Obesity is a growing epidemic affecting not only one-third of Americans, but also millions of individuals across the world. This alarming increase in body-weight is largely attributed to increased availability of energy dense food and decreased opportunity for physical activity, leading to a situation where energy intake exceeds energy expenditure. Current efforts to combat the rising obesity epidemic focus on lifestyle changes including diet and exercise. However, these strategies have limited success. As a result, recent research has turned to understanding and developing methods to increase energy expenditure to offset increased caloric intake. Thermogenesis is the process by which energy is converted into heat and represents an important regulatory facet of energy homeostasis. Recent studies in humans have identified metabolically active BAT depots in adults, which is depleted in overweight individuals. Alterations in brain-derived neurotrophic factor (BDNF) signaling through the high-affinity BDNF receptor, TrkB, lead to a profound imbalance in energy homeostasis due in part to reduced energy expenditure. Studies have revealed that BDNF-expressing neurons in the PVH (PVHBDNF) are required for cold-induced adaptive thermogenesis, while BDNF-expressing neurons in the preoptic area (POABDNF) inhibit thermogenesis and promote cooling. Although progress has been made in defining the sites and function of BDNF-expressing neurons in thermoregulation, the location and action of reciprocal TrkB- expressing neurons remains unknown. In preliminary studies, we found evidence that TrkB-expressing neurons in the DMH (DMHTrkB) project to the PVH and the POA. Furthermore, we demonstrate that excitation of DMHTrkB neurons, using the hM3Dq DREADD receptor, increases body temperature, activity, and energy expenditure in mice. Given the involvement of PVHBDNF and POABDNF neurons in regulating thermogenesis, we propose that DMHTrkB neurons are responsive to changes in temperature and play an important role as either pre- or post-synaptic modulators of circuits that regulate thermogenesis.
In Aim 1, we will determine if temperature sensitive DMHTrkB neurons are excitatory or inhibitory in nature and confirm anatomical connections with PVHBDNF and POABDNF neurons using viral tracing methods.
Aim 2 will reveal the mechanisms through which TrkB expression in the DMH influences thermogenesis. Finally, Aim 3 will delineate the functional neural circuitry of DMHTrkB neurons that leads to increased energy expenditure. The results of this study have the potential to reveal novel pathways and neuronal populations that will be essential to understanding the mechanism through which neurotrophin signaling influences metabolism.
Activation of thermogenesis in brown adipose tissue (BAT) has emerged as an attractive therapeutic target for increasing energy expenditure to combat the recent and alarming rise in obesity. The results of this study will identify previously unrecognized populations of TrkB-expressing neurons that regulate energy expenditure and thermogenesis. Furthermore, this proposal will delineate neural circuits between BDNF- and TrkB-expressing neurons that represent important thermoregulatory pathways influencing BAT activity.
