Distribution of cells responsive to 5-HT6 receptor antagonist-induced hypophagia

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5-HT obesity medication efficacy via POMC activation is maintained during aging

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Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice

Acknowledgments We thank Luca Giordano, Giovanni Esposito and Angelo Russo for technical assistance and Dr. Livio Luongo (Second University of Naples–Italy) for critical discussions. This work was supported by a Grant PRIN from Ministry of Education, Universities and Research (MIUR), Italy, to A.C. and the Wellcome Trust (WT098012) to L.K.H. and BBSRC (BB/K001418/1) to L.K.H. and G.D’A. G.D’A. received partial supports from a “FORGIARE” post-doctoral fellowship cofounded by the Polo delle Scienze e Tecnologie per la Vita, University of Naples Federico II and Compagnia di San Paolo Foundation, Turin, Italy (2010–2012).Peer reviewedPublisher PD

A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

We gratefully acknowledge Dr F. Naneix for advice on optogenetics and editorial advice, and staff within the University of Aberdeen Medical Research Facility and the Microscopy Facility for their technical assistance. This work was supported by the ERC (MSCA-IF-NeuroEE538 660219) to PBM, Wellcome Trust Institutional Strategic Support Fund (204815/Z/16/Z) to PBM and LKH, and the Biotechnology and Biological Sciences Research Council (BB/V010557/1) to JAG and (BB/V016849/1) to LKH and SS. GKCD is funded by a BBSRC CASE 4-year PhD studentship, co-funded by Novo Nordisk. GSHY is funded by the UK Medical Research Council (MC_UU_00014/1).Publisher PD

A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

Open Access via the Elsevier Open Access Agreement. We gratefully acknowledge Dr F. Naneix for advice on optogenetics and editorial advice, and staff within the University of Aberdeen Medical Research Facility and the Microscopy Facility for their technical assistance. This work was supported by the ERC (MSCA-IF-NeuroEE-660219) to PBM, Wellcome Trust Institutional Strategic Support Fund (204815/Z/16/Z) to PBM and LKH, and the Biotechnology and Biological Sciences Research Council (BB/V010557/1) to JAG and (BB/V016849/1) to LKH and SS. GKCD is funded by a BBSRC CASE 4-year PhD studentship, co-funded by Novo Nordisk. GSHY is funded by the UK Medical Research Council (MC_UU_00014/1).Peer reviewe

Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice

Acknowledgments and Disclosures This work was supported by the National Institutes of Health (Grant Nos. R01DK093587 and R01DK101379 [to YX], R01DK092605 to [QT], R01DK078056 [to MM]), the Klarman Family Foundation (to YX), the Naman Family Fund for Basic Research (to YX), Curtis Hankamer Basic Research Fund (to YX), American Diabetes Association (Grant Nos. 7-13-JF-61 [to QW] and 1-15-BS-184 [to QT]), American Heart Association postdoctoral fellowship (to PX), Wellcome Trust (Grant No. WT098012 [to LKH]), and Biotechnology and Biological Sciences Research Council (Grant No. BB/K001418/1 [to LKH]). The anxiety tests (e.g., open-field test, light-dark test, elevated plus maze test) were performed in the Mouse Neurobehavior Core, Baylor College of Medicine, which was supported by National Institutes of Health Grant No. P30HD024064. PX and YH were involved in experimental design and most of the procedures, data acquisition and analyses, and writing the manuscript. XC assisted in the electrophysiological recordings; LV-T assisted in the histology study; XY, KS, CW, YY, AH, LZ, and GS assisted in surgical procedures and production of study mice. MGM, QW, QT, and LKH were involved in study design and writing the manuscript. YX is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors report no biomedical financial interests or potential conflicts of interest.Peer reviewedPublisher PD

Brain glucose sensors play a significant role in the regulation of pancreatic glucose-stimulated insulin secretion.

As patients decline from health to type 2 diabetes, glucose-stimulated insulin secretion (GSIS) typically becomes impaired. Although GSIS is driven predominantly by direct sensing of a rise in blood glucose by pancreatic β-cells, there is growing evidence that hypothalamic neurons control other aspects of peripheral glucose metabolism. Here we investigated the role of the brain in the modulation of GSIS. To examine the effects of increasing or decreasing hypothalamic glucose sensing on glucose tolerance and insulin secretion, glucose or inhibitors of glucokinase, respectively, were infused into the third ventricle during intravenous glucose tolerance tests (IVGTTs). Glucose-infused rats displayed improved glucose handling, particularly within the first few minutes of the IVGTT, with a significantly lower area under the excursion curve within the first 10 min (AUC0-10). This was explained by increased insulin secretion. In contrast, infusion of the glucokinase inhibitors glucosamine or mannoheptulose worsened glucose tolerance and decreased GSIS in the first few minutes of IVGTT. Our data suggest a role for brain glucose sensors in the regulation of GSIS, particularly during the early phase. We propose that pharmacological agents targeting hypothalamic glucose-sensing pathways may represent novel therapeutic strategies for enhancing early phase insulin secretion in type 2 diabetes

5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication:an effect mediated via increased proportion of pro-opiomelanocortin neurons activated

An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (∼25% each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity of ARC POMC neurons by revealing distinct subpopulations of POMC cells activated by 5-HT2CRs and disinhibited by 5-HT1BRs. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment

Recurrent Hypoglycemia Is Associated with Loss of Activation in Rat Brain Cingulate Cortex

A subset of people with diabetes fail to mount defensive counterregulatory responses (CRR) to hypoglycemia. Although the mechanisms by which this occurs remain unclear, recurrent exposure to hypoglycemia may be an important etiological factor. We hypothesized that loss of CRR to recurrent exposure to hypoglycemia represents a type of stress desensitization, in which limbic brain circuitry involved in modulating stress responses might be implicated. Here, we compared activation of limbic brain regions associated with stress desensitization during acute hypoglycemia (AH) and recurrent hypoglycemia (RH). Healthy Sprague Dawley rats were exposed to either acute or recurrent 3-d hypoglycemia. We also examined whether changes in neuronal activation were caused directly by the CRR itself by infusing epinephrine, glucagon, and corticosterone without hypoglycemia. AH increased neuronal activity as quantified by c-fos immunoreactivity (FOS-IR) in the cingulate cortex and associated ectorhinal and perirhinal cortices but not in an adjacent control area (primary somatosensory cortex). FOS-IR was not observed after hormone infusion, suggesting that AH-associated activation was caused by hypoglycemia rather than by CRR. Importantly, AH FOS-IR activation was significantly blunted in rats exposed to RH. In conclusion, analogous with other models of stress habituation, activation in the cingulate cortex and associated brain areas is lost with exposure to RH. Our data support the hypothesis that limbic brain areas may be associated with the loss of CRR to RH in diabetes

Specific Subpopulations of Hypothalamic Leptin Receptor-Expressing Neurons Mediate the Effects of Early Developmental Leptin Receptor Deletion on Energy Balance

ACKNOWLEDGEMENTS We thank MedImmune, Inc. and James Trevaskis, PhD and Christopher Rhodes, PhD for the gift of leptin. We thank members of the Myers and Olson labs for helpful discussions. Research support was provided by the Michigan Diabetes Research Center (NIH P3 0 DK020572, including the Molecular Genetics, Animal Phenotyping, and Clinical Cores), the American Diabetes Association (MGM), the Marilyn H. Vincent Foundation (MGM), the NIH (MGM: D K05673 1; ACR:DK071212; MBA: DK097861), the BBSRC (LKH: BB/NO17838/1) and WellcomeTrust (LKH: 098012).Peer reviewedPublisher PD