Nutrient excess triggers profound functional changes in the hypothalamus, a critical brain site that mediates metabolic control throughout the body. For example, excess calorie intake provokes hypothalamic inflammation and diminishes hypothalamic cellular responses to key metabolic hormones such as insulin and leptin, thereby promoting chronic metabolic disease. We aim to identify intrinsic and extrinsic signals arising from excess caloric intake that regulate hypothalamic metabolic pathways.
Signaling mechanisms controlling hypothalamic leptin actions.
We are interested in 'leptin resistance' in obesity, a concept similar to insulin resistance in type 2 diabetes. Leptin is a hormone secreted by fat cells that acts directly on the brain to effectively suppress eating and reduce body weight. However, leptin is insensitive to exogenous administration in obese people who have high levels of circulating leptin. To investigate how leptin becomes insensitive in obesity, we use organotypic brain slices as an in vitro model that recapitulates cellular leptin resistance to identify molecular pathways and hormonal factors affecting cellular leptin action. Subsequently, we use genetic manipulations to assess their in vivo role in leptin action and obesity.
A gut-brain signal via the gut hormone GIP.
Using candidate ligand screening, we recently identified the gut hormone GIP as a potential circulating factor that inhibits leptin action in the hypothalamus. This finding led us to focus on the potential role of GIP in the brain, which has been little studied in the context of metabolic regulation. We are investigating the role of the brain GIP receptor in the control of metabolism using a genetic and pharmacological approach.
Mutant mice that are resistant to the anti-diabetic effect of metformin.
More recently, we have unexpectedly found that mice with a selective loss of the small GTPase Rap1 in the brain are unresponsive to metformin. This effect is highly specific to metformin, as the mice remain sensitive to other classes of anti-diabetic drugs. These important observations point to the brain as a potential target for metformin's anti-diabetic action. At the molecular level, Rap1 signaling may be the long-sought effector pathway for metformin. Using the metformin-unresponsive mice in combination with sophisticated genetic, neural, and metabolic techniques, we are exploring previously unrecognized neural mechanisms of metformin action.
