Burnett L.C.,Columbia University |
Burnett L.C.,Naomi Berrie Diabetes Center |
Skowronski A.A.,Columbia University |
Skowronski A.A.,Naomi Berrie Diabetes Center |
And 8 more authors.
International Journal of Obesity | Year: 2017
Background:The adipokine hormone, leptin, is a major component of body weight homeostasis. Numerous studies have been performed administering recombinant mouse leptin as an experimental reagent; however, the half-life of circulating leptin following exogenous administration of recombinant mouse leptin has not been carefully evaluated.Methods:Exogenous leptin was administered (3 mg leptin per kg body weight) to 10-week-old fasted non-obese male mice and plasma was serially collected at seven time points; plasma leptin concentration was measured by enzyme-linked immunosorbent assay at each time point to estimate the circulating half-life of mouse leptin.Results:Under the physiological circumstances tested, the half-life of mouse leptin was 40.2 (±2.2) min. Circulating leptin concentrations up to 1 h following exogenous leptin administration were 170-fold higher than endogenous levels at fasting.Conclusions:The half-life of mouse leptin was determined to be 40.2 min. These results should be useful in planning and interpreting experiments employing exogenous leptin. The unphysiological elevations in circulating leptin resulting from widely used dosing regimens for exogenous leptin are likely to confound inferences regarding some aspects of the hormone's clinical biology. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Westerterp M.,Columbia University |
Westerterp M.,University of Groningen |
Tsuchiya K.,Naomi Berrie Diabetes Center |
Tsuchiya K.,Tokyo Medical and Dental University |
And 10 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2016
Objective-Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1. Approach and Results-Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding Abca1fl/flAbcg1fl/flLdlr-/- mice with the Tie2Cre strain, followed by irradiation and transplantation of Abca1fl/flAbcg1fl/fl bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-Type diet, both single EC-Abca1 and Abcg1 deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-Abca1/g1 deficiency caused a significant further increase in lesion area at both sites. EC-Abca1/g1 deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque. Abca1/g1 deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by ABCG1 deficiency in human aortic ECs. Conclusions-These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow. © 2016 American Heart Association, Inc.
News Article | December 12, 2016
NEW YORK NY (December 12, 2016)--Columbia University Medical Center (CUMC) researchers have discovered that a deficiency of the enzyme prohormone covertase (PC1) in the brain is linked to most of the neuro-hormonal abnormalities in Prader-Willi syndrome, a genetic condition that causes extreme hunger and severe obesity beginning in childhood. The discovery provides insight into the molecular mechanisms underlying the syndrome and highlights a novel target for drug therapy. The findings were published online today in the Journal of Clinical Investigation. "While we've known for some time which genes are implicated in Prader-Willi syndrome, it has not been clear how those mutations actually trigger the disease," said lead author Lisa C. Burnett, PhD, a post-doctoral research scientist in pediatrics at CUMC. "Now that we have found a key link between these mutations and the syndrome's major hormonal features, we can begin to search for new, more precisely targeted therapies." An estimated one in 15,000 people have Prader-Willi syndrome (PWS). The syndrome is caused by abnormalities in a small region of chromosome 15, which leads to dysfunction in the hypothalamus--which contains cells that regulate hunger and satiety--and other regions of the brain. A defining characteristic of PWS is insatiable hunger. People with PWS typically have extreme obesity, reduced growth hormone and insulin levels, excessive levels of ghrelin (a hormone that triggers hunger), and developmental disabilities. There is no cure and few effective treatments for PWS. Dr. Burnett and her colleagues used stem cell techniques to convert skin cells from PWS patients and unaffected controls into brain cells. Analysis of the stem cell-derived neurons revealed significantly reduced levels of PC1 in the patients' cells, compared to the controls. The cells from PWS patients also had abnormally low levels of a protein, NHLH2, which is made by NHLH2, a gene that also helps to produce PC1. To confirm whether PC1 deficiency plays a role in PWS, the researchers examined transgenic mice that do not express Snord116, a gene that is deleted in the region of chromosome 