Control of body weight by specialized brain-adipose loop neurons

Introduction

Disruption of energy homeostasis can lead to obesity, a major health issue worldwide. Therapeutic efforts to reduce adiposity are nullified by metabolic adaptations. The mechanisms underlying these phenomena are unclear, precluding efficient intervention.

Hormonal Factors and WAT Innervation

Although it is well established that important hormonal factors control adiposity, it is less appreciated that fat (white adipose tissue, WAT) is innervated by sympathetic and sensory fibers forming, with discrete brain nuclei, loop circuits. These circuits are well-positioned for enabling WAT-brain bidirectional, non-hormonal communication, yet they remain uncharacterized.

Project Objectives

This project will uncover the brain circuits processing sensory-sympathetic homeostatic control of body weight. The objectives include:

1. Using labeling tracing strategies of the WAT to identify the brain areas containing loop neurons.
2. Interrogating their role in regulating body weight and processing WAT-derived inputs, using cutting-edge and complementary single-cell imaging and transcriptomic analysis.
3. Functionally manipulating, using opto- and chemo-genetics tools, the activity of loop neurons and their brain→WAT outputs in lean mice, mimicking activity changes in obesity, and assessing system-wide effects on behavior, metabolism, and body weight.

Expertise and Impact

My expertise in both central and peripheral systems gives me a unique perspective to address these fundamental questions. Uncovering the role of non-hormonal WAT-body communication in the regulation of energy homeostasis will revolutionize our understanding of weight regulation in health and disease.

Future Directions

This project will identify new molecular targets to develop better therapeutic strategies for obesity while also creating a platform for synergy between brain circuits and body organs, facilitating a host of future advances and new research directions.