Circadian Control of Systemic Metabolism in Physiology and Type 2 Diabetes

Introduction

Type 2 diabetes is a global epidemic, with a prevalence of over 500 million. The current obesogenic environment, favoring high caloric foods and physical inactivity, is a major driver of this epidemic.

Circadian Rhythms and Metabolism

An evolutionarily conserved mechanism by which environmental factors impact whole body physiology is through internal biological clocks and the control of circadian rhythms. This machinery is a transcription/translation feedback loop that anticipates day/night cycles to optimize organismal physiology.

However, the underlying mechanisms regulating metabolic rhythmicity and its role in type 2 diabetes pathogenesis remain enigmatic. Cellular energy sensors relay information about the environment to the circadian clock machinery, but the extent to which this biology can be modified to improve systemic metabolism is unknown.

Research Objectives

We will uncover mechanisms that underpin the relationship between the circadian clock, energy sensors, and metabolism, as well as their dysfunction in type 2 diabetes. Our overarching hypothesis is that synchronizing energetic stressors to the molecular circadian clock may maximize the health benefits on metabolism.

Methodology

We will elucidate the mechanism by which the timing of energetic stressors acts on peripheral tissues controlling energy homeostasis. Our approach includes:

1. Studying temporal dynamics of cell and organ physiology, rather than snapshots in time.
2. Integrating “omics” analyses with rigorous physiological phenotyping of genetically modified mouse models.
3. Conducting clinical investigations in people with type 2 diabetes to temporally resolve dynamic networks of transcription, protein signaling, and metabolites, which synchronously control metabolism.

Expected Outcomes

In doing so, we will come closer to understanding the dynamic changes that occur with metabolic dysfunction. The work has the potential to make a breakthrough in clarifying underlying mechanisms for molecular regulation of metabolic rhythmicity, how this is perturbed in type 2 diabetes, and ultimately, insight into new treatments.