
The Good Fat: Understanding Adipogenesis and Function of Brown Fat
Tuesday, March 12, 2013
The New York Academy of Sciences
This conference is aimed at presenting recent developments in the field of adipogenesis research. Animal studies suggest that Brown Adipose Tissue (BAT) levels are associated with diet-induced obesity and the effects of aging. This symposium will explore the origin of BAT, how White Adipose Tissue (WAT) may be converted into BAT-like tissue, and how to enable the pursuit of BAT as a therapeutic target. The audience includes students and scientists working on fat metabolism and nutrition research and its application in preventive and curative medicine.
*Reception to follow.
Registration Pricing
By 2/1/2013 | After 2/1/2013 | Onsite | |
Member | $25 | $30 | $35 |
Student/Postdoc Member | $15 | $20 | $25 |
Nonmember (Academia) | $55 | $65 | $75 |
Nonmember (Corporate) | $75 | $85 | $95 |
Nonmember (Non-profit) | $55 | $65 | $75 |
Nonmember (Student / Postdoc / Fellow) | $35 | $45 | $50 |
Presented by
Agenda
* Presentation times are subject to change.
Tuesday, March 12, 2013 | |
8:30 AM | Registration and Breakfast |
9:00 AM | Welcome Remarks |
Session 1. The Molecular Underpinning of Making Brown Adipose Tissue | |
9:15 AM | Transcriptional Control of Brown and Beige Fat: Toward a New Generation of Therapeutics |
9:40 AM | Coercing Bad Fat to Work |
10:05 AM | Role of Bone Morphogenetic Proteins in Brown Adipogenesis, Thermoregulation, and Energy Homeostasis |
10:30 AM | TYK2 and STAT3 Regulate Brown Adipose Tissue Differentiation and Obesity |
10:55 AM | Break |
Session 2. Making, Converting and Stimulating BAT | |
11:15 AM | The Search for Thermogenic Compounds in the Management of Obesity |
11:40 AM | Blockade of the Activin Receptor IIB Activates Functional Brown Adipogenesis and Thermogenesis by Inducing Mitochondrial Oxidative Metabolism |
12:05 PM | Integrating the Hormonal Signals at the Heart of Brown Adipocyte Recruitment |
12:30 PM | Ketone Esters Increase Brown Fat in Mice and Overcome Insulin Resistance in Other Tissues of Rat |
12:55 PM | Lunch |
2:00 PM | Brown Adipose Tissue Regulation by Thyroid Hormone |
2:25 PM | Knockdown of NPY in the Dorsomedial Hypothalamus Promotes White to Brown Adipocyte Transformation |
2:50 PM | Relevance of Brown Adipose Tissue in Childhood and Adolescence |
3:15 PM | Break |
3:30 PM | Panel Discussion: Applications for Obesity Treatment and Prevention? Panelists: |
4:30 PM | Reception |
5:30 PM | Close |
Speakers
Organizers
Sandra J. Engle, PhD
Pfizer, Inc
Sandra Engle received a BA in Biology with an emphasis in Human Genetics from Ball State University Muncie, Indiana. She attended graduate school at Indiana University School of Medicine and earned a PhD in Medical and Molecular Genetics, working in the laboratory of Jay Tischfield, where she generated a mouse model of human APRT deficiency. She continued pursuing her interest in genetically modified mouse models with two postdoctoral fellowships at the University Of Cincinnati School Of Medicine; under the tutelage of Drs. Nelson Horseman and Tom Doetschman. In 2001, she took a position with the Genetically Modified Models Group at Aventis, a pharmaceutical company, before moving to a similar group at Pfizer in 2004. Building upon her expertise with mouse embryonic stem cells, she begin working with human pluripotent stem cells in 2007 and is currently a Senior Principal Scientist leading the Pluripotent Stem Cell Biology Laboratory of the Primary Pharmacology Group within Pfizer Inc. Her lab focuses on the generation of human induced pluripotent stem cells, in vitro differentiation of stem cells to terminally differentiated cell types of interest and the genetic modification of human stem cells in support of drug discovery efforts.
