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Growth hormone: an endocrine factor that integrates thermogenic and circadian signals to regulate brown adipose tissue activity.

Periodic Reporting for period 1 - GRO-BAT (Growth hormone: an endocrine factor that integrates thermogenic and circadian signals to regulate brown adipose tissue activity.)

Reporting period: 2016-10-01 to 2018-09-30

The intertwined diseases of obesity and diabetes is one of the greatest threats to health worldwide. The potent fat-burning and glucose-consuming functions of brown adipose tissue (BAT) make it an appealing avenue to target both obesity and diabetes. In addition to the classic adrenergic activation of BAT in the cold, it has recently been shown that heat production in BAT is tightly controlled by the body’s circadian rhythm. This breakthrough has opened up new approaches to better understand how thermogenesis in fat tissue is regulated by intrinsic cues from the molecular clock and extrinsic cues from environmental temperature. However, little is known about how these cues coordinate inter-organ signals to regulate the metabolic activity of the tissue. We have identified an endocrine system that may integrate environmental and circadian signals to suppress BAT activity. This endocrine system is suppressed in mice during cold activation of BAT and is increased when the circadian clock turns thermogenesis off during sleep. siRNA-mediated knockdown in vitro increases uncoupled respiration in brown and beige adipocytes. Loss-of-function genetic models show a disruption to circadian temperature regulation and increased heat production during cold exposure. Identification of a novel endocrine system that dually coordinates the cold response and circadian rhythm of adipose thermogenesis could lead to new approaches to increase energy consumption in brown and beige fat.
This project included both training and scientific objectives. During year 1, we generated a novel BAT-specific knockout mouse model to study hormonal regulation of adipose thermogenesis. While this was being generated, we performed circadian studies in cells and control animals to determine circadian gene expression patterns under basal conditions, and also performed cold-exposure studies to determine how thermal stress regulates gene transcription in mice. During this period, we also used an in vitro cell culture system to investigate cell signaling pathways activated by adrenergic signaling and generate a model of cold-activation of cell signaling pathways regulated by the processes of thermal stress. During this time, there was a strong focus on professional development, including attending international conferences and trainings, as well as several courses and workshops in Denmark focused on scientific writing, grant writing, career choices and didactic skills. PRofessional leadership development was nurtured through service on the board of the European Young Endocrine Scientists organization that included chairing scientific sessions at meetings.

During the second year, we utilized the novel mice generated during the first year to investigate the thermogenic and circadian regulation of adipose thermogenesis in knockout animal models using state-of-the-art technologies and techniques such as telemetric temperature and activity recordings. Systemic metabolic effects were determined using indirect calorimetry and insulin and glucose tolerance tests. We also determined the potential translational potential of our discoveries using human immortal adipose cultures and primary human adipocytes. In conjunction with this, we analyzed genetic datasets to determine the impact of mutations in some of our key interest genes on human metabolism. Professional development activities continued through the second year, including attending conferences, training workshops, serving on the EYES board and co-founding and co-chairing the NNF CBMR Metabolism Association for Postdocs and Students (MAPS). We are currently writing up the results for imminent submission for publication consideration.
The pandemics of obesity and diabetes are tremendous healthcare challenges. Once published, we expect our results will push the state-of-the-art by revealing novel hormonal mechanisms that regulate adipose thermogenesis. This has broad implications because there is a strong potential for thermogenic adipose tissue to be used to consume calories in order to fight obesity and/or diabetes. We expect that our findings will eventually lead to new therapeutic targets and a better understanding of hormonal regulation of systemic metabolism.