Determining how the sensory system affects metabolism
Project title: Identification of Sensory Neural Circuits Controlling Metabolic Disorders
Institution: Cedars-Sinai Medical Center
Pathway project publications: 1
Moved from the University of California, Berkeley to Cedars-Sinai Medical Center to start first independent faculty position as Assistant Professor in 2016
Our efforts to identify peripheral and central regulators of metabolic health have led to the discovery of two major and uncharacterized neurocircuits in obesity and diabetes. First, we evidenced a circulating factor secreted by sensory fibers in the viscera involved in metabolic health. Calcitonin gene-related peptide (CGRP) becomes elevated upon metabolic imbalance such as obesity and diabetes. Our results indicate that reducing CGRP levels is beneficial to improve insulin secretion in these conditions, and ameliorate glucose homeostasis and weight loss in obesity and diabetes.
Second, we were able to show that olfactory inputs play a role in energy balance. By genetically manipulating olfactory neurons, we engineered animals with reduced olfactory perception using the diphteria toxin receptor genetic ablation method, rendering these animals resistant to diet-induced obesity. Interestingly, these animals presented increased energy expenditure when loosing olfactory neurons. In addition, acute loss of smell perception after obesity onset not only abrogated further weight gain, but improved fat mass and insulin resistance.
Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory acuity in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals. This body of work helped me obtain a prestigious nomination for the HelDi award in 2017 and form a collaborative research agreement with Teva Pharmaceutical Industries in 2016.
Diabetes medications mainly function by lowering glucose levels in the blood. Here we propose a novel approach to target diabetes. The sensory neurons which we have showed to play a fundamental role in metabolic diseases, can be targeted specifically by a large array of natural and synthetic molecules, therefore opening the route towards discovery of safer treatments including better insulin secretagogues and sensitizers. We are adapting and developing tissue and cell-specific systems to identify cellular communication events that are responsible for diabetes in a genetically tractable mammalian model, in which disease phenotypes and cures can be applied to humans.
Getting the Pathway award is giving me a voice in a new field of study, and allows me to introduce a new angle to the classical approaches undertaken to study diabetes. Without the Pathway award, it would have been nearly impossible for a young investigator like myself to propose and carry on such research. Initially, my postdoctoral studies were first dedicated to the study of specific sensory neurons which control aging in invertebrate models, and then evolved towards the study of these same neurons in age-dependent metabolic decline in mice.
Receiving this award has provided the peer recognition and financial support required to fully switch towards the study of mouse metabolism in the context of diabetes and obesity. My research on olfactory and neural systems is providing a new level of understanding on the neurons that modulate energy homeostasis in the brain and at the periphery and leads to important therapeutic avenues to treat metabolic diseases.