John E. Hambor, PhD
Boehringer Ingelheim
Dr. John Hambor is currently a Distinguished Research Fellow at Boehringer Ingelheim where he coordinates a strategic postdoctoral research program focused on developing new drug concepts in collaboration with academic investigators. Previously, Dr. Hambor was a consultant with the Cell Therapy Group, specializing in stem cell-based drug discovery. Prior to serving as CEO of CellDesign, a developer of next generation stem cell technologies, he contributed 17 years of research at Pfizer where he identified and validated new drug targets in the areas of inflammation and immunology and developed stem cell-based assays for drug efficacy and safety studies. Dr. Hambor received both a BA and MS degree in Microbiology from Miami University of Ohio, and earned a PhD in Pathology from Case Western Reserve University. As a postdoctoral fellow at Yale University in the Department of Immunobiology, he researched the molecular basis of CD8 expression during T cell development. He has been an Adjunct Assistant Professor at Connecticut College since 2000 as where he teaches Immunology. He also serves as a member of the board of directors for the VA Connecticut Research and Education Foundation.
Mandana Arabi, MD, PhD
The Sackler Institute for Nutrition Science
Speakers
Sheng Bi, MD
Johns Hopkins University School of Medicine
Sheng Bi received his medical degree and master degree in pharmacology from Zhejiang University School of Medicine, Hangzhou, China. After graduation, he spent one year as a visiting scholar in the Institute of Human Genetics at the University of Lübeck, Lübeck, Germany, four years as a postdoctoral fellow in the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, Bethesda, and one year as a postdoctoral fellow at the Johns Hopkins University School of Medicine, Baltimore. He joined the faculty of the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine in 2001 and was promoted to Associate Professor in 2009. Bi's research interests focus on the hypothalamic controls of energy balance and glucose homeostasis. His group has recently identified that knockdown of neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) promotes brown adipocyte development, prevents diet-induced obesity, and enhances insulin sensitivity. Ongoing research is aimed at teasing out the molecular and neural mechanisms underlying these effects. The overall goal of his research project is to extend the bench observations to the bed side to eventually prevent/treat obesity, diabetes and related metabolic syndromes.
Sheila Collins, PhD
Sanford-Burnham Medical Research Institute, Diabetes and Obesity Research Center
Dr. Collins received her BD degree in Zoology from the University of Massachusetts at Amherst. After a few years as a Research Technician at Massachusetts General Hospital and the California Institute of Technology, Dr. Collins received her PhD in biochemistry and pharmacology from the Massachusetts Institute of Technology, where she trained with Dr. Michael Marletta. Dr. Collins performed her postdoctoral training studies with Dr. Robert Lefkowitz of Duke University, and then joined the faculty of the Duke University Medical Center, where she was awarded tenure in the department of Psychiatry and Behavioral Sciences.
Since 2010, Dr. Collins has been a Professor of Metabolic Signaling and Disease in the Diabetes and Obesity Research Center of Sanford-Burnham Medical Research Institute in Orlando, FL. Dr. Collins's laboratory is interested in the biochemical mechanisms that regulate body weight. Activation of the adrenaline receptors, specifically the members of the beta-adrenergic receptor (beta-AR) family, provides the major stimulus for the hydrolysis and release of stored lipids. They are also key drivers of a process called ‘nonshivering thermogenesis’ in brown fat. Brown fat cells are specialized cells rich in mitochondria and largely defined by their ability to express the mitochondrial uncoupling protein UCP1, which allows the dissipation of the proton gradient in the inner mitochondrial membrane to yield heat at the expense of ATP production.
Abdul G. Dulloo, PhD
University of Fribourg, Switzerland
Abdul Dulloo is Professor of Physiology in the Department of Medicine at the University of Fribourg, Switzerland. He obtained a Bachelor degree in Physiology and a PhD degree in Nutrition, both from the University of London, and then spent two years as a postdoctoral Research Fellow in the laboratory of Prof. Lewis Landsberg at Harvard Medical School in Boston. He subsequently worked as a research associate of Prof. Lucien Girardier in the Physiology Department at the Faculty of Medicine of the University of Geneva, before joining in 1999 the University of Fribourg, where he has since been directing the Laboratory of Nutritional Energetics and Body Composition Regulation. His research interests center on elucidating the mechanisms that interlink thermogenesis, body composition regulation and insulin resistance, and upon the search for bioactive food ingredients with thermogenic and insulin-sensitizing properties for managing obesity and diabetes. Abdul Dulloo is currently an executive committee member of the Swiss Association for Study Obesity and an editorial board member of the International Journal of Obesity.
