Deconstructing Hypothalamic Neurocircuitry Architecture and Function in Metabolic Control during Health and Disease

Introduction

Understanding the exact nature of CNS-dependent regulation of body weight has become of utmost societal importance as we are witnessing an ever-increasing number of overweight and obese subjects who exhibit a predisposition for a plethora of obesity-associated diseases such as type 2 diabetes mellitus, cardiovascular diseases, and certain types of cancers.

Current Challenges

However, despite the tremendous advances made in defining the neurocircuitry basis underlying the central control of feeding and metabolism, critical open questions still remain.

Key Questions

For example:

1. How can we reliably identify the exact anatomical localization of the recently identified molecularly heterogeneous cell types in the hypothalamus?
2. What are yet unknown energy state- or food cue-regulated neuronal cell types and what is their functional contribution to energy homeostasis?
3. Which are yet unidentified neurocircuits critical for the initiation of adverse metabolic effects upon highly palatable food consumption?
4. What are the lipotoxic species accumulating in energy state-regulated neuronal cell types upon obesity development?

Proposed Work Program

The proposed work program will employ state-of-the-art technologies in modern molecular systems neuroscience and mouse genetics and will focus on the following four key aims:

1. Establishment of a high-resolution spatial transcriptional map of the murine hypothalamus
2. Identification, validation, and functional characterization of novel hypothalamic neuronal cell types activated during fasting/feeding transitions and upon sensory food perception
3. Discovery of novel hypothalamic neurocircuits activated during obesity development
4. Assessment of cell-intrinsic lipidomic changes in metabolism regulatory neurons during obesity development

Conclusion

Thus, the proposed work program will not only advance our fundamental understanding of the CNS-dependent regulation of metabolism, but could also open up new channels of drug discovery for tackling obesity and obesity-associated metabolic diseases.