2016 Pathway Initiator Awardee Zachary A. Knight, PhD

Examining how the brain controls obesity

Project title: Reinvestigation of the arcuate feeding circuit
Institution: University of California, San Francisco
Pathway project publications: 3
Has delivered 25 invited lectures related to his Pathway project

Major accomplishments:

We have elucidated some of the neural mechanisms by which AgRP hunger neurons control food intake and contribute to obesity. By recording for the first time the activity of these hunger neurons in awake, behaving mice, we discovered unexpectedly that these neurons are rapidly inhibited by the sight and smell of food. This raised the question of how these neurons can promote feeding at all.  We have shown that they do this through an unusual sustained hunger signal, in which the activity of these neurons before food availability can drive food consumption for tens of minutes after these neurons are silenced.

We showed that this long-lasting hunger signal acts by potentiating the rewarding sensory properties of food, and that AgRP neuron activity is positively reinforcing. Finally, we have begun to elucidate the mechanism underlying the long-lasting behavioral effects of AgRP neuron activity. We have shown that these effects are entirely dependent on NPY, a neurotransmitter released from these cells. We are currently trying to understand how NPY exerts its long-lasting effects.

Impact statement:

Obesity is the single greatest risk factor for the development of type 2 diabetes. A major obstacle to the development of safe and effective anti-obesity therapies is a lack of information about the origin of obesity -- i.e. the specific site in the brain where environmental or dietary signals override the energy homeostasis system and induce weight gain. My research seeks to address this knowledge gap, by using new technologies for optical monitoring and manipulation of neural circuits to investigate the key neurons in the mouse brain that control food intake. Specifically, we seek to (1) identify the signal arising from the body that activates these neurons and generates the sensation of hunger, (2) determine the neural mechanism by which these key neurons generate the motivation to consume food, and (3) clarify how diet-induced obesity causes dysregulation of these key neurons and thereby enables maintenance of an elevated body weight. The results of these studies will shed light on the basic neural mechanisms underlying the development of obesity and possibly identify points of intervention that can reverse these changes.

The Pathway award has been critical in providing the funding that has allowed us to pursue this research, by enabling us to access cutting edge tools and perform difficult, high-risk experiments. The Pathway award has also been critical for my scientific development through the interactions it has provided with other scientists, including especially the members of the Mentor Advisory Group.