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Naiyan Chen, Hiroki Sugihara, Jinah Kim, Zhanyan Fu, Boaz Barak, Mriganka Sur, Guoping Feng, Weiping Han
Multiple hypothalamic neuronal populations that regulate energy balance have been identified. Although hypothalamic glia exist in abundance and form intimate structural connections with neurons, their roles in energy homeostasis are less known. Here we show that selective Ca(2+) activation of glia in the mouse arcuate nucleus (ARC) reversibly induces increased food intake while disruption of Ca(2+) signaling pathway in ARC glia reduces food intake. The specific activation of ARC glia enhances the activity of agouti-related protein/neuropeptide Y (AgRP/NPY)-expressing neurons but induces no net response in pro-opiomelanocortin (POMC)-expressing neurons...
October 18, 2016: ELife
S Pauliina Markkula, David Lyons, Chen-Yu Yueh, Christine Riches, Paul Hurst, Barbara Fielding, Lora K Heisler, Mark L Evans
Specialized metabolic-sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counter regulatory responses. Hypothalamic reactive oxygen species (ROS) may act as a metabolic signal mediating responses to changes in glucose, other substrates and hormones. The role of ROS in the brain's control of glucose homeostasis remains unclear. We hypothesized that hydrogen peroxide (H2O2), a relatively stable form of ROS, acts as a sensor of neuronal glucose consumption and availability and that lowering brain H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose...
October 14, 2016: Endocrinology
Dongyun Zhang, Marvin Bergsneider, Marilene B Wang, Anthony P Heaney
We recently demonstrated that the orphan nuclear receptor testicular receptor 4 (TR4) is a potent regulator of corticotroph tumor growth and hormone secretion. The Ras/Raf/MEK/ERK pathway is commonly overactivated in human tumors and we have demonstrated that corticotroph tumor TR4 is activated by ERK1/2-mediated phosphorylation. We evaluated effects of MEK-162, a selective, non-ATP-competitive allosteric inhibitor of MEK1/2, on murine and human in vitro and in vivo corticotroph tumor proliferation and adrenocorticotrophic hormone (ACTH) secretion...
September 30, 2016: Oncotarget
Miranda D Johnson, Sebastien G Bouret, Ambrose A Dunn-Meynell, Christina Neuner Boyle, Thomas A Lutz, Barry E Levin
Selectively bred diet-induced obese (DIO) rats become obese on a high fat diet and are leptin resistant before becoming obese. As compared to diet-resistant (DR) neonates, DIO neonates have impaired leptin-dependent arcuate (ARC) neuropeptide Y/agouti-related peptide (NPY/AgRP) and α-melanocyte-stimulating hormone (αMSH; from pro-opiomelanocortin (POMC) neurons) axon outgrowth to the paraventricular nucleus (PVN). Using phosphorylation of STAT3 (pSTAT3) as a surrogate, we show that reduced DIO ARC leptin signaling develops by postnatal day 7 (P7) and is reduced within POMC, but not NPY/AgRP neurons...
September 14, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Yi Zhu, Yong Gao, Caroline Tao, Mengle Shao, Shangang Zhao, Wei Huang, Ting Yao, Joshua A Johnson, Tiemin Liu, Aaron M Cypess, Olga Gupta, William L Holland, Rana K Gupta, David C Spray, Herbert B Tanowitz, Lei Cao, Matthew D Lynes, Yu-Hua Tseng, Joel K Elmquist, Kevin W Williams, Hua V Lin, Philipp E Scherer
"Beige" adipocytes reside in white adipose tissue (WAT) and dissipate energy as heat. Several studies have shown that cold temperature can activate pro-opiomelanocortin-expressing (POMC) neurons and increase sympathetic neuronal tone to regulate WAT beiging. WAT, however, is traditionally known to be sparsely innervated. Details regarding the neuronal innervation and, more importantly, the propagation of the signal within the population of "beige" adipocytes are sparse. Here, we demonstrate that beige adipocytes display an increased cell-to-cell coupling via connexin 43 (Cx43) gap junction channels...
September 13, 2016: Cell Metabolism
Seong Lin Teoh, Srijit Das
Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death...
