concentrating hormone (MCH) and orexin-containing neurones. In addition, MCH neurones contained GABA(A)R alpha(2) immunoreactivity. In neurones of the tuberomammillary nucleus, GABA(A)R alpha(2) and alpha(5) subunits were colocalized with histidine decarboxylase, a marker for histamine-containing neurones.

Animals↗
PubMed2003

Cloning of a novel orphan G protein-coupled receptor (GPCR-2037): in situ hybridization reveals high mRNA expression in rat brain restricted to neurons of the habenular complex.

The family of G protein-coupled receptors (GPCRs) is one of the largest protein families in the mammalian genome. Receptors belonging to this class mediate the effects of very diverse ligands and are responsible for signaling events by affecting the activities of enzymes and ion channels. Here we describe the cloning and identification of GPCR-2037, a novel and previously not identified member of the large family of GPCRs. This orphan GPCR displays several typical features of family A type of GPCRs and shows highest homology with the galanin receptors 2 and 3. In rat brain, in situ hybridization showed that expression of GPCR-2037 mRNA was exclusively localized to neurons of the habenular complex. The expression was particularly prominent in the medial habenular nucleus, whereas the lateral habenular nucleus exhibited a lower number of labeled cells. The restricted and unique expression pattern of GPCR-2037 in the rat brain suggests a role for this orphan GPCR in the habenular complex, a brain structure implicated in the modulation of various physiological functions. Further studies involving the identification of the GPCR ligand will enable the functional characterization of this orphan receptor and its role in regulating the habenular complex.

Amino Acid Sequence↗
PubMed2003

Chemical coding of GABA(B) receptor-immunoreactive neurones in hypothalamic regions regulating body weight.

Gamma-aminobutyric acid (GABA) interacts with hypothalamic neuronal pathways regulating feeding behaviour. GABA has been reported to stimulate feeding via both ionotropic GABA(A) and metabotropic GABA(B) receptors. The functional form of the GABA(B) receptor is a heterodimer consisting of GABA(B) receptor-1 (GABA(B)R1) and GABA(B) receptor-2 (GABA(B)R2) proteins. Within the heterodimer, the GABA-binding site is localized to GABA(B)R1. In the present study, we used an antiserum to the GABA(B)R1 protein in order to investigate the cellular localization of GABA(B)R1-immunoreactive neurones in discrete hypothalamic regions implicated in the control of body weight. The colocalization of GABA(B)R1 immunoreactivity with different chemical messengers that regulate food intake was analysed. GABA(B)R1-immunoreactive cell bodies were found in the periventricular, paraventricular (PVN), supraoptic, arcuate, ventromedial hypothalamic, dorsomedial hypothalamic, tuberomammillary nuclei and lateral hypothalamic area (LHA). Direct double-labelling showed that glutamic acid decarboxylase (GAD)-positive terminals were in close contact with GABA(B)R1-containing cell bodies located in all these regions. In the ventromedial part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were found to contain neuropeptide Y, agouti-related peptide (AGRP) and GAD. In the ventrolateral part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were shown to contain pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. In the LHA, GABA(B)R1 immunoreactivity was present in both melanin-concentrating hormone- and orexin-containing cell populations. In the tuberomammillary nucleus, GABA(B)R1-immunoreactive cell bodies expressed histidine decarboxylase, a marker for histamine-containing neurones. In addition, GAD and AGRP were found to be colocalized in some nerve terminals surrounding GABA(B)R1-immunoreactive cell bodies in the parvocellular part of the PVN. The results may provide a morphological basis for the understanding of how GABA regulates the hypothalamic control of food intake and body weight via GABA(B) receptors.

Animals↗
PubMed2003

Use of a quantitative TaqMan-PCR for the fast quantification of mycobacteria in broth culture, eukaryotic cell culture and tissue.

