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C. Ronald Kahn

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https://www.readbyqxmd.com/read/29724723/mice-carrying-a-dominant-negative-human-pi-3-kinase-mutation-are-protected-from-obesity-and-hepatic-steatosis-but-not-diabetes
#1
Marie H Solheim, Jonathon N Winnay, Thiago M Batista, Anders Molven, Pål R Njølstad, C Ronald Kahn
Phosphatidylinositol 3-kinase (PI3K) plays a central role in insulin signaling, glucose metabolism, cell growth, cell development, and apoptosis. A heterozygous missense mutation (R649W) in the p85α regulatory subunit gene of PI3K ( PIK3R1 ) has been identified in patients with SHORT syndrome - a disorder characterized by postnatal growth retardation, insulin resistance, and partial lipodystrophy. Knock-in mice with the same heterozygous mutation mirror the human phenotype. In this study, we show that when Pik3r1 R649W knock-in mice are fed a high-fat diet (HFD), they have reduced weight gain and adipose accumulation...
May 3, 2018: Diabetes
https://www.readbyqxmd.com/read/29681509/regional-differences-in-brain-glucose-metabolism-determined-by-imaging-mass-spectrometry
#2
André Kleinridders, Heather A Ferris, Michelle L Reyzer, Michaela Rath, Marion Soto, M Lisa Manier, Jeffrey Spraggins, Zhihong Yang, Robert C Stanton, Richard M Caprioli, C Ronald Kahn
OBJECTIVE: Glucose is the major energy substrate of the brain and crucial for normal brain function. In diabetes, the brain is subject to episodes of hypo- and hyperglycemia resulting in acute outcomes ranging from confusion to seizures, while chronic metabolic dysregulation puts patients at increased risk for depression and Alzheimer's disease. In the present study, we aimed to determine how glucose is metabolized in different regions of the brain using imaging mass spectrometry (IMS)...
April 6, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29664737/insulin-regulates-astrocyte-gliotransmission-and-modulates-behavior
#3
Weikang Cai, Chang Xue, Masaji Sakaguchi, Masahiro Konishi, Alireza Shirazian, Heather A Ferris, Mengyao Li, Ruichao Yu, Andre Kleinridders, Emmanuel N Pothos, C Ronald Kahn
Complications of diabetes affect tissues throughout body, including central nervous system. Epidemiological studies show that diabetic patients have increased risk of depression, anxiety, age-related cognitive decline and Alzheimer's disease. Mice lacking insulin receptor in brain or on hypothalamic neurons display an array of metabolic abnormalities, however, the role of insulin action on astrocytes and neurobehaviors remains less well-studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety and depressive-like behaviors in mice...
April 17, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29550500/distinct-signalling-properties-of-insulin-receptor-substrate-irs-1-and-irs-2-in-mediating-insulin-igf-1-action
#4
Atefeh Rabiee, Marcus Krüger, Jacob Ardenkjær-Larsen, C Ronald Kahn, Brice Emanuelli
Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type, IRS-1-/- and IRS-2-/- mice in the basal and IGF-1-stimulated states...
July 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29539432/diet-genetics-and-the-gut-microbiome-drive-dynamic-changes-in-plasma-metabolites
#5
Shiho Fujisaka, Julian Avila-Pacheco, Marion Soto, Aleksandar Kostic, Jonathan M Dreyfuss, Hui Pan, Siegfried Ussar, Emrah Altindis, Ning Li, Lynn Bry, Clary B Clish, C Ronald Kahn
Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the mechanisms linking these factors, we performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ, and 129S6/SvEvTac mice on chow or a high-fat diet (HFD) and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism...
March 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29493547/divergent-effects-of-glucose-and-fructose-on-hepatic-lipogenesis-and-insulin-signaling
#6
Samir Softic, Manoj K Gupta, Guo-Xiao Wang, Shiho Fujisaka, Brian T O'Neill, Tata Nageswara Rao, Jennifer Willoughby, Carole Harbison, Kevin Fitzgerald, Olga Ilkayeva, Christopher B Newgard, David E Cohen, C Ronald Kahn
No abstract text is available yet for this article.
March 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29467286/viral-insulin-like-peptides-activate-human-insulin-and-igf-1-receptor-signaling-a-paradigm-shift-for-host-microbe-interactions
#7
Emrah Altindis, Weikang Cai, Masaji Sakaguchi, Fa Zhang, Wang GuoXiao, Fa Liu, Pierre De Meyts, Vasily Gelfanov, Hui Pan, Richard DiMarchi, C Ronald Kahn
Viruses are the most abundant biological entities and carry a wide variety of genetic material, including the ability to encode host-like proteins. Here we show that viruses carry sequences with significant homology to several human peptide hormones including insulin, insulin-like growth factors (IGF)-1 and -2, FGF-19 and -21, endothelin-1, inhibin, adiponectin, and resistin. Among the strongest homologies were those for four viral insulin/IGF-1-like peptides (VILPs), each encoded by a different member of the family Iridoviridae VILPs show up to 50% homology to human insulin/IGF-1, contain all critical cysteine residues, and are predicted to form similar 3D structures...
