2010 Annual Report
1a.Objectives (from AD-416)
1. Define the role and mechanisms of adipocyte death in obesity-associated
inflammation and metabolic disorders using genetic and nutritional models of
adipocyte growth and death.
2. Determine the role of the macrophage in modulating adipocyte death and associated adipose tissue inflammation using genetically altered animal models.
3. Determine the mechanisms by which alterations in Lipid Droplet (LD) proteins
modulate lipolysis and risk of developing metabolic disorders.
1b.Approach (from AD-416)
The role of adipocyte death in obesity will be investigated using a combination of transgenic and knockout mouse models and bone-marrow transplantation in mice fed different diets to understand the influence of obesity. In vivo and in vitro studies will investigate glucose and insulin homeostasis complemented by histological, immunohistological, electron microscopic, gene expression, FACS analysis, adipocyte lipolysis and Akt signaling studies. For studies investigating lipid droplet proteins, we will use both adenovirus expression vectors and possibly transgenic animals to determine how alterations in expression and intracellular signaling regulate protein expression, metabolic pathways, and lipolysis in cultured cells and animals. Depending upon which tissue is studied, we will examine lipolysis and protein expression, alterations in cytokine, lipid accumulation, signal transduction pathways, and oxidative gene expression.
As one approach to defining the role of fat cell (adipocyte) death in promoting fat tissue inflammation observed in obese individuals and its consequences, we have established a breeding colony of specific type of mouse called the FAT-ATTAC mouse over the past year. This mouse has an alteration specifically in fat cells that allows the investigator to induce fat cell death at the discretion of the researcher and will be used in future research studies.
To determine the role of the macrophage inflammation in modulating fat cell death and fat tissue inflammation, we have established a breeding colony of a second, specific line of mice. In these mice, the IKK beta gene, which has a central role in regulating inflammation, is specifically deleted in macrophages. Macrophages are a type of cell that is thought to be very important in promoting fat tissue inflammation in obese individuals.
For publications related to this project, see parent project #1950-51000-071-00D.
Estrogen increases skeletal muscle’s ability to burn fat. When women stop producing estrogen during the transition to menopause they are at an increased risk of developing obesity; however, the protective anti-obesity actions of estrogen are poorly understood. ARS-funded researchers from Tufts University in Boston, MA compared the characteristics of skeletal muscle in female mice that have lost the ability to produce estrogen as compared to female mice which produce estrogen normally. Our studies demonstrated that estrogen acts on muscle to produce a group of proteins that enhances the ability of muscle to burn fat. The results of this study demonstrate an important mechanism by which estrogen functions in women to protect against the development of obesity. Importantly this observation will direct researchers to investigate and identify nutrients that will mimic estrogen’s actions on skeletal muscle to facilitate fat burning.