Fat Tissue

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Fat Tissue

Monday, February 28, 2011

The New York Academy of Sciences

Adipose tissue is now recognized as the largest endocrine organ in the human body with multiple adipokines, hormone receptors, growth factors and complex functions affecting the vital processes of reproduction and energy balance as well as the pathology of prevalent chronic diseases. New technology has enabled re-examination of adipogenesis, depot-specific cellularity and "lipostatic" mechanisms. This meeting assembles leaders in the field of adipose tissue research with very diverse backgrounds and foci who will provide a unique overview of a dominant factor in the chronic inflammatory insulin resistant syndrome of chronic overnutrition: adiposity.

Agenda

*Presentation times are subject to change.


1:00 PM

Opening Remarks
Jennifer S. Henry, PhD, The New York Academy of Sciences
John G. Kral, MD, PhD, SUNY Downstate Medical Center

1:10 PM

Introduction
The History and Utility of Measuring Cell Number and Size in Adipose Tissue

Jules Hirsch, MD, The Rockefeller University

1:30 PM

Keynote Presentation
Overview of Adipogenesis (Phylo- and Ontogeny) with Implications

Peter Arner, MD, PhD, Karolinska Institutet , Sweden

2:10 PM

Morphological and Molecular Aspects of Fetal Adipogenesis
Gary J. Hausman, PhD, USDA ARS

2:35 PM

Function and Dysfunction of Human Fetal Fat Accretion
Sylvie Hauguel-de Mouzon, PhD, Case Western Reserve University at MetroHealth Medical Center

2:55 PM

Discussion of Adipogenesis

3:15 PM

Coffee Break

3:45 PM

Introductory Comments
Pathophysiology and Metabolism
John G. Kral, MD, PhD, SUNY Downstate Medical Center

3:55 PM

Adipose Tissues: Innervation and Neural Regulatory Mechanisms
Timothy J. Bartness, PhD, Georgia State University

4:25 PM

Energy Balance on the Cellular Level – DAG and Lipodystrophy
Gerald Shulman, MD, PhD, Yale University School of Medicine

5:00 PM

An Immune Response to Weight Loss and Lipolysis
Anthony W. Ferrante Jr, MD, PhD, Columbia University

5:25 PM

Discussion

6:00 PM

Networking Reception

Speakers

Organizers

John G. Kral, MD, PhD

SUNY Downstate Medical Center

While researching the metabolic and cardiovascular effects of novel adrenergic receptor blockers Dr. Kral was recruited to the laboratory of Per Björntorp to study the influence(s) of adipocyte morphology on lipostatic mechanisms after surgical reduction of adipose tissue ("adipectomy") in rats. As a board certified surgeon he extended these studies, evaluating the effects of lipectomy and of metabolic gastro-intestinal operations for weightloss on body composition, adipose tissue receptors, and lipid and carbohydrate metabolism in severely obese patients. After completing his PhD Dr. Kral was recruited to the first NIH-funded Obesity Research Center at St. Luke’s Hospital, Columbia University, where he was appointed Director of Surgical Metabolism in 1981. In 1988 he was appointed Director of Surgery at Kings County Hospital Center and Professor of Surgery at Downstate Medical Center, resigning the directorship in 1992. His main scientific interests are appetite regulation, early-life stress and the intrauterine environment of gestational overnutrition and diabetes.

Jennifer S. Henry, PhD

The New York Academy of Sciences

Introduction

Jules Hirsch, MD

The Rockefeller University

Keynote speaker

Peter Arner, MD, PhD

Karolinska Institutet

Peter Arner is senior consultant in Endocrinology at Karolinska University Hospital and professor of Medicine at Karolinska Institutet, Stockholm, Sweden where he also is deputy chairman of the Department of Medicine. His main research focus is on human adipose tissue. Dr Arner has published > 400 papers about adipose tissue and related fields and is one of the most cited researchers in obesity according to ISI. He is cited over 18,000 times and has an H-index of 68. He was the first to study the endocrine function and inflammation in human adipose tissue and has made numerous original observations on the regulation of human fat cell lipolysis, the genetics of human fat cells and the impact of the adipose region; the current research focus is on the regulation of fat cell size and number in humans. He has several ongoing and past positions as associate editor and editorial board member of prestigious journals such as Diabetologia, International Journal of Obesity, Obesity and Obesity Reviews.

