Dr. Marc Van Gilst

Research Interests

VAN GILST LAB RESEARCH OVERVIEW
Animals adopt fundamentally distinct metabolic states when food is available or absent. The fed state is optimized for growth and reproduction, and relies on carbohydrates as the primary fuel source while excess nutrients are diverted for fat storage. In contrast, prolonged fasting initiates an alternative metabolic program that releases stored fat for energy production while postponing growth, reproduction, and aging. These programs have opposing effects on fat storage and expenditure, cellular growth and proliferation, and aging; therefore, feeding and fasting metabolism is likely to have a significant and underappreciated impact on human disease and longevity. The goals of my research program are to better understand the metabolic changes that occur between the fed and fasted states, and to define how these changes alter nutrient partitioning, reproduction, and longevity.


I. Flipping the Switch: Characterization of Signaling Mechanisms that Orchestrate the Metabolic Shift Between the Fed and Fasted States

Given the significance of fed and fasted state metabolism to human health, it is a primary objective of my research group to identify and characterize signaling molecules that help initiate these distinct programs. We have discovered one such factor, NHR-49, which is a close homolog of the human nuclear receptor HNF4alpha;. NHR-49 regulates a large set of metabolic genes in response to feeding and fasting and the function of NHR-49 is required for fasting dependent longevity and starvation dependent extension of reproductive lifespan. We will exploit the genetic advantages of C. elegans to define the molecular identity of the NHR-49 ligand and to isolate additional factors that function upstream and downstream of NHR-49 in the nutritional response mechanism.

II. Stopping the Clock: The Impact of Fasting on Aging and Reproductive Lifespan

We have found that intermittent fasting can significantly increase the longevity of adult nematodes. In fact, our results suggest that the aging process is halted during periods of fasting. Through gene expression studies, we have gathered evidence that discrete fatty acid beta oxidation complexes are instilled in the fed and fasted states, and we propose that fasting specific beta oxidation enzymes contribute to lifespan extension by facilitating "cleaner" energy production. We are currently working to define the composition of these distinct complexes.

We have also found that starvation can dramatically extend the reproductive lifespan of fully mature adults. This phenomenon requires establishment of a reproductive diapause that functions to protect germline stem cells during prolonged starvation. This adult diapause has yet to described in C. elegans and presents a novel genetic system to understand the relationship of nutrition to stem cell proliferation and quiescence. Our future efforts are focused on understanding the signals that communicate nutritional status to the reproductive system and its associated stem cells.

III. Nutritional Availability and Distribution of Resources: Employing New Isotope Labeling Strategies to Identify Genetic and Environmental Factors that Affect Nutrient Partitioning

Dietary fuel is preferentially partitioned for growth and storage during the fed state, and genetic factors that influence this partitioning may have considerable impact on obesity, cancer, and aging. To identify novel factors involved in nutrient partitioning, we have developed an innovative isotope tracer approach to quantify nutrient trafficking in vivo. Due to cost and time constraints, an approach of this magnitude could not be carried out in other commonly employed metazoan models, making C. elegans the perfect system for our goals. We will apply this strategy to identify genes involved in the allocation of dietary nutrients to fat synthesis and storage, or genes that facilitate the usage of dietary nutrients for cellular growth, proliferation, and/or repair.