The Neural Basis of Sugar and Fat Cravings

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Remarkably, animals can develop a strong preference for sugar even if they lack a functional sweet taste receptor, pointing to a detection mechanism independent of the sense of taste. Here, I demonstrate that a specific population of neurons in the brainstem is activated via the vagus nerve to create preference for sugar. These neurons are stimulated in response to sugar but not to artificial sweeteners, and are activated by direct delivery of sugar to the gut. By functional imaging of vagal neurons activated by intestinal delivery of glucose, we molecularly identified the glucose-specific transducer, SGLT1, in the gut. Next, I engineered animals where synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioral preference for sugar. Moreover, I demonstrated that these sugar preference neurons are genetically marked by enriched expression of the gene Penk, and that hijacking this circuit with a designer drug can condition preferences to initially non-preferred stimuli. These findings uncover a gut-brain circuit mediating sugar’s highly appetitive effects. Intriguingly, I discovered that dietary fat is also sensed via a post-ingestive gut-to-brain pathway, and engages the same preference-creating brainstem circuit as sugar. My results unveil an elegant convergent system where sugar and fat, which are likely sensed separately by specific gut transducers, share a unified gut-brain preference circuit for reinforcing their consumption. In the bigger picture, my findings suggest that it may be possible to develop a new class of chemicals that target the gut-brain preference axis to moderate the cravings for sugar and fat.