Autophagy Governs Circadian Clock and Blood Glucose Levels

Autophagy Governs Circadian Clock and Blood Glucose Levels

Our circadian clocks are centered in the brain and control key physiological processes—sleep, body temperature, organ function, and metabolic activities such as maintaining blood glucose levels. Disrupting the clock can potentially lead to diabetes and other metabolic diseases.

In a study involving mice that was published online on June 21 in Cell Metabolism, Rajat Singh, M.D., M.B.B.S., and his team discovered that autophagy—the cellular process for cleaning up and recycling old proteins and other material—helps regulate circadian rhythms and also governs the daily fluctuations in blood glucose levels.

In autophagy, the unwanted material is digested within enzyme-filled structures called lysosomes. The researchers found that autophagic digestion selectively targets proteins controlling the circadian clock, most notably the clock protein CRY1. CRY1 is a key regulator of circadian cycles and also helps maintain blood glucose levels by inhibiting the liver from forming and secreting glucose. The researchers found that by digesting CRY1 mainly between 3 pm and 11 pm, autophagy encourages the liver’s output of glucose during those hours—the period when mice are not feeding and therefore need a boost in blood glucose to fuel their activities. Feeding the mice a high-fat diet accelerated CRY1 degradation via autophagy, which contributed to obesity-associated hyperglycemia. Conversely, blocking the protein’s autophagic degradation led to a decrease in blood glucose levels.

For CRY1 to be digested by autophagy, CRY1 molecules must attach to specific proteins in the autophagy machinery, which targets them to lysosomes for digestion. Dr. Singh and colleagues found that CRY1 possesses two distinct amino acid sequences that allow them to be recognized for digestion by autophagy. The researchers hope to develop drugs that will prevent the autophagy of CRY1 by interfering with the autophagic machinery’s ability to recognize and interact with CRY1. By preventing CRY1’s degradation, these drugs should help stabilize CRY1 levels and lower blood glucose levels in people with diabetes.

Dr. Singh is associate professor of medicine and molecular pharmacology at Einstein.

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