Vicente Gilsanz, MD, PhD
Children’s Hospital Los Angeles
Vicente Gilsanz is a Professor of Radiology and Pediatrics at the Keck School of Medicine of USC and Director of the Imaging Research Program at Children’s Hospital Los Angeles, which has continuously been funded by the National Institute of Health since 1993. He is board certified in internal medicine (Mayo Clinic), diagnostic radiology (Mount Sinai Hospital, New York), and pediatric radiology (Boston Children’s Hospital). Based on his training, his research centers on the use of imaging technologies to identify children at risk for common adult diseases, such as osteoporosis. He has extensive experience in utilizing digital data from all imaging modalities for the development of imaging biomarkers. For the past two years, he has collaborated with a multi-disciplinary group of individuals with an extensive expertise in imaging, pediatrics, bioengineering, and cell biology to investigate the relevance of brown adipose tissue (BAT) in humans, specifically the influence of BAT on body composition in infants, children, and teenagers.
Andrew Larner, MD, PhD
Virginia Commonwealth University
Andrew Larner received a BA in Biology from Haverford College. He attended graduate and medical school at The University of Virginia and earned a PhD in Pharmacolgy, working in the laboratory of Elliot Ross, a world expert on G-proteins. He was a postdoctoral fellow in the laboratory of James Darnell at Rockefeller University, an expert on cytokine regulated gene expression. During his tenure at Rockefeller, he isolated and characterized one of the first described genes activated by interferons. After completing a residency in Pathology at NCI, he remained in Bethesda in the Center for Biologics at the FDA. He relocated to Cleveland Clinic in 1997 and moved to Virginia Commonwealth University in 2007 where he is a Professor of Biochemistry and holds the Martha Anne Hatcher Professorship of Oncology. He has served on the Editorial Boards of The Journal of Biological Chemistry and the Journal of Interferon and Cytokine Research.
David A. Price, PhD
Pfizer, Inc
Devanjan Sikder, DVM, PhD
Sanford-Burnham Medical Research Institute, Diabetes and Obesity Research Center
After graduating with a DVM degree in Veterinary Medicine, Dr. Sikder pursued a career in research with a PhD in Genetic Engineering from the Indian Institute of Science, Bangalore in 2001. During his post doctoral training in neurobiology at UT Southwestern Medical School at Dallas, he met Dr. Masashi Yanagisawa (co-discoverer of orexin/hypocretin) who inspired him to take up research on orexin biology. Dr. Sikder now runs his independent laboratory as an Assistant Professor at Sanford-Burnham Medical Research Institute (2009-present). His team’s focus is on investigating the role of orexin in obesity, narcolepsy and cancer, noting that individuals who are orexin-deficient have increased incidence of metabolic problems.
J. Enrique Silva, MD, FACP
Tufts University School of Medicine
Dr. J. Enrique Silva, MD, FACP, was born and grew up in Santiago, Chile, where he obtained his MD degree from the University of Chile School of Medicine. He trained at this Institution in Internal Medicine and Experimental Medicine. He wrote a doctoral thesis “Mechanisms of adaptation to iodine deficiency in the rats and humans” (PhD equivalent). He continued his training in New York, at the Montefiore Hospital and Medical Center, under Dr. Jack H. Oppenheimer. He then was Research Fellow in Medicine at Harvard Medical School, under Dr. Reed Larsen, in Boston. He returned to Chile to establish his own research program and laboratory but immigrated back to the United States in view of the crisis affecting Chilean Universities. He returned a Associate Investigator in Howard Hughes Medical Institute at Harvard, where he stayed for over years, reaching the level of Associate Professor of Medicine and Chief of the Thyroid Unit at Beth Israel Hospital. He then moved to Montreal, Canada, to become Professor of Medicine and Physiology at McGill University. Seven years ago, he returned to the USA and currently is Professor of Medicine at Tufts University School of Medicine and Adjunct Professor of Biology at University of Massachusetts, Amherst. He has received numerous awards and National and International recognitions and been in the Editorial Boards of J Clin. Investigation, Endocrinology, J Clin. Endocrinology and Thyroid, among others. He has published over 160 articles, the majority original research in peer-reviewed journals. His research focus has always been thyroid hormone physiology, specifically its thermogenic effect, which has brought him to his current interest in temperature homeostasis and energy balance.
