Jens C Brüning - C 05

Obesity and obesity-associated type 2 diabetes mellitus are on constant epidemiological rise and only limited therapeutic options exist. Nevertheless, the neuronal mechanisms underlying deregulated energy homeostasis during consumption of calorie dense food are not yet defined.

Unravelling novel neurocircuits in control of feeding, defining their deregulation in obesity development and identifying drugable targets on these circuits to modulate their activity pharmacologically represents a critical prerequisite to develop novel therapeutic approaches for these diseases.

Hypothalamic neurocircuits are key regulators of energy homeostasis and systemic glucose metabolism, and their deregulation upon consumption of highly palatable, calorie-rich diets represents a central mechanism in the development of obesity and type 2 diabetes mellitus.

Particularly, the inhibition of food-intake suppressing proopiomelanocortin (POMC)-expressing neurons has been demonstrated to contribute to this effect, and the mechanisms of obesity-induced POMC neuron inhibition include both cell autonomous impairments as well as increased inhibitory synaptic contacts.

We have identified a previously unrecognized population of GABAergic, inhibitory prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC), which are readily activated upon high fat feeding of mice, and which provide inhibitory synaptic input to POMC neurons.

Therefore, these neurons may be central to the diet-induced synaptic inhibition of critical feeding-regulatory POMC neurons during obesity development. In the current proposal, we aim at 1. characterizing the cell-intrinsic properties of hypothalamic PNOC neurons, 2. defining their neuronal network structure, 3. unraveling their regulation in vivo.

Collectively the project addresses a question of utmost clinical importance with the ultimate aim to define novel mechanisms for pharmacological intervention with prevalent metabolic disorders, for which currently only limited therapies exist.

1. Molecularly define PNOC Neurons
2. Identify their neuronal network structure
3. Define their physiologicaly and pathophysiologically relevant regulatory mechanisms