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https://www.readbyqxmd.com/read/27789403/induced-pluripotent-stem-cells-ipsc-created-from-skin-fibroblasts-of-patients-with-prader-willi-syndrome-pws-retain-the-molecular-signature-of-pws
#1
Lisa C Burnett, Charles A LeDuc, Carlos R Sulsona, Daniel Paull, Sanaa Eddiry, Brynn Levy, Jean Pierre Salles, Maithe Tauber, Daniel J Driscoll, Dieter Egli, Rudolph L Leibel
Prader-Willi syndrome (PWS) is a syndromic obesity caused by loss of paternal gene expression in an imprinted interval on 15q11.2-q13. Induced pluripotent stem cells were generated from skin cells of three large deletion PWS patients and one unique microdeletion PWS patient. We found that genes within the PWS region, including SNRPN and NDN, showed persistence of DNA methylation after iPSC reprogramming and differentiation to neurons. Genes within the PWS minimum critical deletion region remain silenced in both PWS large deletion and microdeletion iPSC following reprogramming...
August 16, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27460711/models-of-energy-homeostasis-in-response-to-maintenance-of-reduced-body-weight
#2
Michael Rosenbaum, Rudolph L Leibel
OBJECTIVE: To test three proposed models for adaptive thermogenesis in compartments of energy expenditure following different degrees of weight loss. Specifically, (1) there is no adaptive thermogenesis [constant relationship of energy expenditure (EE) to metabolic mass]. (2) There is a fixed degree of adaptive thermogenesis once fat stores are below a "threshold." (3) The degree of adaptive thermogenesis is proportional to weight loss. METHODS: The relationship between weight loss and EE was examined in 17 inpatient subjects with stable weight and obesity studied at usual weight and again following a 10% and a 20% weight loss...
August 2016: Obesity
https://www.readbyqxmd.com/read/27385608/energy-expenditure-and-body-composition-changes-after-an-isocaloric-ketogenic-diet-in-overweight-and-obese-men
#3
Kevin D Hall, Kong Y Chen, Juen Guo, Yan Y Lam, Rudolph L Leibel, Laurel Es Mayer, Marc L Reitman, Michael Rosenbaum, Steven R Smith, B Timothy Walsh, Eric Ravussin
BACKGROUND: The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat...
August 2016: American Journal of Clinical Nutrition
https://www.readbyqxmd.com/read/27367166/efficient-generation-of-hypothalamic-neurons-from-human-pluripotent-stem-cells
#4
Liheng Wang, Dieter Egli, Rudolph L Leibel
The hypothalamus comprises neuronal clusters that are essential for body weight regulation and other physiological functions. Insights into the complex cellular physiology of this region of the brain are critical to understanding the pathogenesis of obesity, but human hypothalamic cells are largely inaccessible for direct study. Here we describe a technique for generation of arcuate-like hypothalamic neurons from human pluripotent stem (hPS) cells. Early activation of SHH signaling and inhibition of BMP and TGFβ signaling, followed by timed inhibition of NOTCH, can efficiently differentiate hPS cells into NKX2...
2016: Current Protocols in Human Genetics
https://www.readbyqxmd.com/read/27353377/znf70-a-novel-ildr2-interacting-protein-contributes-to-the-regulation-of-hes1-gene-expression
#5
Kazuhisa Watanabe, Kazuhiro Nakayama, Satoshi Ohta, Kenji Tago, Supichaya Boonvisut, Elizabeth J Millings, Stuart G Fischer, Charles A LeDuc, Rudolph L Leibel, Sadahiko Iwamoto
A diabetes susceptibility gene, immunoglobulin-like domain containing receptor 2 (Ildr2), encodes a transmembrane protein localized to the endoplasmic reticulum membrane that is closely related to hepatic lipid metabolism. The livers of ob/ob mice in which Ildr2 is transiently overexpressed are relieved of hepatic steatosis. However, the molecular mechanisms through which ILDR2 affects these changes in hepatic lipid metabolism remain unknown. This study aimed to identify ILDR2-interacting proteins to further elucidate the molecular mechanisms underlying the role of ILDR2 in lipid homeostasis...
September 2, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27064284/hypomorphism-of-fto-and-rpgrip1l-causes-obesity-in-mice
#6
George Stratigopoulos, Lisa Cole Burnett, Richard Rausch, Richard Gill, David Barth Penn, Alicja A Skowronski, Charles A LeDuc, Anthony J Lanzano, Pumin Zhang, Daniel R Storm, Dieter Egli, Rudolph L Leibel
Noncoding polymorphisms in the fat mass and obesity-associated (FTO) gene represent common alleles that are strongly associated with effects on food intake and adiposity in humans. Previous studies have suggested that the obesity-risk allele rs8050136 in the first intron of FTO alters a regulatory element recognized by the transcription factor CUX1, thereby leading to decreased expression of FTO and retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Here, we evaluated the effects of rs8050136 and another potential CUX1 element in rs1421085 on expression of nearby genes in human induced pluripotent stem cell-derived (iPSC-derived) neurons...