March 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29311303/pyruvate-induces-torpor-in-obese-mice
#8
Marion Soto, Lucie Orliaguet, Michelle L Reyzer, M Lisa Manier, Richard M Caprioli, C Ronald Kahn
Mice subjected to cold or caloric deprivation can reduce body temperature and metabolic rate and enter a state of torpor. Here we show that administration of pyruvate, an energy-rich metabolic intermediate, can induce torpor in mice with diet-induced or genetic obesity. This is associated with marked hypothermia, decreased activity, and decreased metabolic rate. The drop in body temperature correlates with the degree of obesity and is blunted by housing mice at thermoneutrality. Induction of torpor by pyruvate in obese mice relies on adenosine signaling and is accompanied by changes in brain levels of hexose bisphosphate and GABA as detected by mass spectroscopy-based imaging...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29241534/integrating-extracellular-flux-measurements-and-genome-scale-modeling-reveals-differences-between-brown-and-white-adipocytes
#9
Alfred K Ramirez, Matthew D Lynes, Farnaz Shamsi, Ruidan Xue, Yu-Hua Tseng, C Ronald Kahn, Simon Kasif, Jonathan M Dreyfuss
White adipocytes are specialized for energy storage, whereas brown adipocytes are specialized for energy expenditure. Explicating this difference can help identify therapeutic targets for obesity. A common tool to assess metabolic differences between such cells is the Seahorse Extracellular Flux (XF) Analyzer, which measures oxygen consumption and media acidification in the presence of different substrates and perturbagens. Here, we integrate the Analyzer's metabolic profile from human white and brown adipocytes with a genome-scale metabolic model to predict flux differences across the metabolic map...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/28985207/erratum-thermoneutral-housing-exacerbates-nonalcoholic-fatty-liver-disease-in-mice-and-allows-for-sex-independent-disease-modeling
#10
Daniel A Giles, Maria E Moreno-Fernandez, Traci E Stankiewicz, Simon Graspeuntner, Monica Cappelletti, David Wu, Rajib Mukherjee, Calvin C Chan, Matthew J Lawson, Jared Klarquist, Annika Sünderhauf, Samir Softic, C Ronald Kahn, Kerstin Stemmer, Yoichiro Iwakura, Bruce J Aronow, Rebekah Karns, Kris A Steinbrecher, Christopher L Karp, Rachel Sheridan, Shiva K Shanmukhappa, Damien Reynaud, David B Haslam, Christian Sina, Jan Rupp, Simon P Hogan, Senad Divanovic
This corrects the article DOI: 10.1038/nm.4346.
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28972537/divergent-effects-of-glucose-and-fructose-on-hepatic-lipogenesis-and-insulin-signaling
#11
Samir Softic, Manoj K Gupta, Guo-Xiao Wang, Shiho Fujisaka, Brian T O'Neill, Tata Nageswara Rao, Jennifer Willoughby, Carole Harbison, Kevin Fitzgerald, Olga Ilkayeva, Christopher B Newgard, David E Cohen, C Ronald Kahn
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake...
November 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28923931/endothelial-insulin-receptors-differentially-control-insulin-signaling-kinetics-in-peripheral-tissues-and-brain-of-mice
#12
Masahiro Konishi, Masaji Sakaguchi, Samuel M Lockhart, Weikang Cai, Mengyao Ella Li, Erica P Homan, Christian Rask-Madsen, C Ronald Kahn
Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28632845/iris-malformation-and-anterior-segment-dysgenesis-in-mice-and-humans-with-a-mutation-in-pi-3-kinase
#13
Marie H Solheim, Allen C Clermont, Jonathon N Winnay, Erlend Hallstensen, Anders Molven, Pål R Njølstad, Eyvind Rødahl, C Ronald Kahn
Purpose: To determine the ocular consequences of a dominant-negative mutation in the p85α subunit of phosphatidylinositol 3-kinase (PIK3R1) using a knock-in mouse model of SHORT syndrome, a syndrome associated with short stature, lipodystrophy, diabetes, and Rieger anomaly in humans. Methods: We investigated knock-in mice heterozygous for the SHORT syndrome mutation changing arginine 649 to tryptophan in p85α (PIK3R1) using physical examination, optical coherence tomography (OCT), tonometry, and histopathologic sections from paraffin-embedded eyes, and compared the findings to similar investigations in two human subjects with SHORT syndrome heterozygous for the same mutation...