The quantification of slow-growing mycobacteria such as Mycobacterium tuberculosis or M. bovis from in vitro and in vivo samples is complicated by their long generation time, their ability to form aggregates, and their capacity to persist in a state of dormancy. We compared different methods for the establishment of growth curves for broth cultures of M. bovis bacille Calmette-Guérin (BCG). A quantitative TaqMan-PCR yielded results comparable with those obtained by protein quantification and measurement of the ATP content of the cultures. The quantitative TaqMan-PCR furthermore turned out to be particularly suitable for the measurement of multiplication of BCG within eukaryotic cells. Furthermore, it is a fast method allowing an estimation of the mycobacterial load in tissue long before colony counts can be obtained.

Animals↗
PubMed2001

Immunohistochemical characterization of localization of long-form leptin receptor (OB-Rb) in neurochemically defined cells in the ovine hypothalamus.

Leptin, a hormone secreted from the adipose tissue, is involved in the regulation of food intake and neuroendocrine function, by modulation of the expression and/or function of various neuropeptides in the hypothalamus. The long isoform (OB-Rb) is the major signaling form of the leptin receptor in the hypothalamus. We have used double-labeling immunohistochemistry to examine the extent of OB-Rb expression in neurochemically defined cell types in the ovine hypothalamus. OB-Rb-like immunoreactivity was widespread within cells localized to the periventricular, paraventricular, supraoptic, dorsomedial hypothalamic, ventromedial hypothalamic and arcuate nuclei, as well as the median eminence, perifornical, anterior hypothalamic and lateral hypothalamic areas and the zona incerta. Double-labeling showed expression of OB-Rb in 59.6+/-6.0% neuropeptide Y-containing cells, 60.8+/-4.7% galanin-containing cells, 89.8+/-2.65% pro-opiomelanocortin-containing cells, 73.4+/-3.5% tyrosine hydroxylase-containing cells and 31.8+/-2.8% corticotropin-releasing factor-containing cells. Interestingly 100% of melanin-concentrating hormone and orexin positive cells were also OB-Rb immunoreactive. These data provide semi-quantitative information on the extent to which various cell types express OB-Rb in the hypothalamus. Expression of OB-Rb within specific neuropeptidergic neurons provides evidence for the direct action of leptin upon the various neurochemical systems that regulate food intake, neuroendocrine and autonomic function in the brain.

Animals↗
PubMed2001

Overexpression of rat neuronal calcium sensor-1 in rodent NG108-15 cells enhances synapse formation and transmission.

The role of rat neuronal calcium sensor-1 (NCS-1), a Ca2+-binding protein, in synapse formation and transmitter release was examined in mouse neuroblastoma x rat glioma hybrid NG108-15 cells in culture. Wild-type NG108-15 cells expressed rodent NCS-1. Endogenous NCS-1 was partially co-localized with the synaptic protein SNAP-25 at the plasma membrane in both cell bodies and processes, but not with the Golgi marker [beta]-COP, an individual coat subunit of the coatomer complex present on Golgi-derived vesicles. In NG108-15 cells co-cultured with rat myotubes, partial co-localization of SNAP-25 and NCS-1 was observed at the plasma membrane of neurites and growth cones, some of which had synaptic contacts to muscle cells. Transient co-transfection of the rat NCS-1 cDNA and green fluorescent protein (GFP) resulted in NCS-1 overexpression in about 30 % of the cells as determined by fluorescence microscopy. The rate of functional synapse formation with co-cultured rat myotubes increased 2-fold as determined by the presence of miniature endplate potentials (MEPPs) in NCS-1-overexpressing NG108-15 cells compared to non- and mock-transfected cells. The number of neurites per cell, branches per neurite and length of neurites was slightly less in cells that were either transiently transfected (GFP-NCS-1-fluorescence positive) or stably transformed with NCS-1 compared to GFP-NCS-1-negative, non-transfected or mock-transfected NG108-15 cells. The number of action potentials that elicited endplate potentials increased in NG108-15 cells stably transformed with rat NCS-1. The mean number of quanta per impulse (m) increased 5-fold. These results show that NCS-1 functions to facilitate synapse formation, probably because of the increased quantal content of evoked acetylcholine release.