Bruce M. Spiegelman, PhD
Dana-Farber Cancer Institute, Harvard Medical School
Bruce M. Spiegelman is the Stanley J. Korsmeyer Professor of Cell Biology and Medicine at Harvard Medical School and Dana-Farber Cancer Institute. Dr. Spiegelman received a BS with highest honors from the College of William and Mary in 1974, his PhD in biochemistry from Princeton University in 1978, and completed postdoctoral work at MIT. He joined Harvard Medical School and Dana-Farber Cancer Institute in 1982. His research focuses on fat cell biology, diabetes and muscular diseases. Dr.Spiegelman has been honored with many awards including Bristol-Myers Squibb Award for Distinguished Achievement in Metabolic Research; the Solomon Berson Award, American Physiological Society; the Rolf Luft Award in Endocrinology, Karolinska Institute (Sweden); the Trans-Atlantic Medal, British Endocrine Society; the Naomi Berrie Award for Outstanding Achievement in Diabetes Research, Columbia University, Banting Medal for Scientific Achievement 2012, American Diabetes Association. In 2002 Dr. Spiegelman was elected to the American Academy of Arts and Sciences and the National Academy of Science.
Anne-Ulrike Trendelenburg, PhD
Novartis Institutes for BioMedical Research
Anne-Ulrike is Director at the Muscle program (FiP) of the Novartis Institutes for Biomedical Research in Cambridge (USA). She studied Pharmacy at the University of Freiburg in Germany and earned her PhD in Pharmacology and Toxicology at the Albert Ludwigs University, Freiburg, Germany, working in the lab of Professor Klaus Starke an expert on synaptic transmission and its modulation, followed by a position as Assistant Scientist and Lecturer in the same department. She studied presynaptic modulation of neurotransmission by G-protein coupled receptors in various species. Her work in mouse sympathetic neuron cultures and knockout mice in collaborations with the labs of Brian Kobilka (University of Stanford, USA) and Lutz Hein (University of Wuerzburg, Germany) resulted in new insights into the nature of 2-adrenceptor subtypes in the regulation of sympathetic neurotransmission. In 2001, she completed her state doctorate and obtained the "venia legendi" in Pharmacology and Toxicology at the Albert Ludwigs University, Freiburg, Germany.
In 2001, Trendelenburg joined the Novartis Ophthalmics Research, later Ophthalmology Disease Area (DA), in the Novartis Institutes for Biomedical Research (NIBR), as labhead, was promoted to Scientific Expert Pharmacology in 2002 and to Unit Head Target and Lead Discovery in 2004. She led Research Unit, project teams of drug discovery and exploratory projects, managed various internal and external collaborations and represented DA in Council, International Project Team (IPT) and cross-functional boards. In 2005, she completed her Master's Certificate in Project Management, ESI/George Washington University, USA and joined newly formed Muscle FiP in July 2005 led by David Glass an world expert on muscle signaling and research, where she has established muscle research lab, exploratory and drug discovery projects as well as various collaborations with internal departments and supported build-up of Muscle FiP. Her work on muscle, aging and fat signaling discovered new entry points into signaling of the TGF-family and connections to cytokine signaling. She represents NIBR in the Endostem consortium focusing on endogenous stem cell activation to treat muscle diseases. In 2011, she relocated to NIBR Cambridge where she leads the Cambridge group of Muscle Diseases.
Trendelenburg serves as Advisory Editor for Naunyn-Schmiedeberg's Archives of Pharmacology.