June 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28604704/thermoneutral-housing-exacerbates-nonalcoholic-fatty-liver-disease-in-mice-and-allows-for-sex-independent-disease-modeling
#14
Daniel A Giles, Maria E Moreno-Fernandez, Traci E Stankiewicz, Simon Graspeuntner, Monica Cappelletti, David Wu, Rajib Mukherjee, Calvin C Chan, Matthew J Lawson, Jared Klarquist, Annika Sünderhauf, Samir Softic, C Ronald Kahn, Kerstin Stemmer, Yoichiro Iwakura, Bruce J Aronow, Rebekah Karns, Kris A Steinbrecher, Christopher L Karp, Rachel Sheridan, Shiva K Shanmukhappa, Damien Reynaud, David B Haslam, Christian Sina, Jan Rupp, Simon P Hogan, Senad Divanovic
Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis...
July 2017: Nature Medicine
https://www.readbyqxmd.com/read/28544360/impairment-of-insulin-signalling-in-peripheral-tissue-fails-to-extend-murine-lifespan
#15
Troy L Merry, Doreen Kuhlow, Beate Laube, Doris Pöhlmann, Andreas F H Pfeiffer, C Ronald Kahn, Michael Ristow, Kim Zarse
Impaired insulin/IGF1 signalling has been shown to extend lifespan in model organisms ranging from yeast to mammals. Here we sought to determine the effect of targeted disruption of the insulin receptor (IR) in non-neuronal tissues of adult mice on the lifespan. We induced hemizygous (PerIRKO+/- ) or homozygous (PerIRKO-/- ) disruption of the IR in peripheral tissue of 15-weeks-old mice using a tamoxifen-inducible Cre transgenic mouse with only peripheral tissue expression, and subsequently monitored glucose metabolism, insulin signalling and spontaneous death rates over 4 years...
August 2017: Aging Cell
https://www.readbyqxmd.com/read/28492253/corrigendum-adipose-derived-circulating-mirnas-regulate-gene-expression-in-other-tissues
#16
Thomas Thomou, Marcelo A Mori, Jonathan M Dreyfuss, Masahiro Konishi, Masaji Sakaguchi, Christian Wolfrum, Tata Nageswara Rao, Jonathon N Winnay, Ruben Garcia-Martin, Steven K Grinspoon, Phillip Gorden, C Ronald Kahn
No abstract text is available yet for this article.
May 10, 2017: Nature
https://www.readbyqxmd.com/read/28436968/metabolic-control-of-primed-human-pluripotent-stem-cell-fate-and-function-by-the-mir-200c-sirt2-axis
#17
Young Cha, Min-Joon Han, Hyuk-Jin Cha, Janet Zoldan, Alison Burkart, Jin Hyuk Jung, Yongwoo Jang, Chun-Hyung Kim, Ho-Chang Jeong, Byung-Gyu Kim, Robert Langer, C Ronald Kahn, Leonard Guarente, Kwang-Soo Kim
A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the 'Warburg effect', which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase...
May 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28363934/positive-and-negative-roles-of-p85%C3%AE-and-p85%C3%AE-regulatory-subunits-of-phosphoinositide-3-kinase-in-insulin-signaling
#18
Kohjiro Ueki, David A Fruman, Claudine M Yballe, Mathias Fasshauer, Johannes Klein, Tomoichiro Asano, Lewis C Cantley, C Ronald Kahn
No abstract text is available yet for this article.
March 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28345670/domain-dependent-effects-of-insulin-and-igf-1-receptors-on-signalling-and-gene-expression
#19
Weikang Cai, Masaji Sakaguchi, Andre Kleinridders, Gonzalo Gonzalez-Del Pino, Jonathan M Dreyfuss, Brian T O'Neill, Alfred K Ramirez, Hui Pan, Jonathon N Winnay, Jeremie Boucher, Michael J Eck, C Ronald Kahn
Despite a high degree of homology, insulin receptor (IR) and IGF-1 receptor (IGF1R) mediate distinct cellular and physiological functions. Here, we demonstrate how domain differences between IR and IGF1R contribute to the distinct functions of these receptors using chimeric and site-mutated receptors. Receptors with the intracellular domain of IGF1R show increased activation of Shc and Gab-1 and more potent regulation of genes involved in proliferation, corresponding to their higher mitogenic activity. Conversely, receptors with the intracellular domain of IR display higher IRS-1 phosphorylation, stronger regulation of genes in metabolic pathways and more dramatic glycolytic responses to hormonal stimulation...
March 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28199304/adipose-derived-circulating-mirnas-regulate-gene-expression-in-other-tissues
#20
Thomas Thomou, Marcelo A Mori, Jonathan M Dreyfuss, Masahiro Konishi, Masaji Sakaguchi, Christian Wolfrum, Tata Nageswara Rao, Jonathon N Winnay, Ruben Garcia-Martin, Steven K Grinspoon, Phillip Gorden, C Ronald Kahn
Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21...
February 23, 2017: Nature
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