15 that is associated with PWS. The mice were found to be deficient in NHLH2 and PC1 and displayed most of the hormone-related abnormalities seen in PWS, according to study leader Rudolph L. Leibel, MD, professor of pediatrics and medicine and co-director of the Naomi Berrie Diabetes Center at CUMC. "The findings strongly suggest that PC1 is a good therapeutic target for PWS," said Dr. Burnett. "There doesn't seem to be anything wrong with the gene that makes PC1--it's just not getting activated properly. If we could elevate levels of PC1 using drugs, we might be able to alleviate some of the symptoms of the syndrome." "This is an outstanding example how research on human stem cells can lead to novel insight into a disease and provide a platform for the testing of new therapies," said Dieter Egli, PhD, a stem cell scientist who is an assistant professor of developmental cell biology (in Pediatrics) and a senior author on the paper. "This study changes how we think about this devastating disorder," said Theresa Strong, PhD, chair of the scientific advisory board of the Foundation for Prader-Willi Research and the mother of a child with PWS. "The symptoms of PWS have been very confusing and hard to reconcile. Now that we have an explanation for the wide array of symptoms, we can move forward with developing a drug that addresses their underlying cause, instead of treating each symptom individually." Following the findings reported in this paper, the Columbia research team began collaborating with Levo Therapeutics, a PWS-focused biotechnology company, to translate the current research into therapeutics. The study is titled, "Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome." The other contributors are: Charles A. LeDuc (CUMC), Carlos R. Sulsona (University of Florida College of Medicine Gainesville, FL), Daniel Paull (New York Stem Cell Foundation Research Institute, New York, NY), Richard Rausch (CUMC), Sanaa Eddiry (Université Paul Sabatier, Toulouse, France), Jayne F. Martin Carli (CUMC), Michael V. Morabito (CUMC), Alicja A. Skowronski (CUMC), Gabriela Hubner (Packer Collegiate Institute), Matthew Zimmer (New York Stem Cell Foundation Research Institute), Liheng Wang (CUMC), Robert Day (Université de Sherbrooke, Quebec, Canada), Brynn Levy (CUMC), Ilene Fennoy (CUMC), Beatrice Dubern (Sorbonne University, University Pierre et Marie-Curie, Paris, France), Christine Poitou (Sorbonne University), Karine Clement (Sorbonne University), Merlin G. Butler (Kansas University Medical Center, Kansas City, KS), Michael Rosenbaum (CUMC), Jean Pierre Salles (Université de Toulouse. Toulouse, France), Maithe Tauber (Université de Toulouse), Daniel J. Driscoll (University of Florida College of Medicine), and Dieter Egli (CUMC and New York Stem Cell Foundation Research Institute). The study was supported by grants from the Foundation for Prader-Willi Research, Russell Berrie Foundation, Rudin Foundation, The New York Stem Cell Foundation, Helmsley Foundation, and National Institutes of Health (RO1DK52431 and P30 DK26687). The authors declare no conflicts of interest. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.
News Article | November 23, 2016
NEW YORK, NY (November 23, 2016)--Columbia University has awarded the 2016 Naomi Berrie Award for Outstanding Achievement in Diabetes Research to Peter Arner, MD, PhD, a Distinguished Professor in the Department of Medicine at the Karolinska Institute, whose studies on the turnover of fat tissue in the human body has revealed processes that contribute to obesity and diabetes. The Naomi Berrie Award for Outstanding Achievement is Columbia University's top honor for excellence in diabetes research, and Dr. Arner is the 18th winner since the award's inception in 1999. Dr. Arner received the award on November 19 at a ceremony which took place at the Frontiers in Diabetes Research Symposium in the Russ Berrie Medical Science Pavilion at Columbia University Medical Center (CUMC). "Peter has been responsible for identifying some of the key molecules, genes, and pathways that influence the production of fat cells and their growth," said Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, co-director of the Naomi Berrie Diabetes Center, and chair of the award selection committee. "These discoveries have had a major impact on how we understand the role of body fat in metabolic diseases." Dr. Arner and his collaborators were the first to show that the human body continues to produce fat cells into adulthood. Dr. Arner's team developed a method of measuring fat cell turnover in adults, which led to the discovery that fat cells are renewed relatively rapidly--around 8 percent of adult fat cells die every year and are replaced by new ones. Fat turnover was the same for all individuals