Acetylcholine↗
PubMed2001

Intact T-cell regenerative capacity in childhood acute lymphoblastic leukemia after remission induction therapy.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a bone marrow disease. This may adversely affect the capacity of T cells to recover from chemotherapy-induced T-cell depletion and thus contribute to the prevailing immune deficiency in ALL patients. PROCEDURE: We tested the capacity of T-cells to regenerate in 18 ALL children in first clinical remission (median age 4.2 years) at the time of hematologic reconstitution after BFM-ALL induction therapy (treatment-free interval 22 days, median; range 12 to 52 days). All patients had experienced a period of leukopenia (white blood cell count [WBC] <0.95 x 10(9)/l, median) during the final four weeks of induction therapy. T-cells and T-cell subsets were examined by FACS. RESULTS: At the time of investigation the WBC was near normal (3.5 x 10(9)/l, median). Surprisingly, most cases (78%) showed a complete regeneration of T-cells and its subsets including 1) normal total (CD3+) T-cells (1635/microl, median; range 756-3440/microl); 2) normal T-helper (CD4+) cells (697/microl, median; range 128-1523/microl); and 3) normal T-cytotoxic/suppressor (CD8+) cells (686/microl, median; range 348-1540/microl). Eight patients achieved a normal CD4+/CD8+ ratio (0.8, median). Subset analyses of T-helper cells revealed a normal proportion of CD4+CD45RA+ cells (52%, median) in all but one patient below the age of 6 years, indicating an intact residual thymic activity. No correlation was observed between age at diagnosis and a normal CD4+ count (r = 0.086) or between a normal CD4+ count and a normal proportion of CD4+CD45RA+ cells r = 0.136). A long-term survey in four patients showed altered T-cells after reinduction and during maintenance therapy. CONCLUSIONS: The findings suggest that ALL per se does not inhibit T-cell regenerative capacity. Thus, the frequently observed longlasting impairment of the T-cell system in ALL is attributable to the treatment rather than to the underlying disease.

Adolescent↗
PubMed2001

Expression and regulation of leptin receptor proteins in afferent and efferent neurons of the vagus nerve.

Leptin, the product of the ob gene, plays a key role in the regulation of food intake via a cross-talk between hypothalamic leptin receptors and neuropeptides that affect feeding behaviour. Recent studies have shown a synergistic interaction between leptin and cholecystokinin (CCK) leading to suppression of food intake, which involves CCK-1 receptors and capsaicin-sensitive vagal fibres. In this study, we have investigated the presence of leptin receptors in afferent and efferent neurons of the vagus nerve. By using reverse transcription-polymerase chain reaction, mRNAs encoding long (Ob-Rb) and short (Ob-Ra) leptin receptor isoforms were detected in the rat nodose ganglion, which contains the cell bodies of the vagal afferent neurons. Western blot analysis confirmed the presence of leptin receptor-immunoreactive proteins in extracts from the vagal trunk. Immunohistochemistry showed the presence of leptin receptors and the leptin-induced transcription factor STAT3 in the cytoplasm of nodose ganglion cells. In cervical vagal segments, levels of leptin receptor protein displayed physiological regulation, with decreased amounts after feeding and increased levels after food restriction. In addition, leptin receptor and STAT3 immunoreactivities were detected in neurons of the nucleus of tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) by immunofluorescence histochemistry. Furthermore, direct double-labelling demonstrated colocalization of Ob-Rb and STAT3 immunoreactivities in cholinergic vagal efferent cell bodies of the DMNX. It is speculated that vagal leptin receptors, apart from being activated by adipocyte-derived leptin, may also be influenced by leptin produced by the stomach. This may explain the synergistic action of leptin and CCK on neuronal activity in the NTS and on food intake.

Afferent Pathways↗
PubMed2001

High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia.

