Fat Tissue

Agenda

*Presentation times are subject to change.

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.

Travel & Lodging

Our Location

The New York Academy of Sciences

7 World Trade Center
250 Greenwich Street, 40th floor
New York, NY 10007-2157
212.298.8600

Click here for directions.

Hotels Near 7 World Trade Center

Recommended partner hotel:

The New York Academy of Sciences is a part of the Club Quarters network. Please feel free to make accommodations with Club Quarters on-line to save significantly on hotel costs.

Club Quarters Reservation Password: NYAS

Club Quarters, World Trade Center
140 Washington Street
New York, NY 10006
Phone: (212) 577-1133

Located on the south side of the World Trade Center, opposite Memorial Plaza, Club Quarters, 140 Washington Street, is just a short walk to our location.

Other hotels located near 7 WTC: