Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

Geibel, Mirjam; Badurek, Sylvia; Horn, Jacqueline M.; Vatanashevanopakorn, Chinnavuth; Koudelka, Juraj; Wunderlich, Claudia M.; Brönneke, Hella S.; Wunderlich, Frank; Minichiello, Liliana

doi:10.1038/ncomms4427

Cited by 13 publications

(16 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CCK is also co-localized with sleep-promoting preoptic neurons in the hypothalamus [36], which may relate to fatigue and unrefreshing sleep symptoms in ME/CFS. Finally, recent evidence suggests that CCK has a role regulating the differentiation of CD4+ T-cells [37], and that CCK-expressing neurons are a critical cellular component of the hypothalamic-pituitary-adrenal axis [38]. These roles of CCK in components of the immune system are consistent with suggested immune dysregulation in ME/CFS [8,9,[11][12][13][14][15].…”

Section: Characterisation Of Snp Rs11712777supporting

confidence: 55%

Genome-epigenome interactions associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

et al. 2018

View full text Add to dashboard Cite

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease of unknown etiology. Multiple studies point to disruptions in immune functioning in ME/CFS patients as well as specific genetic polymorphisms and alterations of the DNA methylome in lymphocytes. However, potential interactions between DNA methylation and genetic background in relation to ME/CFS have not been examined. In this study we explored this association by characterizing the epigenetic (~480 thousand CpG loci) and genetic (~4.3 million SNPs) variation between cohorts of ME/CFS patients and healthy controls. We found significant associations of DNA methylation states in T-lymphocytes at several CpG loci and regions with ME/CFS phenotype. These methylation anomalies are in close proximity to genes involved with immune function and cellular metabolism. Finally, we found significant correlations of genotypes with methylation modifications associated with ME/CFS. The findings from this study highlight the role of epigenetic and genetic interactions in complex diseases, and suggest several genetic and epigenetic elements potentially involved in the mechanisms of disease in ME/CFS. ARTICLE HISTORY

show abstract

Section: Characterisation Of Snp Rs11712777supporting

confidence: 55%

Genome-epigenome interactions associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Because pyramidal cells in the CA1 area can express low levels of CCK and Cre , light‐evoked ChR2 currents could mask synaptic EPSCs in these experiments (Geibel et al, ). We therefore washed in glutamate receptor blockers NBQX (25 µM) and DL ‐APV (100 µM) at the end to measure ChR2‐contribution to light stimulation‐evoked excitatory currents.…”

Section: Resultsmentioning

confidence: 99%

“…) and BAC‐ CCK‐ Cre tg/+ mice (Fig. ) transduced with AAV:ChR2‐eYFP (see Materials and Methods) (Geibel et al, ). We first stimulated ChR2‐expressing PV+ GABAergic interneuron axons with paired‐pulse laser light pulses (3 ms, 50 ms interval) in the CA1 area, and found that wash‐in of the agonist CGS21680 (30 nM) increased IPSC amplitude in postsynaptic interneurons to 1.35 ± 0.04 of baseline ( P < 0.001, n = 12, t ‐test) (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Mice were anaesthetized with Na‐pentobarbitone and decapitated in accordance with the United Kingdom Animals (Scientific Procedures) Act (1986), and the European Community guidelines (86/609/EEC). Experiments were conducted on 4‐8 week old heterozygous PV‐Cre mice (The Jackson Laboratory B6;129P2‐Pvalbtm1(cre)Arbr/J), BAC‐CCK‐Cre tg/+ (Geibel et al, ) and CaMKII‐Cre mice tg/+ (B6.Cg‐Tg(Camk2a‐cre)T29‐1Stl/J) and their wild type littermates. Homozygous PV‐Cre mice were crossed with homozygous Ai9 mice ( Ai9 tm/tm ) (B6.Cg‐Gt(ROSA)26Sortm9(CAG‐tdTomato)Hze/J) to produce tdTomato fluorophore expression specifically in PV+ cells.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Synaptic mechanisms of adenosine A_2A receptor‐mediated hyperexcitability in the hippocampus

et al. 2014

Self Cite

View full text Add to dashboard Cite

Adenosine inhibits excitatory neurons widely in the brain through adenosine A 1 receptor, but activation of adenosine A 2A receptor (A 2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A 2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A 2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A 2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A 2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A 2A R activation alters the synaptic excitation -inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A 2A R promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse-and cell type specific adenosine A 2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A 2A R's facilitatory effect on cortical network activity.

show abstract

“…Abnormal ACTH level in human is closely related to development of metabolic syndrome and obesity. Cushing's syndrome caused by excess production of ACTH due to pituitary tumor, share clinical features to metabolic syndrome [24, 25]. In line with this, patients with metabolic syndrome seem to have anterior pituitary gland hyperactivity [5, 6].…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin negatively regulates pituitary ACTH secretion

2015

View full text Add to dashboard Cite

Erythropoietin (Epo) and Epo-receptor (EpoR) signaling, in addition to its classical role in erythropoiesis, exhibit a protective response in non-hematopoietic tissues. Mice with EpoR expression restricted to only hematopoietic tissues (ΔEpoRE), become obese, have low energy expenditure, and are glucose intolerant and insulin resistant. In the arcuate nucleus of the mouse hypothalamus, EpoR expression co-localizes in proopiomelanocortin (POMC) neurons. In vivo high-dose Epo treatment increases hypothalamus POMC, reduces food intake and fat mass accumulation. Here we report that Epo treatment also decreases plasma concentration of the pituitary derived POMC peptide, adrenocorticotropic hormone (ACTH). Conversely, ΔEpoRE mice show reduced hypothalamus POMC and high plasma concentrations of ACTH. In the pituitary, POMC is synthesized in the corticotroph cells, and here we examine Epo effect on pituitary POMC expression using the AtT-20 mouse corticotroph pituitary cell line. In AtT-20 cells, enzyme immunoassay analysis showed that Epo inhibits ACTH secretion. This effect is post-translational, as Epo treatment did not affect POMC mRNA expression but increased intracellular levels of ACTH peptide. Moreover, Epo reduced the basal intracellular calcium (Ca2+) levels, suggesting an effect in the Ca2+-signaling pathway. In summary, our studies suggest a novel regulatory pathway of ACTH secretion in the pituitary via EpoR-signaling. The higher plasma ACTH level in ΔEpoRE mice also suggests a possible mechanism of deregulated pituitary function with loss of Epo-signaling.

show abstract

Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

Cited by 13 publications

References 62 publications

Genome-epigenome interactions associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Genome-epigenome interactions associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Synaptic mechanisms of adenosine A_2A receptor‐mediated hyperexcitability in the hippocampus

Erythropoietin negatively regulates pituitary ACTH secretion

Contact Info

Product

Resources

About

Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

Cited by 13 publications

References 62 publications

Genome-epigenome interactions associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Genome-epigenome interactions associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Synaptic mechanisms of adenosine A2A receptor‐mediated hyperexcitability in the hippocampus

Erythropoietin negatively regulates pituitary ACTH secretion

Contact Info

Product

Resources

About

Synaptic mechanisms of adenosine A_2A receptor‐mediated hyperexcitability in the hippocampus