Interaction of adipokines with orexin signalling

Orexins (also termed hypocretins) are peptides expressed by neurons located specifically in the lateral hypothalamus. Orexin-containing neurons project to various brain areas and closely interact with systems that regulate arousal, energy homeostasis, and reward-motivated behaviour. Orexin neurons are ideally positioned to integrate various hypothalamic and peripheral signals and adipokines may potentially interact with orexin signalling. Furthermore, orexin neurons monitor humoral and neural indicators of energy balance such as extracellular glucose and lactate concentration.

Orexins increase central leptin sensitivity via specific receptor subtypes and enhanced type-2 orexin receptor signalling was shown to prevent diet-induced obesity. On the other hand, via its effect on astrocyte function leptin and, potentially, other adipokines may regulate the activity of orexin neurons. The molecular mechanisms and neuronal circuits mediating these leptin-orexin interactions remain unclear and are addressed with this research project.

Topics for research projects are:

• Interaction of orexin and leptin signalling in hypothalamic neurons at SHP2-ERK signalling pathways and role of ITIMs/ITSMs in orexin receptors
• Effect of leptin/adipocytes on hypothalamic astrocyte metabolism and body weight regulation

Doctoral researcher/students will employ molecular biology techniques, primary neuron/astrocyte cultures, and hypothalamic slices as well as mouse models to study food intake/energy expenditure using indirect calorimetry.