Yu-Hua Tseng, PhD
Joslin Diabetes Center, Harvard Medical School
Yu-Hua Tseng is an Assistant Professor of Medicine at Harvard Medical School, an Investigator in the Section on Integrative Physiology and Metabolism at Joslin Diabetes Center, and a Principal Faculty of Harvard Stem Cell Institute. She received her doctorate in Developmental Biology and Cellular and Molecular Biology from the University of Wisconsin-Madison under the supervision of Dr. Linda Schuler. She completed postdoctoral training in the laboratory of Dr. C. Ronald Kahn at Joslin Diabetes Center/Harvard Medical School. Tseng's current research focuses include brown fat development and function, and regulation of systemic energy metabolism. Dr. Tseng was an Eleanor and Miles Shore Scholar in Medicine at Harvard Medical School.
Richard L. Veech, MD, DPhil
National Institute on Alcohol Abuse and Alcoholism/NIH
Richard L. Veech is Chief in the Unit on Metabolic Control at the National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health. Dr. Veech received is MD in Medicine from Harvard Medical School in 1962 and his DPhil in Biochemistry from Oxford University in 1968. His primary interests are in metabolic control analysis as related to new therapeutic applications to disease states. Dr. Veech has over 250 publications in peer reviewed journals and is a member of the American society of Biochemistry and Molecular Biology.
Abstracts
Transcriptional Control of Brown and Beige Fat: Toward a New Generation of Therapeutics
Bruce M. Spiegelman, PhD, Dana-Farber Cancer Institute, Harvard Medical School
Our group has been interested in the development of both white and brown fat, particularly at the level of gene transcription. PGC1α is a dominant regulator of oxidative metabolism in many tissues, including brown fat and skeletal muscle. PGC1α and its newly discovered isoform, PGC1α4 are both induced in muscle with exercise and drive gene programs linked to exercise. We have found recently that PGC1α expression in muscle control the expression of Fndc5, a cell membrane protein. Fndc5 is proteolytically cleaved to give rise to a new secreted protein of 112 amino acids that we have called irisin. Irisin circulates in both mouse and man, and an even mild elevation of irisin activates the browning of white fat, causing increased energy expenditure and reducing obesity. Most recently we have produced versions of the irisin protein that are active in both cultured cells and in vivo.
Irisin acts on a specific cell type called beige adipose cells. We isolated and cloned these cells from the subcutaneous fat of mice and have now made immortalized beige cell lines. Importantly, we show that the brown fat previously identified in adult humans corresponds much more closely to beige fat than the brown fat of mice. Finally we have found that primary beige fat precursors can be sorted from mice using the cell surface marker cd137. The cells are much more sensitive to irisin than the low cd137 preadipocytes. Finally, we will finally discuss therapy involving beige fat, irisin and other novel myokines.
Coercing Bad Fat to Work
Devanjan Sikder, DVM, PhD, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute
White to brown fat conversion, observed in multiple genetic models, is thought to provide protection against diet-induced obesity, prompting the argument that 'diet-dependent browning' may have a physiological significance in metabolic homeostasis. However, 'diet-dependent browning' of white fat has not been observed in non-mutant animals, suggesting that either alternate obesity resistance mechanisms are operative in aforementioned genetic models or that the target for diet-dependent browning has yet to be identified. Here, we provide evidence for diet as a potent physiological cue regulating brown-like transformation in back subcutaneous WAT (bsWAT). In lean mice, bsWAT is unremarkable in size; bears canonical white fat characteristics but expresses orexin (OX) and high levels of PRDM16. In response to HFD, the tissue expands in size, produces OX-receptor-2 (OXR2) and expresses more PRDM16, while transitioning from the typical storage to thermogenically competent brown-like tissue. This diet-dependent bsWAT browning is regulated by OX-signaling via OXR2. Loss of OXR2 signaling disrupts bsWAT browning and leads to obesity in mice. Orexin injected lean mice resist diet-induced weight gain without reducing their food intake. The anti-obesity property of OX is associated with enhanced thermogenic capacity of both white and brown portions of the interscapular depot. Thus, as a potent regulator of interscapular metabolism, orexin has a promise in combating obesity.