Speakers

Timothy J. Bartness, PhD

Georgia State University

Dr. Timothy J. Bartness is a Regents' Professor of Biology, an Associate member of the Neuroscience Institute, with a joint appointment in the Department of Psychology at Georgia State University. His laboratory studies the sympathetic and sensory nervous system innervation of white and brown fat, brown fat thermogenesis, obesity reversal, peptidergic control of appetitive ingestive behaviors (foraging and hoarding) and photoperiodism/melatonin. These studies are supported by National Institutes of Health research grants, most recently via a NIDDK MERIT Award.  Dr. Bartness is an Associate Editor for Obesity and Academic Editor for PLoSOne. He is on the Editorial Board of the American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, Neuroendocrinology, the Journal of Biological Rhythms, and the International Journal of Obesity. He also perform ad hoc reviews of manuscripts for over 90 additional different journals. He has been an impaneled member of National Institutes of Health Initial Review Group (Neuroendocrinology, Neuroimmunology and Behavior) and serves as an ad hoc reviewer for other National Institutes of Health Initial Review and Special Emphasis grant review panels, as well as doing so for the National Science Foundation, Israel Science Foundation, Medical Research Council of Canada, Dutch Diabetes Foundation, Research Grants Council of Hong Kong, Research Grants Council of Singapore, and the Australian National Health and Medical Research Council. He has given over 55 invited addresses and other special talks at international science meetings including an Alfred Nobel Foundation symposium on the adipocyte, and more than 70 invited seminars at US and international universities. He has published ~150 primary research papers and ~45 reviews/book chapters on obesity & ingestive behaviors. He is Past President and Board Member of the Society for the Study of Ingestive Behavior, and Program Committee Member for The Obesity Society.

Anthony W. Ferrante, MD, PhD

Columbia University

Tony Ferrante received his BA in physics from Yale University and his MD and PhD degrees from the Albert Einstein College of Medicine.  After completing his training in internal medicine at New York Presbyterian Hospital/Columbia University Medical Center, he performed post-doctoral studies with Rudy Leibel.   He subsequently joined the Naomi Berrie Diabetes Center at Columbia University where he is the Dorothy and Daniel Silberberg Assistant Professor of Medicine.

Dr. Ferrante's laboratory studies the role of immune cells in metabolic function.  Studies from his laboratory revealed that obesity leads to a recruitment of immune cells to adipose tissue, so that in the most obese rodents and humans ~50% of the cells in an adipose tissue depot are macrophages.  Current studies focus on the ways in which immune cells modulate the metabolic function of adipocytes, hepatocytes and other central metabolic cells.

Sylvie Hauguel-de Mouzon, PhD

Case Western Reserve University at MetroHealth Medical Center

Dr. Sylvie Hauguel-de Mouzon is Professor of Reproductive Biology at Case Western Reserve University as well as Research Director at National Institute of Medical Research (INSERM), France. She is also currently Director of the Molecular Obstetrics Research laboratory at MetroHealth Medical Center in Cleveland. Dr. Hauguel-de Mouzon completed her undergraduate studies in biochemistry and received her PhD and DSc degrees at the University of Paris 7. Her long term research interest has been on mechanisms regulating fetal growth and development at the cellular and molecular level. Her work has contributed several advances in our understanding of the regulation of the feto-placental unit metabolic function in humans with a recent focus on in utero metabolic programming of diabetes and obesity. Dr Hauguel-de Mouzon has served on numerous international committees and scientific associations and her latest honor is the Norbert Freinkel award for Outstanding Scientific Achievement in diabetes in pregnancy.

Gary J. Hausman, PhD

USDA ARS

Dr. Hausman has authored or co-authored 185 scientific articles published in refereed journals,119 abstracts, 10 book chapters, 14 reviews, 7 proceedings, 3 miscellaneous publications and has given 19 invited presentations at scientific meetings. Dr. Hausman's national and international reputation is reflected in invitations to present and discuss research data at national and international meetings and requests to consult with colleagues in academia, in industry, and in other governmental institutions throughout the world.  In addition, he has concieved, planned and organized major symposia for the national American Society of Animal Science and Experimental Biology Meetings. Dr. Hausman has also served on an NIH grant review panel and several committees that impact Agency, Departmental and Congressional policy makers.

Jules Hirsch, MD

The Rockefeller University

Jules Hirsch is Sherman M. Fairchild Professor Emeritus at The Rockefeller University, where he heads the Laboratory of Human Behavior and Metabolism. From 1992 to 1996, he served as Physician-in-Chief of The Rockefeller University Hospital. Dr .Hirsch is a leading authority on the metabolic and behavioral aspects of obesity and its role in degenerative disease. Through studies of fat cells, he has helped to explain why so many people have difficulty losing weight, why many who do lose weight suffer from the physical and emotional symptoms of starvation, why many individuals regain the weight they have lost, and what factors contribute to obesity. Dr. Hirsch has served on numerous national advisory councils and held leadership positions with the American Society for Clinical Nutrition, the American Psychosomatic Society and the Association for Patient-Oriented Research. In 1993, he was elected to the Institute of Medicine. He is the recipient of an honorary doctorate of science from the State University of New York, and he has been named a Fellow of the American Association for the Advancement of Science, the New York Academy of Medicine, the American Institute of Nutrition and the Royal College of Physicians in Edinburgh.