September 14, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Julie-Ann P De Bond, Kristen P Tolson, Chanond Nasamran, Alexander S Kauffman, Jeremy T Smith
Kisspeptin controls reproduction by stimulating GnRH neurons via its receptor Kiss1r. Kiss1r is also expressed other brain areas and in peripheral tissues, suggesting additional non-reproductive roles. We recently determined that Kiss1r knockout (KO) mice develop an obese and diabetic phenotype. Here, we investigated whether Kiss1r KOs develop this metabolic phenotype due to alterations in the expression of metabolic genes involved in the appetite regulating system of the hypothalamus, including neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc), as well as leptin receptor (Lepr), ghrelin receptor (Ghsr), and melanocortin receptor 3 and 4 (Mc3r, Mc4r)...
September 7, 2016: Journal of Neuroendocrinology
Peter Kühnen, Daniela Handke, Robert A Waterland, Branwen J Hennig, Matt Silver, Anthony J Fulford, Paula Dominguez-Salas, Sophie E Moore, Andrew M Prentice, Joachim Spranger, Anke Hinney, Johannes Hebebrand, Frank L Heppner, Lena Walzer, Carsten Grötzinger, Jörg Gromoll, Susanna Wiegand, Annette Grüters, Heiko Krude
The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritability." We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI...
September 13, 2016: Cell Metabolism
Yuzhong Xiao, Tingting Xia, Junjie Yu, Yalan Deng, Hao Liu, Bin Liu, Shanghai Chen, Yong Liu, Feifan Guo
Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue...
August 2016: Open Biology
Xianyong Ma, Wei Fang, Zongyong Jiang, Li Wang, Xuefen Yang, Kaiguo Gao
BACKGROUND: The mechanism of db-cAMP regulating fat deposition and improving lean percentage is unclear and needs to be further studied. METHODS: Eighteen 100-day-old Duroc × Landrance × Large White barrows (49.75 ± 0.75 kg) were used for experiment 1, and 15 eighteen 135-day-old barrows (78.34 ± 1.22 kg) were used for experiment 2 to investigate the effects of dietary dibutyryl-cAMP (db-cAMP) on fat deposition in finishing pigs. Pigs were fed with a corn-soybean meal-based diet supplemented with 0 or 15 mg/kg db-cAMP, and both experiments lasted 35 days, respectively...
2016: Genes & Nutrition
Xiaobing Zhang, Anthony N van den Pol
Energy homeostasis, food intake, and body weight are regulated by specific brain circuits. Here we introduce an unexpected neuron, the tyrosine hydroxylase (TH) neuron of the arcuate nucleus (ARC), that we show makes an orexigenic contribution. Optogenetic stimulation of mouse ARC TH neurons increased food intake; attenuating transmitter release reduced body weight. Optogenetic stimulation of ARC TH cells inhibited pro-opiomelanocortin (POMC) neurons through synaptic mechanisms. ARC TH cells project to the hypothalamic paraventricular nucleus; optogenetic stimulation of ARC TH axons inhibited paraventricular nucleus neurons by dopamine and GABA co-release...
October 2016: Nature Neuroscience
Maria Cernea, Rebecca Phillips, Vasantha Padmanabhan, Lique M Coolen, Michael N Lehman
Insulin serves as a link between the metabolic and reproductive systems, communicating energy availability to the hypothalamus and enabling reproductive mechanisms. Adult Suffolk ewes prenatally exposed to testosterone (T) display an array of reproductive and metabolic dysfunctions similar to those seen in women with polycystic ovarian syndrome (PCOS), including insulin resistance. Moreover, prenatal T treatment alters neuropeptide expression in KNDy (co-expressing kisspeptin, neurokinin B/dynorphin) and agouti-related peptide (AgRP) neurons in the arcuate nucleus, two populations that play key roles in the control of reproduction and metabolism, respectively...
October 2016: European Journal of Neuroscience
Tae Seok Oh, Hanchae Cho, Jae Hyun Cho, Seong-Woon Yu, Eun-Kyoung Kim
Hypothalamic AMP-activated protein kinase (AMPK) plays important roles in the regulation of food intake by altering the expression of orexigenic or anorexigenic neuropeptides. However, little is known about the mechanisms of this regulation. Here, we report that hypothalamic AMPK modulates the expression of NPY (neuropeptide Y), an orexigenic neuropeptide, and POMC (pro-opiomelanocortin-alpha), an anorexigenic neuropeptide, by regulating autophagic activity in vitro and in vivo. In hypothalamic cell lines subjected to low glucose availability such as 2-deoxy-d-glucose (2DG)-induced glucoprivation or glucose deprivation, autophagy was induced via the activation of AMPK, which regulates ULK1 and MTOR complex 1 followed by increased Npy and decreased Pomc expression...
