Obesity is the most prevalent nutritional problem in western civilization. Much progress has been made in the last 30 years, yet, basic questions remain unanswered. It is currently believed that reaching a """"""""critical"""""""" fat cell size (FCS) in adipose tissue stimulates increases in fat cell number (FCN). This hypothesis of fat cell proliferation has never been proven and there are no experiments that demonstrate the mechanisms or the factors involved in this process. Furthermore, it is likely that the """"""""critical"""""""" fat cell size that triggers proliferation may vary in different models of obesity, and, also from adipose depot to depot. Therefore, the overall goals of this research plan are to test whether the stimulation of fat cell proliferation is due to a consequence of existing fat cells reaching a critical lipid storage capacity, and to determine the mechanisms that underlie fat cell proliferation in obesity. To accomplish these goals, we will test several obesity models to determine if a local or systemic substance (""""""""adipogenic factor"""""""" [AF]) is responsible for increases in fat cell number. Three models of human obesity and two test models will be examined: l) genetic-induced obesity: Zucker fat/fat rats; 2) spontaneous obesity that accompanies old age: Wistar rats; 3) diet-induced obesity: high fat diet (HFD)-fed Wistar rats; 4) seasonal (photoperiod)-induced obesity: Syrian hamsters; and 5) hyperplastic model: Guinea pig. Using a unique approach and the combined expertise of the investigators, each of the defined models will be studied in three stages: l) Identification of an active fat cell proliferative state; 2) Testing for proliferative and differentiative activity of systemic and local AFs at time intervals before, during and after the critical proliferative state identified in Stage 1. Possible adipose tissue metabolic links with AF will be studied. 3) Testing the hypothesis that delaying fat cell size maturation by scheduled food restriction will result in delayed proliferative activity and delayed expression of AFs. The information gathered from each of the five animal models will be used to answer the questions posed in the four specific aims. I) Does a critical FCS lead to fat cell proliferation? 2) Is the proliferation and differentiation of fat cells in adipose tissue associated with the production of a local or systemic AF? 3) Of the known autocrine/paracrine factors present in adipose tissue, is there any one that may be related to FCS and adipogenic activity thus having the characteristics of an AF? 4) Do compositional adipose tissue changes or metabolic events trigger the appearance of the AF during the development of obesity? These studies will help the understanding of the fundamentals of the development of obesity and may suggest possible ways to prevent or arrest fat cell proliferation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047246-04
Application #
2770437
Study Section
Nutrition Study Section (NTN)
Program Officer
Yanovski, Susan Z
Project Start
1995-09-30
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Georgia
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602
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Hausman, Dorothy B; Fine, Jacqueline B; Tagra, Krishna et al. (2003) Regional fat pad growth and cellularity in obese zucker rats: modulation by caloric restriction. Obes Res 11:674-82
Qian, H; Hausman, D B; Compton, M M et al. (2001) TNFalpha induces and insulin inhibits caspase 3-dependent adipocyte apoptosis. Biochem Biophys Res Commun 284:1176-83
Hausman, D B; DiGirolamo, M; Bartness, T J et al. (2001) The biology of white adipocyte proliferation. Obes Rev 2:239-54
Plunkett, S S; Fine, J B; Bartness, T J (2000) Photoperiod and gender affect adipose tissue growth and cellularity in juvenile Syrian hamsters. Physiol Behav 71:493-501
Tchoukalova, Y D; Hausman, D B; Dean, R G et al. (2000) Enhancing effect of troglitazone on porcine adipocyte differentiation in primary culture: a comparison with dexamethasone. Obes Res 8:664-72
Marques, B G; Hausman, D B; Latimer, A M et al. (2000) Insulin-like growth factor I mediates high-fat diet-induced adipogenesis in Osborne-Mendel rats. Am J Physiol Regul Integr Comp Physiol 278:R654-62
Kras, K M; Hausman, D B; Martin, R J (2000) Tumor necrosis factor-alpha stimulates cell proliferation in adipose tissue-derived stromal-vascular cell culture: promotion of adipose tissue expansion by paracrine growth factors. Obes Res 8:186-93
El-Bakry, H A; Plunkett, S S; Bartness, T J (1999) Photoperiod, but not a high-fat diet, alters body fat in Shaw's jird. Physiol Behav 68:87-91
Kras, K M; Hausman, D B; Hausman, G J et al. (1999) Adipocyte development is dependent upon stem cell recruitment and proliferation of preadipocytes. Obes Res 7:491-7

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