Childhood acute lymphoblastic leukaemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. Such extramedullary presentation is important for understanding the biology of childhood ALL and also for developing new prognostic parameters. A potential mechanism in the trafficking of leukaemia cells is the interaction of the chemokine receptor CXCR4, which is expressed on ALL cells, and its ligand stromal cell-derived factor-1 (SDF-1), produced by stromal cells in bone marrow and extramedullary organs. Functionality of CXCR4 was demonstrated by a high correlation between cell surface density of CXCR4 and transendothelial migration of leukaemia blasts towards a gradient of SDF-1 (r = 0.73, P = 0.001). Inhibition of SDF-1-induced migration by an anti-CXCR4 monoclonal antibody (78.33 +/- 23.86% inhibition) evidenced the specificity of CXCR4 to SDF-1. In order to evaluate clinical significance of CXCR4 expression, lymphoblasts from the bone marrow of 73 patients with and without extramedullary organ infiltration were compared. Multiparameter flow cytometry revealed that lymphoblasts from patients with high extramedullary organ infiltration, defined as ultrasonographically measured enlargement of liver or spleen, expressed the CXCR4 receptor at higher fluorescence intensity (median 66.12 +/- 66.17) than patients without extramedullary organ infiltration (median 17.56 +/- 19.29; P < 0.001). Consequently, high expression of CXCR4 was strongly predictive for extramedullary organ involvement, independently of the peripheral lymphoblast count. Highest CXCR4 expression was seen in mature B ALL (median 102.74 +/- 92.13; P < 0.003), a disease characterized by a high incidence of extramedullary bulky disease. As high expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood ALL, we suggest that CXCR4 and its ligand play an essential role in extramedullary invasion.

Antibodies, Monoclonal↗
PubMed2001

GABAergic nature of hypothalamic leptin target neurones in the ventromedial arcuate nucleus.

Leptin is an adipose tissue-derived cytokine hormone, which reduces body weight via interactions with hypothalamic neurones. Leptin receptors capable of activating the JAK-STAT signal transduction pathway are expressed at high levels in the hypothalamus, particularly in the arcuate nucleus. In order to identify the chemical mediators of leptin's action in the hypothalamus, we have examined whether GABA neurones of the hypothalamic arcuate nucleus contain leptin receptors and the leptin-activated transcription factor STAT3. GABAergic neurones, as visualized by antisera to the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) and GABA, were demonstrated in the ventromedial and ventrolateral parts of the arcuate nucleus. GABA neurones in the ventromedial arcuate nucleus were shown to contain leptin receptor immunoreactivity, as revealed using an antiserum generated to a sequence common to all isoforms of the leptin receptor (Ob-R), as well as an antiserum generated to the carboxy-terminal end of the long leptin receptor (Ob-Rb), and immunoreactivity for the leptin-induced signal transduction molecule STAT3. Ventromedial GABA neurones were also shown to contain neuropeptide Y, whereas ventrolateral proopiomelanocortin-containing neurones lacked GAD and GABA immunoreactivity. Levels of mRNA for GAD65, GAD67 and the vesicular GABA transporter (VGAT) were analysed in the arcuate nucleus of leptin-deficient ob/ob mice and lean control mice by in situ hybridization. No significant differences in GAD65, GAD67 or VGAT mRNA were detected in the arcuate nucleus of ob/ob mice as compared to lean control mice. The presence of leptin receptor and STAT3 in GABAergic arcuate neurones, but absence of changes in gene transcription for GAD and VGAT mRNA suggests, that leptin does not transcriptionally regulate the expression of proteins involved in GABAergic transmission in arcuate neurones. However, mechanisms other than transcriptional regulation for leptin to influence arcuate GABA neurones may exist.

Animals↗
PubMed2000

Munc-18 associates with syntaxin and serves as a negative regulator of exocytosis in the pancreatic beta -cell.

The Munc-18 protein (mammalian homologue of the unc-18 gene; also called nSec1 or rbSec1) has been identified as an essential component of the synaptic vesicle fusion protein complex. The cellular and subcellular localization and functional role of Munc-18 protein in pancreatic beta-cells was investigated. Subcellular fractionation of insulin-secreting HIT-T15 cells revealed a 67-kDa protein in both cytosol and membrane fractions. Immunohistochemistry showed punctate Munc-18 immunoreactivity in the cytoplasm of rat pancreatic islet cells. Direct double-labeling immunofluorescence histochemistry combined with confocal laser microscopy revealed the presence of Munc-18 immunoreactivity in insulin-, glucagon-, pancreatic polypeptide-, and somatostatin-containing cells. Syntaxin 1 immunoreactivity was detected in extracts of HIT-T15 cells, which were immunoprecipitated using Munc-18 antiserum, suggesting an intimate association of Munc-18 with syntaxin 1. Administration of Munc-18 peptide or Munc-18 antiserum to streptolysin O-permeabilized HIT-T15 cells resulted in significantly increased insulin release, but did not have any significant effect on voltage-gated Ca(2+) channel activity. The findings taken together show that the Munc-18 protein is present in insulin-secreting beta-cells and implicate Munc-18 as a negative regulator of the insulin secretory machinery via a mechanism that does not involve syntaxin-associated Ca(2+) channels.