Role of Bone Morphogenetic Proteins in Brown Adipogenesis, Thermoregulation, and Energy Homeostasis
Yu-Hua Tseng, PhD, Joslin Diabetes Center, Harvard Medical School
Two distinct types of brown fat exist in mammals: the constitutive (classical) brown fat (cBAT) of embryonic origin, and the so called recruitable BAT (rBAT, also known as inducible BAT, brite or beige cells) that resides within white fat and skeletal muscle. Unlike rBAT, progenitor cells of cBAT express early myogenic markers, such as Myf5. We and others have demonstrated that the developmental regulator bone morphogenetic proteins (BMPs) play an important role in adipose cell fate determination. BMP-downstream signaling is relayed by type 1 and type 2 BMP receptors (BMPRs). To determine the role of BMP signaling in the brown fat development and function, we generated a mouse model in which type 1A BMPR (BMPR1A) is deleted in cells of the Myf5-positive lineage. The knockout mice display a severe paucity of cBAT development. Isolated brown preadipocytes lacking BMPR1A are deficient in differentiation into mature brown adipocytes, suggesting that BMPR1A is required for brown adipocyte differentiation in a cell-autonomous manner. Importantly, loss of cBAT results in a compensatory browning of white fat that involves increased sympathetic outflow to this tissue. This compensatory mechanism, aimed at restoring total brown fat-mediated thermogenic capacity in the body, is sufficient to maintain normal temperature homeostasis and resistance to diet induced obesity. Taken together, these data establish an essential role of BMPR1A in the development of brown adipocytes and suggest a potential cross-talk between the constitutive and recruitable brown fat cells to maintain normal thermogenesis and energy balance.
TYK2 and STAT3 Regulate Brown Adipose Tissue Differentiation and Obesity
Andrew C. Larner, MD, PhD, Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond
Two functionally different types of fat contribute to the maintenance of energy balance. White adipose tissue (WAT) is the primary site of energy storage, and also synthesizes and releases a variety of cytokines and hormones that modulate the actions of insulin. In contrast to WAT, brown adipose tissue (BAT) is responsible for energy expenditure in a process termed thermogenesis. It has recently become appreciated that BAT is present in human adults and may play a role in the pathogenesis of obesity.
Mice lacking the Jak tyrosine kinase member Tyk2 become obese with age due to aberrant BAT development. Skeletal muscle which shares a common progenitor with BAT is also defective in Tyk2-/- mice. Tyk2 levels in BAT and skeletal muscle in mice are decreased in mice placed on a high fat diet. Importantly, compared with lean individuals obese humans with or without type II diabetes also show decreased expression of Tyk2 RNA. Expression of Tyk2 or constitutively active form of the transcription factor Stat3 (CAStat3) restores BAT differentiation in Tyk2-/- preadipocytes. Furthermore, expression of CAStat3 in BAT of Tyk2-/- mice also restores BAT differentiation, normal levels of insulin and prevents the onset of obesity. These studies indicate that Tyk2 is important for BAT development, which acts in concert with BAT transcription factors, PRDM16 and C/EBPβ to maintain energy homeostasis. These studies define novel roles for Tyk2 and Stat3 as critical determinants of brown fat-lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.
Coauthors: Marta Derecka1, Sergei B. Koralov2, Karol Szczepanek1, Magdalena Morgan1, Vidisha Raje1, Jennifer Sisler1, Qifang Zhang1, Birgit Strobl3, Thurl E. Harris4, Patrick Seale5, Aaron P. Russell6, Andrew J. McAinch7, Paul E. O’Brien8, Susanna R. Keller9, Colleen M. Croniger10 and Tomasz Kordula1, 1Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, 2Department of Pathology, New York University Medical School, New York, 3Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Austria, 4Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, 5Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, 6Centre of Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia,7Biomedical and Lifestyle Diseases (BioLED) Unit, School of Biomedical and Health Sciences, Victoria University, St Albans, Australia, 8Centre for Obesity Research and Education (CORE), Monash University, The Alfred Hospital, Melbourne, Australia, 9Department of Medicine, University of Virginia School of Medicine, Charlottesville, 10Department of Nutrition, Case Western University School of Medicine Cleveland, Ohio
The Search for Thermogenic Compounds in the Management of Obesity
Abdul G. Dulloo, PhD, Department of Medicine/Physiology, University of Fribourg
The concept of managing obesity by increasing metabolic rate through the stimulation of thermogenesis and fat oxidation is currently a focus of considerable attention by the pharmaceutical, neutraceutical and functional-foods industries. This lecture first reviews the landmark discoveries that over the past decades have fuelled the search for thermogenic anti-obesity products that range from single-target drugs to multi-target functional foods, and subsequently analyses the thermogenic and fat oxidising potentials of a wide array of 'drugs of every-day-life' and bioactive food ingredients with potential impact on brown adipose tissue. It then discusses whether the targeting of brown adipose tissue and the 'browning' of white adipose tissue could safely increase thermogenesis to an extent that would have clinically significant impact in weight management.
