Our Major Research Interests
- Biology of leptin and leptin receptor signaling
- Regulation of the central melanocortin/POMC system
- Molecular mechanisms for leptin resistance and obesity
Leptin is an adipocyte-derived hormone that acts on specific regions of the brain to regulate food intake, energy expenditure and neuroendocrine function, as well as other processes. Leptin is structurally related to cytokines and acts on receptors that belong to the cytokine-receptor superfamily. Several different leptin receptor isoforms are predicted to exist, including a long form, which has the highest level of expression in regions of the hypothalamus. A short leptin receptor isoform is highly expressed at the blood-brain-barriers and may play a role in transport of leptin into the brain. In vitro and in vivo studies from our lab demonstrate that leptin activates cytokine-like signal transduction by stimulating the JAK-STAT pathway via the long leptin receptor isoform. We have demonstrated presence of functional leptin receptors in regions of the hypothalamus, where signaling is believed to regulate the activity of critical neuropeptides, including the melanocortins (POMC) and NPY and AgRP, that are involved in regulation of energy homeostasis. Leptin receptors also exists outside the hypothalamus, mainly in the mid brain and in the caudal brainstem, where its function is less well described as compared to the hypothalamus.
Lack of functional leptin or of long form leptin receptors, as well as melanocortins, their processing enzymes and receptors, produces severe obesity in mice and in humans. However, most humans with obesity and many rodent models of obesity are characterized by hyperleptinemia and by resistance to leptin that has yet to be explained. Potential mechanisms for leptin resistance include defects in transport of leptin across the blood brain barrier, defects in leptin signal transduction in direct, leptin-receptor expressing target cells in the hypothalamus, and antagonism of leptin's physiologic action at one or more steps beyond the initial leptin-responsive neurons. The overall goals of our research are to increase the understanding of leptin action in the hypothalamus, post-translational processing of hypothalamic POMC and its role in obesity and leptin action, and to identify mechanisms of leptin resistance in obesity.
For a complete listing of Dr. Bjorbaek's publications, click here .