Control of body weight by specialized brain-adipose loop neurons

ongoing

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. 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 fibres forming, with discrete brain nuclei, loop circuits. These circuits are well-positioned for enabling WAT-brain bidirectional, non-hormonal communication, yet they remained uncharacterized. This project will uncover the brain circuits processing sensory-sympathetic homeostatic control of body weight. Using labelling tracing strategies of the WAT, I will identify the brain areas containing loop neurons. I will interrogate their role in regulating body weight and processing WAT-derived inputs, using cutting-edge and complementary single-cell imaging and transcriptomic analysis. Complementarily, I will functionally manipulate, 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 assess system-wide effects on behavior, metabolism, and body weight. 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 revolutionise our understanding of weight regulation in health and disease. 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.