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

A Leptin-regulated Circuit Controls Glucose Mobilization During Noxious Stimuli

Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor–expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores

An Osteoblast-dependent Mechanism Contributes to the Leptin Regulation of Insulin Secretion

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72661/1/j.1749-6632.2009.05061.x.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/72661/2/NYAS_5061_sm_SuppMat.pd

Increased hepatic insulin sensitivity in mice lacking inhibitory leptin receptor signals

Leptin regulates food intake and energy expenditure by activating the long form of the leptin receptor (LepRb). Leptin also regulates glucose homeostasis by improving whole-body insulin sensitivity, but the mechanism remains undefined. Leptin action is mediated by phosphorylation of several tyrosine residues on LepRb. LepRb-Tyr985 plays an important role in the attenuation of LepRb signaling. We determined the contribution of LepRb-Tyr985-mediated signals to leptin action on insulin sensitivity using LepRb-Tyr985 mutant mice (l/l mice). Glucose tolerance and whole-body insulin-mediated glucose utilization were determined in wild-type (+/+) and l/l mice. Glucose tolerance was unaltered between female +/+ and l/l mice but enhanced in the male l/l mice. Serum insulin concentration was decreased at baseline and 15 min after a glucose injection in female l/l vs. +/+ mice (P < 0.05) but unaltered in the male l/l mice. However, basal and insulin-stimulated glucose transport in isolated soleus and extensor digitorum longus muscle was similar between +/+ and l/l mice, indicating skeletal muscle insulin sensitivity in vitro was not enhanced. Moreover, euglycemic-hyperinsulinemic clamps reveal hepatic, rather than peripheral, insulin sensitivity is enhanced in female l/l mice, whereas male l/l mice display both improved hepatic and peripheral insulin sensitivity. In conclusion, signals emanating from leptin receptor Tyr985 control hepatic insulin sensitivity in both female and male l/l mice. Lack of LepRb-Tyr985 signaling enhances whole-body insulin sensitivity partly through increased insulin action on the suppression of hepatic glucose production

Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Leptin directly suppresses the activity of orexigenic neurons in the hypothalamic arcuate nucleus (ARC). We examined c-Fos-like immunoreactivity (CFLIR) as a marker of ARC neuronal activity in db/db mice devoid of the signaling form of the leptin receptor (LRb) and s/s mice that express LRbS1138 [which is defective for STAT3 (signal transducer and activator of transcription) signaling]. Both db/db and s/s animals are hyperphagic and obese. This analysis revealed that CFLIR in agouti related peptide-expressing orexigenic ARC neurons is basally elevated in db/db but not s/s mice. Consistent with these observations, electrophysiologic evaluation of a small number of neurons in s/s animals suggested that leptin appropriately suppresses the frequency of IPSCs on ARC proopiomelanocortin (POMC) neurons that are mediated by the release of GABA from orexigenic ARC neurons. CFLIR in POMC neurons of s/s mice was also increased compared with db/db animals. Thus, these data suggest that, although LRb→STAT3 signaling is crucial for the regulation of feeding, it is not required for the acute or chronic regulation of orexigenic ARC neurons, and the activation of STAT3-mediated transcription by leptin is not required for the appropriate development of leptin responsiveness in these neurons

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

Incarcerated transmesosigmoid hernia presenting in a 60-year-old man: a case report

© 2008 Collins et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

The islet estrogen receptor-alpha is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes

The female steroid, 17beta-estradiol (E2), is important for pancreatic beta-cell function and acts via at least three estrogen receptors (ER), ERalpha, ERbeta, and the G-protein coupled ER (GPER). Using a pancreas-specific ERalpha knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERalphaKO (-)/(-)), we previously reported that islet ERalpha suppresses islet glucolipotoxicity and prevents beta-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERalpha to prevent beta-cell apoptosis in vivo. However, the contribution of the islet ERalpha to beta-cell survival in vivo, without the contribution of ERalpha in other tissues is still unclear. Using the PERalphaKO (-)/(-) mouse, we show that ERalpha mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERalpha elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERalphaKO (-)/(-) mice exhibited a predisposition to beta-cell destruction and insulin deficient diabetes. In male PERalphaKO (-)/(-) mice, exposure to E2 partially prevented alloxan-induced beta-cell destruction and diabetes. ERalpha mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERalpha mRNA by hyperglycemia was retained in insulin receptor-deficient beta-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERalpha expression acts to naturally protect beta-cells against oxidative injury

Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake

The authors wish to thank members of staff of the Medical Research Facility, University of Aberdeen, Ms. Raffaella Chianese and Dr. Susan Jalicy, for technical assistance. PX330 and PX552 plasmids were a gift from Prof. Feng Zhang (Massachusetts Institute of Technology, Massachusetts, USA). DREADD vectors were a gift from Prof. Bryan Roth (University of North Carolina at Chapel Hill, North Carolina, USA). PomcDsRED and PomcNEO mice were a gift from Prof. Malcolm Low (University of Michigan, Michigan, USA). Codes to analyze operant-responding for food were a gift from Dr. Vladimir Orduña Trujillo (National Autonomous University of Mexico, Mexico). This work was supported by the Wellcome Trust (L.K.H.; WT098012), Wellcome Trust and the University of Aberdeen (G.D.; 105625/Z/14/Z), Biotechnology and Biological Sciences Research Council (L.K.H., BB/K001418/1, BB/N017838/1; and J.J.R., BB/K017772/1), Medical Research Council (J.J.R., MR/L002620/1; G.D., MR/P009824/1; L.K.H., J.J.R., G.D., MC/PC/15077), British Society of Neuroendocrinology (G.D.), NIH and the Marilyn H. Vincent Foundation (M.G.M.; DK056731, DK034933).Peer reviewedPublisher PD

Hysteresis, Avalanches, and Disorder Induced Critical Scaling: A Renormalization Group Approach

We study the zero temperature random field Ising model as a model for noise and avalanches in hysteretic systems. Tuning the amount of disorder in the system, we find an ordinary critical point with avalanches on all length scales. Using a mapping to the pure Ising model, we Borel sum the $6-\epsilon$ expansion to $O(\epsilon^5)$ for the correlation length exponent. We sketch a new method for directly calculating avalanche exponents, which we perform to $O(\epsilon)$. Numerical exponents in 3, 4, and 5 dimensions are in good agreement with the analytical predictions.Comment: 134 pages in REVTEX, plus 21 figures. The first two figures can be obtained from the references quoted in their respective figure captions, the remaining 19 figures are supplied separately in uuencoded forma