Animals↗
PubMed2000

Decreased 5-HT transporter mRNA in neurons of the dorsal raphe nucleus and behavioral depression in the obese leptin-deficient ob/ob mouse.

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is an important regulator of feeding behavior. A hypothalamic site of action for 5-HT in body weight control is supported by the presence of 5-HT receptors in hypothalamic regions which are intimately associated with regulation of food intake. In the present study we have investigated whether there may be an interaction between the hormone leptin, an adipose tissue-derived cytokine signaling factor that inhibits food intake and lowers body weight, and the brain serotonergic system. Immunohistochemical analysis of colchicine-treated rats showed colocalization of 5-HT transporter- and leptin receptor-immunoreactivity in cell bodies of the dorsal raphe nucleus, suggesting that dorsal raphe neurons are targets for circulating leptin. Levels of 5-HT transporter mRNA expression were compared in neurons of the dorsal raphe nucleus of obese leptin-deficient ob/ob mice and their lean littermates using in situ hybridization. 5-HT transporter mRNA levels were significantly down-regulated in neurons of the dorsal raphe nucleus of obese ob/ob mice as compared to lean control mice. Behavioral analysis showed that obese ob/ob mice had significantly lower locomotor activity and exhibited increased immobility in Porsolt's test, a model for depression. Taken together, these results suggest that serotonergic cell bodies in the rodent dorsal raphe nucleus possess leptin receptors and that the serotonergic system, as reflected by expression levels of 5-HT transporter mRNA, is down-regulated in the obese behaviorally depressed ob/ob mouse.

Adipose Tissue↗
PubMed2000

Control of food intake via leptin receptors in the hypothalamus.

Food intake is regulated via neural circuits located in the hypothalamus. During the past decade our knowledge on the specific mediators and neuronal networks that regulate food intake and body weight has increased dramatically. An important contribution to the understanding of hypothalamic control of food intake has been the characterization of the ob gene product (leptin) via positional cloning. Absence of circulating, functionally active, leptin hormone results in massive obesity as seen in ob/ob mice. Leptin inhibits food intake and increases energy expenditure via an interaction with specific leptin receptors located in the hypothalamus. Leptin receptors, of which there are several splice variants (Ob-Ra through Ob-Re), belong to the superfamily of cytokine receptors, which use the JAK-STAT pathway of signal transduction. Obese db/db mice, which have a mutation in the db locus, are unable to perform JAK-STAT signal transduction due to absence of functionally active (long form; Ob-Rb) leptin receptors. Ob-Rb is primarily expressed in the hypothalamus, with particularly high levels in the arcuate, paraventricular, and dorsomedial nuclei and in the lateral hypothalamic area. The abundance of leptin receptors in the ventromedial and lateral hypothalamus supports early observations that these two regions are intimately associated with the regulation of food intake. Leptin receptors have been identified in neuropeptide Y (NPY)/lagouti-related peptide (AgRP)- and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-containing neurons of the ventromedial and ventrolateral arcuate nucleus, respectively, and in melanin-concentrating hormone (MCH)- and hypocretin/orexin-containing neurons of the lateral hypothalamus, suggesting that the above-mentioned messengers are mediators of leptin's action in the hypothalamus. Indeed, functional studies show that NPY, AgRP, POMC-derived peptides, CART, MCH, and hypocretins/orexins all are important regulators of food intake. Leptin is essential for normal body weight balance, but the exact mechanisms by which leptin activates hypothalamic neuronal circuitries is known to a limited extent. In order to find pharmaceutical approaches to treat obesity, further studies will be needed to reveal the exact mechanisms by which leptin lowers body weight and which role leptin and leptin receptors have in the pathogenesis of human obesity.

Animals↗