August 17, 2016: Autophagy
Claudia Fischer, Tanja Mueller, Martina Pfeffer, Helmut Wicht, Charlotte von Gall, Horst-Werner Korf
BACKGROUND/METHODS: Melatonin, the neurohormone for darkness, mediates photoperiod dependent changes in physiology and behavior by targeting specific membrane bound receptors (MT1 and MT2). In the present study, we investigated the impact of MT1 receptor-deficiency on feeding behavior, locomotor activity and mRNA expression levels encoding for the polypeptide Pomc and neuropeptide Y (Npy) in the hypothalamic arcuate nucleus (ARC) and the adenohypophysis (pars distalis, PD and pars intermedia, PI) in a comparison between wild-type (WT) and MT1-deficient (MT1-/-) mice...
August 5, 2016: Neuroendocrinology
María F Andreoli, Cora Stoker, Gisela P Lazzarino, Guillermina Canesini, Enrique H Luque, Jorge G Ramos
Removing dietary phyto-oestrogens in adult male rats causes obesity and diabetes. As whey proteins have been reported to reduce food intake and improve glucose homoeostasis, we investigated whether they could attenuate susceptibility to obesity and diabetes due to phyto-oestrogen deprivation. To this end, thirty male Wistar rats were fed a high-phyto-oestrogen (HP) or a phyto-oestrogen-free (PF) diet for 10 weeks; six rats from each group were killed. The remaining HP animals (six animals) continued receiving the HP diet for 6 weeks...
September 2016: British Journal of Nutrition
Timo D Müller, Matthias H Tschöp, Stephen O'Rahilly
Pro-opiomelanocortin deficiency is a rare cause of severe intractable obesity. Two patients have experienced dramatic weight loss in response to setmelanotide, a melanocortin-4 receptor activator. The drug has potential in broader populations, but caution is warranted as it may act at other melanocortin receptors.
August 9, 2016: Cell Metabolism
Sakda D Hewagalamulage, Iain J Clarke, Alexandra Rao, Belinda A Henry
Within any population, the cortisol response to ACTH covers a considerable range. High responders (HRs) exhibit a greater cortisol secretory response to stress or ACTH, compared with individuals classified as low cortisol responders (LRs). We administered ACTH (0.2 μg/kg, iv) to 160 female sheep and selected subpopulations of animals as LR and HR. In the present study, we aimed to characterize the hypothalamo-pituitary-adrenal axis in HR and LR and to identify factors that underlie the differing cortisol responses to ACTH...
September 2016: Endocrinology
Jonathan F Gill, Julien Delezie, Gesa Santos, Christoph Handschin
OBJECTIVE: Food intake and whole-body energy homeostasis are controlled by agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus of the hypothalamus. Key energy sensors, such as the AMP-activated protein kinase (AMPK) or sirtuin 1 (SIRT1), are essential in AgRP and POMC cells to ensure proper energy balance. In peripheral tissues, the transcriptional coactivator PGC-1α closely associates with these sensors to regulate cellular metabolism...
July 2016: Molecular Metabolism
Zhaiyi Zhang, Manli Shen, Paul J Gresch, Masoud Ghamari-Langroudi, Alexander G Rabchevsky, Ronald B Emeson, Stefan Stamm
The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full-length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full-length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full-length, constitutively active receptor at the cell surface...
2016: EMBO Molecular Medicine
Vineet C Chitravanshi, Kazumi Kawabe, Hreday N Sapru
Hypothalamic arcuate nucleus (ARCN) stimulation elicited increases in sympathetic nerve activity (IBATSNA) and temperature (TBAT) of interscapular brown adipose tissue (IBAT). The role of hypothalamic dorsomedial (DMN) and paraventricular (PVN) nuclei in mediating these responses was studied in urethane-anesthetized, artificially ventilated, male Wistar rats. In different groups of rats, inhibition of neurons in the DMN and PVN by microinjections of muscimol attenuated the increases in IBATSNA and TBAT elicited by microinjections of N-methyl-d-aspartic acid into the ipsilateral ARCN...
August 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
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