EXCEED THE SPACE PROVIDED. The regulation of body weight and energy balance involves communicationbetween signals emanating from peripheral tissues and the brain, most importantly, specific neural groups within the hypothalamus. Leptin is a hormone produced in adipose tissue that influences body weight and metabolism through actions in the brain, and to a lesser extent, in peripheral tissues. In most human and rodent obesity, there is an important degree of resistance to leptin action, the mechanism for which is not understood. A second important hormone that regulates energy balance and metabolism is insulin. Insulin resistance is also a characteristic of obesity and Type II diabetes. Suppressor of Cytokine Signaling 3 (SOCS3) is a molecule that we have shown to be capable of causing resistance to both leptin and insulin signaling and action. In addition, SOCS3 is expressedat higher levels in tissues of obese animals. This proposal will address the causes for leptin and insulin resistance in the brain and the peripheral tissues, and in particular, the role of SOCS3 in this process.
Aim 1 will involve detailed studies of mice with haploinsufficency of SOCS3, which have approximately half of the normal amount of this protein. The consequences of this reduced SOCS3 expression for leptin signaling in periphery and brain, and leptin physiologic actions on food intake and energy expenditure will be assessed. We will also determine the basis for greater sensitivity of female mice to SOCS3 deficiency, and the interactions between SOCS3 and another regulator of leptin and insulin sensitivity, PTP1b.
In Aim 2, we will determine the factors that regulate levels of SOCS3 expression in vitro and in vivo, and the cellular pathways through which they do so.
In Aim 3, we will determine the in vivo consequences of altered SOCS3 expression in hepatocytes and adipocytes. To do this, we wilf create mice with transgenic overexpression or conditional deletion of SOCS3 in hepatocytes and adipocytes, followed by studies of leptin and insulin signaling and biological actions in these tissues, as well as effects on systemic energy homeostasis. PERFORMANCE StTE(S) (organization, city, state) Beth Israel Deaconess Medical Center 330 BrooklineAve. Boston, MA 02215 KEY PERSONNEL ========================================Section End===========================================
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