in the study, including those who had lost a significant amount of weight, showing that the volume of fat cells, not their abundance, that causes body mass to rise and fall during a lifetime. Dr. Arner is also credited with discovering several adipokines--molecules released from fat tissue that can trigger inflammation and regulate the size and number of fat cells. His group showed that a molecule called Tumor Necrosis Factor alpha (TNFα) alters the levels of leptin, a hormone secreted from fat that plays a critical role in the regulation of body weight. In the clinic, Dr. Arner's group designed and conducted a clinical trial of the drug ibertesan, showing that it slowed the progression of neuropathy--a type of nerve damage that develops in 40 per cent of type 2 diabetes patients. Peter Arner studied medicine at the Karolinska Institute, and received specialty training in internal medicine and in Endocrinology. The Naomi Berrie Award for Outstanding Achievement in Diabetes Research includes an award of $130,000 that is used by the recipient to support a junior investigator in his or her laboratory for two years. The program also includes a similar award to a junior-level investigator at Columbia University. These individuals are designated "Berrie Fellows in Diabetes Research." The Berrie Fellowships for 2016 were awarded to Hui Gao, PhD and Kristin McCabe, PhD. Dr. Gao is a senior researcher in the Department of Biosciences and Nutrition at the Karolinska Institute, Sweden. He will work under Dr. Arner on the role of long non-coding RNA molecules in regulating genes in the adipose tissue of patients with diabetes. Dr. McCabe is a postdoctoral research scientist in the laboratory of Alan Tall, MD, at CUMC. She will investigate the ability of specialized heat-producing "brown" fat cells to reduce obesity risk, with a focus on a molecule called TTC39B. Taiyi Kuo, PhD, Yann Ravussin, PhD, and Lina Sui, PhD, are the Russell Berrie Foundation Scholars for 2016. This program provides support to international scientists to work at the Naomi Berrie Diabetes Center in collaboration with Columbia scientists. Each scholar will receive $75,000 in support of their research activities. Dr. Kuo completed her PhD at the University of California, Berkeley, and is a postdoctoral fellow in the lab of Domenico Accili, MD, the Russell Berrie Foundation Professor of Diabetes (in Medicine) at CUMC. She will research the role of epigenetics on insulin release from pancreatic beta cells. Dr. Ravussin completed his undergraduate training at the Université de Lausanne, his PhD at Columbia, and has worked at the National Institutes of Health. Currently, he is a postdoctoral fellow in the laboratory of Anthony Ferrante, MD, PhD, an associate professor of medicine at CUMC. He will investigate overfeeding and pathways that regulate body weight. Dr. Sui completed her PhD at Vrije Universiteit Brussel, and was a Research Associate scientist at the Institute of Biophysics, Chinese Academy of Science. Currently, she is a postdoctoral scientist in the laboratory of Dietrich Egli, PhD, assistant professor of developmental cell biology (in Pediatrics) at CUMC. Dr. Sui will use stem cells to dissect the pathways that cause beta cells to fail when starved of glucose. The Naomi Berrie Diabetes Center at Columbia University Medical Center opened in 1998 to serve the 1.6 million people with diabetes in the New York area, by combining world-class diabetes research and education programs with family-oriented patient care. Founded with support from the Russell Berrie Foundation and other friends, the center is named in honor of the mother of the late Russell Berrie, founder of RUSS™ Toys. The Center's more than 100 faculty and students conduct basic and clinical research related to the pathogenesis and treatment of all forms of diabetes and its complications. For more information, visit http://www. . Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.
Li P.,University of Alabama at Birmingham |
Tiwari H.K.,University of Alabama at Birmingham |
Lin W.-Y.,National Taiwan University |
Allison D.B.,University of Alabama at Birmingham |
And 6 more authors.
International Journal of Obesity | Year: 2014
Objective: Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). Methods: We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age 2, gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects. Results: With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. Conclusion: Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context. © 2014 Macmillan Publishers Limited All rights reserved.
Wakae-Takada N.,Columbia University |
Wakae-Takada N.,Naomi Berrie Diabetes Center |
Xuan S.,Columbia University |
Watanabe K.,Columbia University |
And 4 more authors.
