Homeostatic control of body weight depends on the ability of the brain to sense and respond to changes in peripheral energy stores. Leptin and insulin, adiposity signals that circulate in proportion to the body fat mass, enter the brain and act on specific hypothalamic neurons to inhibit food intake and increase energy expenditure. Recent evidence shows that insulin and leptin also act in the hypothalamus to regulate glucose homeostasis. Therefore, communication between leptin, insulin and key hypothalamic neurons is essential for normal energy balance and glucose homeostasis, deregulation of which will lead to obesity and type 2 diabetes. Indeed, in many forms of obesity, hypothalamic leptin and insulin resistance develops, in which leptin and insulin are less effective in causing anorexia and body weight loss.

Our laboratory is interested in understanding how hypothalamic neurons sense and integrate peripheral adiposity signals such as leptin and insulin. We are currently using a combination of mouse genetic, physiologic and real time imaging approaches to address the following questions:

1. What are the leptin and insulin target neurons in the hypothalamus, and what are the functions of these neurons in energy balance and glucose homeostasis?

We and others have demonstrated that hypothalamic Proopiomelanocortin (Pomc) and Agouti-related Protein (Agrp) expressing neurons are essential for the regulation of energy balance. Ablation of the Pomc neurons leads to profound obesity and defects in compensatory refeeding while ablation of the Agrp neurons results in severe anorexia. We are carrying out experiments to further study the function of these neurons and to identify novel targets for leptin and insulin action.

2. What are the intracellular signaling mechanisms utilized by leptin in hypothalamic neurons?

We and others have illustrated that leptin signals through the Jak-Stat3 and PI3K signaling pathways in key hypothalamic neurons. We are interested in further defining the functional role of each of these signaling pathways in energy balance and glucose homeostasis in specific neuronal subgroups.

3. What are the mechanisms of hypothalamic leptin and insulin resistance?

Defects in intracellular signaling have been proposed to be an underlying mechanism of leptin and insulin resistance. We are using a combination of genetic and physiologic approaches to manipulate signaling events in key hypothalamic neurons in order to understand how leptin and insulin resistance develops and if perturbation of leptin and insulin signaling leads to obesity and type 2 diabetes.

Xu, A.W., Kaelin, C.B., Morton, G., Ogimoto K., Stanhope, K., Graham, J., Baskin D.G., Havel, P., Schwartz, M.W. and Barsh, G.S. Effects of melanocortinergic neurodegeneration on energy balance. In press, PLoS Biology. 2005.

Xu, A.W., Kaelin, C.B., Takeda, K., Akira, S., Schwartz, M.W., and Barsh, G.S. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 2005, 115 (4): 951-958.

Gropp, E., Shanabrough, M., Borok, E., Xu, A.W., Janoschek, R., Buch, T., Plum, L., Balthasar N., Hampel, B., Waisman, A., Barsh, G.S., Horvath, T.L. and Bruning, J.C. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. 2005, 8(10): 1289-91

Choudhury, A.I., Heffron, H., Smith, M.A., Al-Qassab, H., Xu, A.W., Selman, C., Simmgen, M., Clements, M., Claret, M., Maccol, G., Hisadome, K., Diakonov, I., Moosajee, V., Bell, J.D., Speakman, J.R., Batterham, R.L., Barsh, G.S., Ashford, M.L.J. and Withers, D.J. The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J. Clin. Invest. 2005, 115 (4): 940-950.

Kaelin, C.B, Xu, A.W., Lu, X.Y. and Barsh, G.S. Transcriptional regulation of Agouti-related protein (Agrp) in transgenic mice. Endocrinology. 2004,145 (12): 5798-5806.