Gerald I. Shulman, MD, PhD

Yale University School of Medicine

Dr. Shulman is currently the George R. Cowgill Professor of Physiological Chemistry, Medicine and Cellular & Molecular Physiology at Yale University School of Medicine as well as an Investigator of the Howard Hughes Medical Institute. He is also Associate Director of the Yale Diabetes-Endocrinology Research Center and Associate Director of the Yale Medical Scientist Training Program. Dr. Shulman completed his undergraduate studies in biophysics at the University of Michigan, and he received his M.D. and Ph.D. degrees from Wayne State University. Following internship and residency at Duke University Medical Center, he did an endocrinology fellowship at the Massachusetts General Hospital and additional postdoctoral work in molecular biophysics and biochemistry at Yale before joining the faculty at Harvard Medical School. He was subsequently recruited back to Yale and has remained there ever since. Dr. Shulman has pioneered the use of magnetic resonance spectroscopy (MRS) to non-invasively examine intracellular glucose and fat metabolism in humans. This has afforded a dynamic view of intracellular metabolism in humans, not before possible, that has led to several fundamental discoveries in our understanding of the regulation of liver and muscle glucose metabolism in humans and its dysregulation in patients with T2DM. His work has been recognized with numerous honors and awards including the Outstanding Investigator Award from the American Federation for Clinical Research, the Diabetes Care Research Award from the Juvenile Diabetes Research Foundation, the Novartis Award in Diabetes, the Outstanding Scientific Achievement Award and the Distinguished Clinical Scientist Award from the American Diabetes Association and the Korsmeyer Award from the American Society for Clinical Investigation. Dr. Shulman has been elected to the Institute of Medicine and the National Academy of Sciences.

Sponsors

For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8658.

Academy friend

Seahorse Bioscience, Inc

Grant Support

This event is funded in part by the Life Technologies™ Foundation.

Abstracts

Overview of Adipogenesis (Phylo- and Ontogeny) with Implications

Peter Arner, MD, PhD Karolinska Institutet, Sweden

In the past it was believed that in humans fat cells were made up predominantly during the early period of life and that adults regulate their fat mass mainly by empting and filling pre-existing adipocytes. However, recent studies suggest that human adipose tissue is in a highly dynamic state with constant turnover of fat cells during the entire adult life span. As much as 10% of the total fat cell pools is renewed each year due to constant generation of new fat cells (adipogenesis) and death of old ones. This turnover is much accelerated among obese people but also important for the morphology of adipose tissue regardless of body weight status. Adipose tissue may consist of few but large fat cells (hypertrophy) or many small fat cells (hyperplasia). This is of clinical importance because adipose hypertrophy is associated with markedly increased risk of developing type 2 diabetes. Other recent studies show that development of adipose hypertrophy is due to a low rate of adipocyte turnover in both lean and obese people. The region of adipose tissue is also important for the morphology of human adipose tissue. Hypertrophy in the visceral area is related to dyslipidemia whereas, in the subcutaneous region, it is related to insulin resistance. What regulates adipocyte turnover in man? Last year it was demonstrated that local inflammation (previously considered to be a sign of adipose malfunction) is important for the normal fat mass and adipose morphology in lean young and healthy people. In particular the local production of the inflammatory protein tumour necrosis factor alpha is of important for the fat mass and adipose tissue morphology under normal conditions. Adipocyte turnover is a novel potential target for treatment of common disorders such as obesity, dyslipidemia and insulin resistance.

