Cellular mechanisms governing nutrient sensing and organismal energy homeostasis

PROJECT SUMMARY From bacteria to humans, organisms modulate their food intake and energy expenditure in accordance with their internal nutrient state, allowing them to maintain a healthy energy balance. During evolution, conserved homeostatic mechanisms developed to cope with potential nutrient deprivation from a fluctuating food supply. Hence, when food is plentiful, excess energy is stored as fat reserves and mobilized during future scarcity. However, in the 21st-century nutritional scarcity is the exception rather than the norm, resulting in an increasing prevalence of obesity in humans. Obesity impacts cancer progression, accelerates aging, compromises immunity, and impedes a healthy lifestyle. We posited that understanding mechanisms and molecules at the interface of opposing nutrient states — scarcity and surplus — will reveal processes that control critical metabolic outcomes. Furthermore, we proposed that certain proteins function as molecular switches to control processes that allow an organism to operate in both states efficiently. We further surmised that chronic nutrient surplus impairs the capacity of the ‘molecular switch’ proteins to efficiently alternate in response to the nutritional state, resulting in energy imbalance. Once we identified such proteins, we determined to use them as an entry point to identify cellular mechanisms critical to healthy energy balance. To this end, we investigated one process: how do fat cells retain or release fat hormones – called adipokines— that serve as systemic nutrient surplus signals? Our investigations led to identifying one critical molecular switch, which is recognized as playing a role in membrane fusion events in previous studies. However, unexpectedly, we identified that this protein controls nutrient-state-dependent adipokine intracellular localization and gene expression. Therefore, we have uncovered a molecular switch mechanism that controls unanticipated cellular processes at the intersection of scarcity and surplus. The cellular processes that we have uncovered represent strategic avenues to treat and manage complex metabolic disorders. Hence, we propose to elucidate the following: i) define the molecular pathway by which this molecular switch protein controls nucleocytoplasmic localization and gene expression; ii) understand how diet-induced obesity disrupts this regulation, and iii) map consequences of this cell-intrinsic mechanism to organism-level metabolic outcomes and behaviors. We will use fruit flies for short to medium-term goals, as we have established a robust physiological Drosophila surplus model that mimics the diseased state. We will test conservations of these findings in mammalian systems in the future. In summary, our goal is to address outstanding issues in energy physiology by adopting a comprehensive and conceptually novel approach in a highly tractable model.