Blockade of the Activin Receptor IIB Activates Functional Brown Adipogenesis and Thermogenesis by Inducing Mitochondrial Oxidative Metabolism
Anne-Ulrike Trendelenburg, PhD, Novartis Institutes for BioMedical Research
Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/ActRIIB pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition only enhanced energy expenditure at ambiant temperature or in the cold, but not at thermoneutrality where non-shivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.
Integrating the Hormonal Signals at the Heart of Brown Adipocyte Recruitment
Sheila Collins, PhD, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute
The existence of brown fat, and its ability to generate heat from stored calories, is an ancient mechanism developed by mammals to deal with chilly environmental temperatures. Shivering is one mechanism of heat generation but it is costly and uncomfortable. Shivering may contribute to the activation of brown fat by a muscle-derived peptide termed 'irisin'. The well-known stimulator that responds to the cold environment for the appearance of new brown adipocytes and the ramping up of the machinery and metabolic activity of brown adipocytes is the sympathetic nervous system (SNS) and activation of the β-adrenergic receptors (βARs) on these fat cells. The intracellular signaling mechanisms downstream of the βARs that drive this recruitment of brown adipocytes involve the coordinated regulation of lipolysis together with key transcriptional activation events. In addition to the direct effects of the SNS and βARs on adipocytes, the heart also responds to these stresses and releases a companion signal for brown adipocyte activation: the natriuretic peptides ANP and BNP. The coordinated action of the SNS and the NPs to stimulate the βAR/cAMP pathway and the NP receptor A (NPRA)/cGMP pathway together have a robust ability to increase brown fat activity for heat generation. The potential for these pathways to contribute to net energy expenditure leading to 'burning' of fat and weight loss will be discussed.
Coauthors: Marica Bordicchia, Dianxin Liu, and Eric Weatherford, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute.
Ketone Esters Increase Brown Fat in Mice and Overcome Insulin Resistance in Other Tissues of Rat
Richard L. Veech , MD, DPhil, National Institute on Alcohol Abuse and Alcoholism/NIH/DHHS
Feeding of a ketone body ester, D-β-hydroxybutyrate –R 1,3butandiol monoester as about 30% of caloric intake for up to 1 month increased the number of mitochondria, doubled the amount of mitochondrial electron transport and uncoupling protein 1 and mitochondrial biogenesis regulating proteins in brown adipose tissue. Ketone feeding also increased [18F]-FDG,cAMP and CREB in brown fat. The activation of brown adipose tissue by ketone esters is more marked than that obtained from feeding aketogenic diet.
In working perfused rat heart, ketone bodies result in an increase in acetyl CoA of 15 fold while a maximum dose of insulin increased heart acetyl CoA by 8 fold. Ketone bodies thus mimic the metabolic effects of insulin by overcoming the inhibition of pyruvate dehydrogenase characteristic of insulin resistance. Insulin resistance is a characteristic of cellular injury of nearly any sort. The use of ketosis is therefore a reasonable therapeutic tool in many areas.
Of particular interest is the ability of ketosis to overcome both PDH inhibition and ROS toxicity seen in Alzheimer’s and Parkinson’s disease. Feeding a ketone ester diet to the triple transgenic mice which model early onset Alzheimer’s disease results in a decrease in brain content of amyloid and phosphorylated Tau as well as improving cognitive function.
It would appear that feeding ketone ester would be an important therapeutic tool for insulin resistant states and states with increased free radical toxicity.