Adipose Tissues: Innervation and Neural Regulatory Mechanisms

Timothy J. Bartness, PhD, Georgia State University

Historically, one of the major controlling factors for mobilization of lipid stores from white adipose tissue (WAT) was thought to be via the neural control of epinephrine released from the adrenal medulla into the blood. Similarly, since the discovery of the largely WAT-derived cytokine, leptin, sensory communication from WAT to the brain was thought to be due its release into the blood.  There is, however, recent, growing appreciation for the control of WAT metabolism and growth by its direct sympathetic nervous system (SNS) innervation and of its sensory innervation as a neural conduit for afferent information from WAT to brain.  The primary reason for this focus on bi-directional, neural communication between these two organs rests on the ability to trace efferent and afferent multisynaptic circuits to and from WAT, respectively, using transneuronal viral tract tracers, as we first did for the SNS innervation of WAT using pseudorabies virus (PRV) and for the sensory innervation of WAT using the H129 strain of herpes simplex 1 virus.  Regarding WAT SNS innervation, we have identified some of the neurochemicals involved in the central origins of the SNS outflow from brain to WAT including the melanocortin 4-receptor (MC4-R) found on ~60% of these neurons. Regarding WAT sensory innervation, we have identified leptin receptors (Ob-Rb) on the first order dorsal root ganglia (DRG) afferent neurons. Functionally, central MC4-R agonism increases the SNS drive to WAT (norepinephrine turnover [NETO]), albeit differentially across the WAT pads.  Moreover, we recently adapted Western blot measures of the phosphorylation of perilipin A and hormone sensitive lipase (pPerilipin A, pHSL), intracellular biomarkers of processes necessary for catecholamine-stimulated lipolysis, and used them as in vivo markers of SNS-stimulated lipolysis on a fat pad-specific basis. Only WAT depots showing increases in NETO after central MC4-R agonism have increases in pPerilipin A and pHSL. In terms of the function of WAT sensory innervation, intra-WAT leptin microinjection increases pSTAT3, a marker of Ob-Rb activation in DRG sensory neurons innervating WAT suggesting leptin signaling from WAT to brain via sensory nerves.  Glucoprivation is a stimulus that markedly increases WAT NETO and we recently demonstrated that it is associated with increases in sensory nerve electrophysiological activity, an effect blocked by pretreatment with the pan ß-adrenoceptor blocker, propranolol, suggesting monitoring of lipolysis. Indeed, preliminary studies indicate single neurons in the brain that receive sensory inputs from WAT that are also part of the SNS outflow to WAT, as revealed by injections of the SNS tracer (PRV) and the sensory tracer (H129) both into the same WAT pads thereby suggesting a complete lipolytic neural feedback loop.  Collectively, these data exemplify the importance of the SNS and sensory innervation of WAT for control of WAT metabolism. 

An Immune Response to Weight Loss and Lipolysis

Anthony W. Ferrante, MD, PhD Columbia University

Obesity induces a systemic inflammatory response that is characterized by the production of pro-inflammatory molecules and the mobilization of immune cells to key metabolic tissues.  The central role of the immune system in the development of obesity-induced inflammation suggests that obesity alters some aspect of normal cellular function that is recognized by immune cells.   We hypothesized that lipolysis and local increased concentrations of free fatty acids and other lipids are central regulators of immune cells recruitment and function.  Consistent with this model, in obese individuals basal lipolysis is increased in adipose tissue and there is an increase in adipose tissue macrophages, T-cells and NK cells.  To test whether lipolysis regulates immune cell recruitment to adipose tissue we studied the effects of weight loss, fasting, adrenergic activation and genetic impairment of lipolysis on the accumulation of immune cells in adipose tissue.  Our findings suggest changes in lipid fluxes are recognized by the immune system and are key regulators of the immune and inflammatory response to metabolic perturbations.

Function and Dysfunction of Human Fetal Fat Accretion

Sylvie Hauguel-de Mouzon, PhD, Case Western Reserve University at MetroHealth Medical Center

A prevailing concept in the field of obesity research is that obesity begets obesity, the vicious cycle being precociously initiated in utero. Excess prenatal fat accretion is considered harmful for it may facilitate fat accumulation in later life, a harbinger of metabolic dysfunction. This current view raises the question of how do humans become fat before birth.

Glucose is considered as the preferential fetal energy substrate, a concept long time supported by the increased growth and adiposity of fetuses of diabetic women with poor glycemic control. The increased adiposity of fetuses of normoglycemic obese women suggests that other energy substrates and different hormonal environment also contribute to increase fetal lipogenesis. However, there is minimal information on the physiology of the fetal adipocyte development, particularly, the mechanisms regulating lipogenesis.  

In addressing the mechanisms for enhanced fetal lipogenesis, principles specific to the in utero environment are worth to keep in mind. The nutrient supply for the fetal adipose cell is continuous and, is totally dependent on the quality and quantity of its materno-placental transfer.

If we believe that breaking the early vicious cycle of obesity is critical to stem the tide of the epidemic, research is needed to address the founding mechanisms of adipose tissue development in normal as well as in plethoric environment. 