May 2, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/26833098/genome-wide-meta-analysis-uncovers-novel-loci-influencing-circulating-leptin-levels
#7
Tuomas O Kilpeläinen, Jayne F Martin Carli, Alicja A Skowronski, Qi Sun, Jennifer Kriebel, Mary F Feitosa, Åsa K Hedman, Alexander W Drong, James E Hayes, Jinghua Zhao, Tune H Pers, Ursula Schick, Niels Grarup, Zoltán Kutalik, Stella Trompet, Massimo Mangino, Kati Kristiansson, Marian Beekman, Leo-Pekka Lyytikäinen, Joel Eriksson, Peter Henneman, Jari Lahti, Toshiko Tanaka, Jian'an Luan, Fabiola Del Greco M, Dorota Pasko, Frida Renström, Sara M Willems, Anubha Mahajan, Lynda M Rose, Xiuqing Guo, Yongmei Liu, Marcus E Kleber, Louis Pérusse, Tom Gaunt, Tarunveer S Ahluwalia, Yun Ju Sung, Yolande F Ramos, Najaf Amin, Antoinette Amuzu, Inês Barroso, Claire Bellis, John Blangero, Brendan M Buckley, Stefan Böhringer, Yii-Der I Chen, Anton J N de Craen, David R Crosslin, Caroline E Dale, Zari Dastani, Felix R Day, Joris Deelen, Graciela E Delgado, Ayse Demirkan, Francis M Finucane, Ian Ford, Melissa E Garcia, Christian Gieger, Stefan Gustafsson, Göran Hallmans, Susan E Hankinson, Aki S Havulinna, Christian Herder, Dena Hernandez, Andrew A Hicks, David J Hunter, Thomas Illig, Erik Ingelsson, Andreea Ioan-Facsinay, John-Olov Jansson, Nancy S Jenny, Marit E Jørgensen, Torben Jørgensen, Magnus Karlsson, Wolfgang Koenig, Peter Kraft, Joanneke Kwekkeboom, Tiina Laatikainen, Karl-Heinz Ladwig, Charles A LeDuc, Gordon Lowe, Yingchang Lu, Pedro Marques-Vidal, Christa Meisinger, Cristina Menni, Andrew P Morris, Richard H Myers, Satu Männistö, Mike A Nalls, Lavinia Paternoster, Annette Peters, Aruna D Pradhan, Tuomo Rankinen, Laura J Rasmussen-Torvik, Wolfgang Rathmann, Treva K Rice, J Brent Richards, Paul M Ridker, Naveed Sattar, David B Savage, Stefan Söderberg, Nicholas J Timpson, Liesbeth Vandenput, Diana van Heemst, Hae-Won Uh, Marie-Claude Vohl, Mark Walker, Heinz-Erich Wichmann, Elisabeth Widén, Andrew R Wood, Jie Yao, Tanja Zeller, Yiying Zhang, Ingrid Meulenbelt, Margreet Kloppenburg, Arne Astrup, Thorkild I A Sørensen, Mark A Sarzynski, D C Rao, Pekka Jousilahti, Erkki Vartiainen, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Eero Kajantie, Clive Osmond, Aarno Palotie, Johan G Eriksson, Markku Heliövaara, Paul B Knekt, Seppo Koskinen, Antti Jula, Markus Perola, Risto K Huupponen, Jorma S Viikari, Mika Kähönen, Terho Lehtimäki, Olli T Raitakari, Dan Mellström, Mattias Lorentzon, Juan P Casas, Stefanie Bandinelli, Winfried März, Aaron Isaacs, Ko W van Dijk, Cornelia M van Duijn, Tamara B Harris, Claude Bouchard, Matthew A Allison, Daniel I Chasman, Claes Ohlsson, Lars Lind, Robert A Scott, Claudia Langenberg, Nicholas J Wareham, Luigi Ferrucci, Timothy M Frayling, Peter P Pramstaller, Ingrid B Borecki, Dawn M Waterworth, Sven Bergmann, Gérard Waeber, Peter Vollenweider, Henrik Vestergaard, Torben Hansen, Oluf Pedersen, Frank B Hu, P Eline Slagboom, Harald Grallert, Tim D Spector, J W Jukema, Robert J Klein, Erik E Schadt, Paul W Franks, Cecilia M Lindgren, Rudolph L Leibel, Ruth J F Loos
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO...
