Harnessing an energy-expending, appetite-suppressing fat-brain axis to unlock novel pharmacotherapies

Introduction

Obesity and cardiometabolic diseases are global crises that threaten to cripple healthcare infrastructures. These disorders originate from an excess calorie burden caused by consuming too much food and expending too little energy.

Current Challenges

Yet despite recent advances in obesity drugs, weight-lowering pharmacotherapies only reach about half the efficacy of surgical interventions. This difference could be due to existing drugs only acting to reduce food intake and not boost calorie-burning.

Discovery of a New Signaling Axis

Therefore, I believe our discovery of a leptin-independent signaling axis between adipose tissue (AT) and the central nervous system (CNS) that both decreases food intake and increases energy expenditure poses a breakthrough in obesity research.

Research Methodology

We uncovered this axis through receptor profiling and human genetic association studies and engineered a highly selective agonist that significantly decreases body weight and improves glucose and lipid homeostasis in obese mice. Our preliminary data have already led to a spinout company.

Knowledge Gaps

However, the physiological signaling mechanisms of this receptor in AT and the CNS that shape systemic energy balance through peripheral calorie-burning and central control of food intake remain unknown.

Project Goals

Thus, in HEAT-UP, we will:

1. Delineate AT and CNS receptor circuits with single-cell resolution.
2. Functionally test this signaling in 3D cultures of mouse and human AT.
3. Assess tissue-specific contributions to whole-body metabolism by combining our proprietary, selective agonist with state-of-the-art viral, genetic, and surgical manipulation of the receptor and neuronal wiring in AT and the CNS.

Characterization of Secretory Cells

Viral and genetic cell-labeling strategies will be used to characterize novel secretory cells that we found in mouse and human AT to contain the ligand for this receptor.

Conclusion

Collectively, these studies will provide a comprehensive, physiological overview of a previously unknown fat-brain signaling axis and insight into its potential for counteracting metabolic diseases.