Morphological and Molecular Aspects of Fetal Adipogenesis

Gary J. Hausman, PhD, USDA ARS

The morphological development of adipose tissue in the fetal porcine model commences between 7 to 10 weeks of fetal life depending on location despite little lipid accretion per se. Very small adipocytes closely associated with developing vascular structures increase in number and slightly increase in size throughout fetal development. Anti-adipocyte monoclonal antibodies demonstrated a common developmental lineage for endothelial cells and preadipocytes.  In the fetal pig, there is a cranial to caudal and dorsal to ventral gradient regarding morphological development of adipose tissue. Furthermore, in the fetal pig, development of several layers of subcutaneous adipose tissue (outer, middle, inner) is followed postnatally by growth or expansion of each layer in a layer specific manner. Despite little lipid accretion, subcutaneous layer development in the fetus is predictive of adipogenesis in each layer postnatnatally. Microarray gene expression studies indicated that patterns of over two hundred genes encoding transcription factors, nuclear receptors, enzymes, regulatory proteins and secretory factors were expressed similarly by fetal S-V cell cultures and fetal adipose tissue. Expression of known adipocyte genes included GATA3, RARA, RXRG, c-Fos, STAT5B and conventional transcription factors. Expression of known adipocyte or adipose tissue secreted factors included, leptin, TNF-α, TGF-β1, IL -6, IL-15, and IL-1 β. Expression at the gene and protein level of these and several major adipogenic factors (except for HSL and LPL) is precocious in fetal adipose tissue considering studies of growing animals. In fetal S-V cultures, extensive, precocious and early increases in C/EBPα expression were followed by decreases in expression. However, PPAR γ expression was not precociously expressed since preadipocyte lipid accretion and PPAR γ were strongly linked in fetal S-V cultures. Furthermore, all lipid accreting cells in fetal S-V cultures were C/EBPα and PPARγ reactive. Therefore, co-localization of C/EBPα and PPAR γ in the preadipocyte nucleus is essential to lipid accretion and differentiation. These studies suggest that restricted adipogenesis in the fetus is attributable to limited DEX induced PPAR γ expression. Furthermore, in vivo hormone replacement studies indicate that concurrent action of glucocorticoids and thyroid hormones represent the critical aspect of endocrine regulation of fetal adipocyte number and size and leptin gene expression.

Cellular Mechanisms of Insulin Resistance: Implications for Obesity, Lipodystrophy, Metabolic Syndrome and Type 2 Diabetes

Gerald I. Shulman, MD, PhD, Yale University School of Medicine

Despite much work the cellular mechanisms responsible for insulin resistance in type 2 diabetes and the metabolic syndrome remain unknown. In this regard recent studies measuring muscle triglyceride content by biopsy or intramyocellular lipid content by 1H magnetic resonance spectroscopy have shown a strong relationship between intramuscular lipid content and insulin resistance in skeletal muscle. Recent studies have also demonstrated increases in intramyocellular lipid content in insulin resistant offspring of parents with type 2 diabetes suggesting that dysregulation of fatty acid metabolism may be responsible for mediating the insulin resistance in these individuals. Increases in the intramyocellular concentration of fatty acid metabolites in turn have been postulated to activate a serine kinase cascade leading to decreased insulin stimulated insulin receptor substrate-1 associated phosphatidylinositol 3-kinase activity resulting in reduced glucose transport activity and glycogen synthesis. This presentation will focus on recent studies using noninvasive 13C, 31P and 1H magnetic resonance spectroscopy techniques in humans that elucidate the pathogenesis of insulin resistance that occurs in obesity, type 2 diabetes, lipodystrophy and the metabolic syndrome.

The History and Utility of Measuring Cell Number and Size in Adipose Tissue

Jules Hirsch, MD, The Rockefeller University

Until the middle of the last century, fat or adipose tissue was generally considered to be a biochemically inert storage depot for energy, an insulator for the body and protective pad for organs and joints. In the 1950's, new methods for studying biochemistry by radioactive tracers, chromatography of lipids and the ability to separate adipocytes from stroma by enzymatic means, revolutionized our understanding of the importance of adipose tissue in human metabolism. Exquisite sensitivity of the tissue to hormones such as insulin provided a bioassay for insulin. As it became necessary to express biochemical data on a per cell function, new tools were developed for measuring the cellularity (cell number vs. cell size) in the tissue.

This presentation will describe how these studies of adipose cellularity led to a biologically based understanding of obesity. As molecular genetics developed, more refined tools were applied to the further understanding of obesity. However, the prevalence of obesity at epidemic proportions remains. Further badly needed understanding of obesity and adipose tissue function may profit by an additional search for developmental events that alter adipocyte cellularity.

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