Brown Adipose Tissue Regulation by Thyroid Hormone
J. Enrique Silva, MD, FACP, Tufts University School of Medicine
Thyroid hormone (TH) plays an essential role in temperature homeostasis by supporting and regulating both obligatory and facultative (FT) thermogenesis. Brown adipose tissue (BAT) is a major site of FT in mammals. BAT FT is activated by the sympathetic nervous system (SNS) but TH is essential for a full response. The SNS stimulates the type-2 thyroxine 5’deiodinase (D2) that activates TH by converting thyroxine (T4) into triiodothyronine (T3). BAT concentration of T3 may thus increase to saturate the local T3 receptors. T3 interacts synergistically with SNS to maximize the expression of key BAT genes, most notably uncoupling protein 1 (UCP1) interacting synergistically with cAMP on this gene enhancer region. T3 also amplifies norepinephrine thermogenic signaling by controlling key genes. In hypothyroidism, BAT SNS stimulation is increased but ineffective. Supraphysiological doses of T4 can directly inhibit D2 activity reducing its own conversion to T3 and can also decrease SNS output from the hypothalamus. On the other hand, transgenic mice with deletion of the UCP1 or T3-receptor alpha have disabled BAT and reduced cold tolerance but not obesity. Increased SNS activity in response to impaired BAT thermogenesis can stimulate D2 in BAT, inguinal fat and skeletal muscle, supporting an alternate form of FT that confers a lean phenotype with reduced sensitivity to diet-induced-thermogenesis, particularly notorious in T3-receptor α KO mice. These observations suggest complex, multilevel thermo-regulatory actions of TH and, further, that BAT has evolved as the least energy expensive way to defend body temperature.
Knockdown of NPY in the Dorsomedial Hypothalamus Promotes White to Brown Adipocyte Transformation
Sheng Bi, MD, Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine
Two types of fat, white adipose tissue (WAT) and brown adipose tissue (BAT), exist in mammals including adult humans. WAT stores excess calories and excessive accumulation of fat causes overweight/obesity, whereas BAT dissipates chemical energy to produce heat, leading to the potential for combating obesity. Using the rat model withadeno-associated virus (AAV)-mediated knockdown of orexigenic neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH), we recently found that NPY knockdown in the DMH promotes development of brown adipocytes in inguinal WAT. This knockdown resulted in elevatedexpression of thermogenic genessuch as uncoupling-protein 1 (Ucp1)and peroxisome proliferator-activated receptor-γ coactivator-1a (Pgc-1a) in inguinal fat and increased inguinal fat temperature. DMH NPY knockdown also elevated Ucp1 expression in interscapular BAT and increased interscapular BAT temperature. Consistent with BAT activation, body energy expenditure was significantly increased in NPY knockdown rats compared to control rats. NPY knockdown rats exhibited increased thermogenic response to cold environment. Moreover, DMH NPY knockdown amelioratedhigh-fat diet-induced hyperphagia, obesity, and impaired glucose tolerance. Together, the recent findings demonstrate that in addition to its feeding effect, DMH NPY plays an importantrole in modulating adiposity and thermogenesis, providing the potential target for combating obesity.
Relevance of Brown Adipose Tissue in Childhood and Adolescence
Vicente Gilsanz, MD, PhD, Children’s Hospital Los Angeles, California
Brown adipose tissue (BAT) was thought to disappear after infancy; however, recent studies finding BAT in patients undergoing positron emission tomography/computed tomography (PET/CT) examinations have renewed the interest in deciphering the relevance of this tissue in humans. Available data suggests that BAT is more prevalent in children than in adults, and that its activation during adolescence is associated to significantly less gains in weight and adiposity. Data also shows that pediatric patients with metabolically-active BAT on PET/CT examinations have significantly greater muscle volume than patients with no identifiable BAT. Both the activity and the amount of BAT increase during puberty. Hence, concurrent with the great gains in skeletal muscle during infancy and puberty, all infants and adolescents accumulate large amounts of BAT. These observations are consistent with in vitro investigations suggesting close interactions between classic brown adipocytes, and myocites. In this presentation, we discuss the potential role of this tissue in regulating weight and musculoskeletal development in children, and we survey several unique imaging signatures of BAT that allow for its reliable identification by magnetic resonance imaging.
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