Charles Weitz, MD, PhD
Professor
Department of Neurobiology, Harvard Medical School
Biological mechanisms of circadian clocks and their roles in metabolic processes
Investigate molecular mechanisms of circadian clocks in the brain, retina, and peripheral tissues
Commercial Opportunities
Investigate the relationship of biological clocks in the context of metabolic and lipid-related disorders, including atherosclerosis/cardiovascular disease, diabetes, and obesity.
Dr. Weitz’s recent findings relating to the important metabolic role of the Bmal1 clock gene in liver raises intriguing questions about the ability of biological clocks in peripheral tissues to regulate glucose and lipid metabolism. It can be envisioned that biological clock transcription feedback loop dysregulation can potentially contribute to the etiology of common disorders, such as atherosclerosis/cardiovascular disease, diabetes, and obesity. Because these disorders are some of the most pressing clinical problems in the Western world today, the ramifications of these findings are striking.
Further studies aimed at elucidating the role of peripheral tissue biological clocks in regulating metabolic processes will likely yield important findings that might have direct relevance to pharmacologic intervention. The identification of novel circadian clock mechanisms that act as efficient rheostats for blood glucose and lipid concentrations may open up entirely new areas of clinically relevant studies.
Current Research Interests
Dr. Weitz is studying the molecular circuitry and gene expression variations that are responsible for numerous activities regulated by circadian rhythms, including behavior and metabolic processes, such as glucose homeostasis. Central circadian clocks in the brain and photoreceptor cells are responsible for correctly coordinating cycling phenomena that influence behavior, locomotor activity, and light-dark oscillations. Moreover, these brain molecular clocks exert profound effects on metabolism, including the complicated metabolic fluctuations accompanying food ingestion and subsequent fasting periods. Dr. Weitz’s lab is exploring mechanisms of these master clocks in the brain, with particular emphasis on transcriptional feedback loops that produce exquisitely sensitive regulatory networks.
The lab is pioneering studies on peripheral tissue circadian clocks. They are unraveling the genetic and biochemical mechanisms of a liver biological clock. The lab uses animal models with tissue-specific gene inactivation to investigate control of circadian rhythms. The lab studies how the Bmal1 gene (encoding a master gene clock factor present in brain and peripheral tissues) coordinates the replenishment of glucose during fasting. Liver regulation of blood glucose is critical for preventing a precipitous drop in glucose levels during fasting (that is, hypoglycemia). This vital regulatory function relates to metabolic control, as well as to functions performed by circadian clocks present in other peripheral tissues.
Research Expertise
Dr. Weitz investigates internal biological time regulators, or circadian clocks, in the suprachiasmatic region of the brain (SCN), in retinal cells, and in various peripheral tissues. Biological clocks of the central nervous system are typically regulated by photoreceptors that sense light-dark cycles. This signal transmission contributes to the brain’s ability to regulate physiological (for example, locomotor functions) and psychological mechanisms by globally altering gene expression patterns.
Dr. Weitz clarified aspects of molecular signaling that mediate circadian rhythms. In particular, Dr. Weitz defined the secreted factors that carry out circadian oscillations. His lab identified a cytokine-resembling cardiotrophin as a strong candidate for a circadian factor that SCN neurons secrete. Cardiotrophin is an interleukin-6 family member that supports cardiac growth, as well as hypertrophy. This newly identified cytokine has an expression profile within the SCN that bears a reciprocal relationship to locomotor activity. Receptor antibody experiments support Dr. Weitz’s contention that this novel molecule is a critical mediator of SCN circadian oscillations.
The lab has also studied circadian clocks in peripheral tissues. In a recent high-profile article, the lab demonstrated that the gene product encoded by the Bmal1 clock factor gene helps the liver to regulate glucose homeostasis.