February 1, 2016: Nature Communications
https://www.readbyqxmd.com/read/26370678/cross-sectional-and-test-retest-characterization-of-pet-with-18-f-fp-dtbz-for-%C3%AE-cell-mass-estimates-in-diabetes
#8
Matthew J Freeby, Patricia Kringas, Robin S Goland, Rudolph L Leibel, Antonella Maffei, Chaitan Divgi, Masanori Ichise, Paul E Harris
PURPOSE: The vesicular monoamine transporter, type 2 (VMAT2) is expressed by insulin producing β cells and was evaluated as a biomarker of β cell mass (BCM) by positron emission tomography (PET) with [(18)F]fluoropropyl-dihydrotetrabenazine ([(18)F]FP-(+)-DTBZ). PROCEDURES: We evaluated the feasibility of longitudinal pancreatic PET VMAT2 quantification in the pancreas in two studies of healthy controls and patients with type 1 or 2 diabetes. VMAT2 binding potential (BPND) was estimated voxelwise using a reference tissue method in a cross-sectional study, followed by assessment of reproducibility using a test-retest paradigm...
April 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/26257300/the-gut-microbiota-in-human-energy-homeostasis-and-obesity
#9
REVIEW
Michael Rosenbaum, Rob Knight, Rudolph L Leibel
Numerous studies of rodents suggest that the gut microbiota populations are sensitive to genetic and environmental influences, and can produce or influence afferent signals that directly or indirectly impinge on energy homeostatic systems affecting both energy balance (weight gain or loss) and energy stores. Fecal transplants from obese and lean human, and from mouse donors to gnotobiotic mice, result in adoption of the donor somatotype by the formerly germ-free rodents. Thus, the microbiota is certainly implicated in the development of obesity, adiposity-related comorbidities, and the response to interventions designed to achieve sustained weight reduction in mice...
September 2015: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/26152765/proopiomelanocortin-agouti-related-protein-and-leptin-in-human-cerebrospinal-fluid-correlations-with-body-weight-and-adiposity
#10
Gabrielle Page-Wilson, Kana Meece, Anne White, Michael Rosenbaum, Rudolph L Leibel, Richard Smiley, Sharon L Wardlaw
Leptin and its neuronal targets, which produce proopiomelanocortin (POMC) and agouti-related protein (AgRP), regulate energy balance. This study characterized leptin, POMC, and AgRP in the cerebrospinal fluid (CSF) of 47 healthy human subjects, 23 lean and 24 overweight/obese (OW/OB), as related to BMI, adiposity, plasma leptin, soluble leptin receptor (s-OB-R), and insulin. POMC was measured since the POMC prohormone is the predominant POMC peptide in CSF and correlates with hypothalamic POMC in rodents. Plasma AgRP was similarly characterized...
September 1, 2015: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/26106187/biologic-responses-to-weight-loss-and-weight-regain-report-from-an-american-diabetes-association-research-symposium
#11
REVIEW
Rudolph L Leibel, Randy J Seeley, Tamara Darsow, Erika Gebel Berg, Steven R Smith, Robert Ratner
No abstract text is available yet for this article.
July 2015: Diabetes
https://www.readbyqxmd.com/read/25555215/differentiation-of-hypothalamic-like-neurons-from-human-pluripotent-stem-cells
#12
Liheng Wang, Kana Meece, Damian J Williams, Kinyui Alice Lo, Matthew Zimmer, Garrett Heinrich, Jayne Martin Carli, Charles A Leduc, Lei Sun, Lori M Zeltser, Matthew Freeby, Robin Goland, Stephen H Tsang, Sharon L Wardlaw, Dieter Egli, Rudolph L Leibel
The hypothalamus is the central regulator of systemic energy homeostasis, and its dysfunction can result in extreme body weight alterations. Insights into the complex cellular physiology of this region are critical to the understanding of obesity pathogenesis; however, human hypothalamic cells are largely inaccessible for direct study. Here, we developed a protocol for efficient generation of hypothalamic neurons from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) obtained from patients with monogenetic forms of obesity...
February 2015: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/25389133/retinoic-acid-receptor-signaling-is-required-to-maintain-glucose-stimulated-insulin-secretion-and-%C3%AE-cell-mass
#13
Pierre-Jacques Brun, Ambar Grijalva, Richard Rausch, Elizabeth Watson, Jason J Yuen, Bhaskar C Das, Koichi Shudo, Hiroyuki Kagechika, Rudolph L Leibel, William S Blaner
Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic β-cells of adult mice. atRA signaling was ablated in β-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-α mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in β-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge...
February 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/25295786/a-missing-link-in-body-weight-homeostasis-the-catabolic-signal-of-the-overfed-state
#14
REVIEW
Yann Ravussin, Rudolph L Leibel, Anthony W Ferrante
Mammals regulate fat mass so that increases or reductions in adipose tissue mass activate responses that favor return to one's previous weight. A reduction in fat mass activates a system that increases food intake and reduces energy expenditure; conversely, overfeeding and rapid adipose tissue expansion reduces food intake and increases energy expenditure. With the identification of leptin nearly two decades ago, the central circuit that defends against reductions in body fat was revealed. However, the systems that defend against rapid expansion of fat mass remain largely unknown...