Diabetologia | Year: 2013
Aims/hypothesis: In rodents and humans, the rate of beta cell proliferation declines rapidly after birth; formation of the islets of Langerhans begins perinatally and continues after birth. Here, we tested the hypothesis that increasing levels of E-cadherin during islet formation mediate the decline in beta cell proliferation rate by contributing to a reduction of nuclear β-catenin and D-cyclins. Methods: We examined E-cadherin, nuclear β-catenin, and D-cyclin levels, as well as cell proliferation during in vitro and in vivo formation of islet cell aggregates, using β-TC6 cells and transgenic mice with green fluorescent protein (GFP)-labelled beta cells, respectively. We tested the role of E-cadherin using antisense-mediated reductions of E-cadherin in β-TC6 cells, and mice segregating for a beta cell-specific E-cadherin knockout (Ecad [also known as Cdh1] βKO). Results: In vitro, pseudo-islets of β-TC6 cells displayed increased E-cadherin but decreased nuclear β-catenin and cyclin D2, and reduced rates of cell proliferation, compared with monolayers. Antisense knockdown of E-cadherin increased cell proliferation and levels of cyclins D1 and D2. After birth, beta cells showed increased levels of E-cadherin, but decreased levels of D-cyclin, whereas islets of Ecad βKO mice showed increased levels of D-cyclins and nuclear β-catenin, as well as increased beta cell proliferation. These islets were significantly larger than those of control mice and displayed reduced levels of connexin 36. These changes correlated with reduced insulin response to ambient glucose, both in vitro and in vivo. Conclusions/ interpretation: The findings support our hypothesis by indicating an important role of E-cadherin in the control of beta cell mass and function. © 2013 Springer-Verlag Berlin Heidelberg.
News Article | February 1, 2016
Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, and the fastest-growing reason for liver transplantation. It is estimated that more than half of patients with type 2 diabetes (T2D) have NAFLD, and even patients with type 1 diabetes have higher risk of developing fatty liver than people without diabetes. There are currently no drugs approved to treat NAFLD. Even more vexing, novel therapeutics for T2D that increase liver insulin sensitivity generally increase fat deposition in the liver, creating a vicious cycle that paradoxically worsens the liver disease. Now, diabetes investigator Utpal Pajvani, M.D., Ph.D., and his team of researchers at the Naomi Berrie Diabetes Center, led by KyeongJin Kim, Ph.D., have discovered that a simple protein, originally thought to do one job, has the capability of doing something completely different—and quite extraordinary. “We found, for the first time, a pathway that prevents insulin or insulin sensitizing therapy from causing fatty liver, without getting rid of the favorable effects of insulin to reduce blood sugar,” said Dr. Pajvani, an Assistant Professor of Medicine at Columbia University In a paper released in the January 2016 issue of Nature Communications. Drs. Kim and Pajvani document the secret life of a protein called Raptor that exists within a protein complex called mTORC1 which is involved in everything from cell growth and cell differentiation to cell usage of glucose or lipids. “mTORC1 is one of the most-studied biological pathways, since it has so many functions, and has been implicated not only in the development of diabetes and fatty liver disease, but also cancer,” said Dr. Pajvani. Raptor has long been known to be the regulatory component of mTORC1’s function to phosphorylate other proteins, but Dr. Pajvani’s group reports for the first time that Raptor not only exists independently from mTORC1, but has the capacity in its free state to reverse fatty liver in mice by stabilizing another protein called PHLPP2, which in turn turns off insulin signaling. Aging or obesity normally cause PHLPP2 to degrade, leaving in its wake “a chronic, smoldering insulin signaling that results in fatty liver. Free Raptor, through protecting PHLPP2 from degradation, turns off the insulin signaling.” While the nomenclature of the protein complex is difficult to the uninitiated (his paper is entitled “mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2”) Dr. Pajvani’s explanation of his discovery as it played out in laboratory mice, is clear, concise and compelling. “As it turns out, young, healthy mice, (and we assume, young, healthy people) have a lot of this free Raptor. As mice age or get fat, free Raptor disappears. When free Raptor disappears, mice get fatty liver. If you give them back free Raptor, fatty liver goes away but leaves insulin’s ability to lower blood sugar intact.” Dr. Pajvani’s work is big news for the other scientists who study insulin resistance, diabetes and other metabolic disorders, but may have stronger impact still in far-flung domains such as cancer biology. This same pathway is targeted by cancer researchers and immunologists, and mTORC1 inhibitors are already in clinical use as chemotherapy for cancer patients and as an immunosuppressant for organ transplant patients. “The role of free Raptor that we discovered is not likely to be limited to hepatic lipid metabolism to prevent age and obesity induced fatty liver,” said Dr. Pajvani. “If we can figure out what frees Raptor from mTOR, we may have accidentally discovered a better means to modulate this very important pathway in order to design a more effective cancer or immunosuppressant drug.” But, we’re some time away from this, he cautions: “All we have are genetic mouse models – we have to prove the relevance of this free Raptor-PHLPP2 axis in people, which may give impetus for pharmaceutical companies to develop a drug to do the same.”