October 7, 2014: Cell Metabolism
https://www.readbyqxmd.com/read/25190097/molecular-pathophysiology-of-metabolic-effects-of-antipsychotic-medications
#15
REVIEW
Jacob S Ballon, Utpal Pajvani, Zachary Freyberg, Rudolph L Leibel, Jeffrey A Lieberman
Antipsychotic medications are associated with major metabolic changes that contribute to medical morbidity and a significantly shortened life span. The mechanisms for these changes provide us with a broader understanding of central nervous and peripheral organ-mediated metabolic regulation. This paper reviews an extensive literature regarding putative mechanisms for effects of antipsychotic medications on weight regulation and glucose homeostasis as well as potential inherent metabolic risks of schizophrenia itself...
November 2014: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/25099551/the-threshold-shift-paradigm-of-obesity-evidence-from-surgically-induced-weight-loss
#16
COMPARATIVE STUDY
Ele Ferrannini, Michael Rosenbaum, Rudolph L Leibel
BACKGROUND: The high prevalence of obesity has called attention to the near-intractable problem of sustained weight reduction and its underlying mechanisms. With diet-induced weight loss, achieved body weight is closely related to initial body weight. OBJECTIVE: The objective was to compare the relation between initial and achieved body mass index (BMI) in patients treated with diet-induced weight loss or bariatric surgery. DESIGN: We analyzed data from a cohort of 223 healthy individuals who lost a mean (±SD) of 5 ± 3 kg body weight over 3 y by diet (diet group) and data from 182 obese individuals [BMI (in kg/m(2)) ≥35] who had lost an average of 47 ± 17 kg 1 y after Roux-en-Y gastric bypass (a restrictive procedure; n = 71) or biliopancreatic diversion (a malabsorptive procedure; n = 111) (surgery group)...
October 2014: American Journal of Clinical Nutrition
https://www.readbyqxmd.com/read/25063755/20-years-of-leptin-role-of-leptin-in-energy-homeostasis-in-humans
#17
REVIEW
Michael Rosenbaum, Rudolph L Leibel
The hyperphagia, low sympathetic nervous system tone, and decreased circulating concentrations of bioactive thyroid hormones that are common to states of congenital leptin deficiency and hypoleptinemia following and during weight loss suggest that the major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. In weight-reduced humans, these phenotypes together with pronounced hypometabolism and increased parasympathetic nervous system tone create the optimal circumstance for weight regain...
October 2014: Journal of Endocrinology
https://www.readbyqxmd.com/read/24979718/foxo1-inhibition-yields-functional-insulin-producing-cells-in-human-gut-organoid-cultures
#18
Ryotaro Bouchi, Kylie S Foo, Haiqing Hua, Kyoichiro Tsuchiya, Yoshiaki Ohmura, P Rodrigo Sandoval, Lloyd E Ratner, Dieter Egli, Rudolph L Leibel, Domenico Accili
Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor cells of mice can be differentiated into glucose-responsive, insulin-producing cells by ablation of transcription factor Foxo1. Here we show that FOXO1 is present in human gut endocrine progenitor and serotonin-producing cells...
June 30, 2014: Nature Communications
https://www.readbyqxmd.com/read/24807221/hypomorphism-for-rpgrip1l-a-ciliary-gene-vicinal-to-the-fto-locus-causes-increased-adiposity-in-mice
#19
George Stratigopoulos, Jayne F Martin Carli, Diana R O'Day, Liheng Wang, Charles A Leduc, Patricia Lanzano, Wendy K Chung, Michael Rosenbaum, Dieter Egli, Daniel A Doherty, Rudolph L Leibel
Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l⁺/⁻ mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration...
May 6, 2014: Cell Metabolism
https://www.readbyqxmd.com/read/24776804/human-oocytes-reprogram-adult-somatic-nuclei-of-a-type-1-diabetic-to-diploid-pluripotent-stem-cells
#20
Mitsutoshi Yamada, Bjarki Johannesson, Ido Sagi, Lisa Cole Burnett, Daniel H Kort, Robert W Prosser, Daniel Paull, Michael W Nestor, Matthew Freeby, Ellen Greenberg, Robin S Goland, Rudolph L Leibel, Susan L Solomon, Nissim Benvenisty, Mark V Sauer, Dieter Egli
The transfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistently equivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Although methods to induce pluripotent stem cells from somatic cells by transcription factors are widely used in basic research, numerous differences between induced pluripotent stem cells and embryonic stem cells have been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploid embryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematically investigated the parameters affecting efficiency of blastocyst development and stem-cell derivation...
June 26, 2014: Nature
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