Exploring the circadian control of glucose metabolism by autophagy

Certain molecules can control the timing of events in liver cells, for instance, production and use of sugars. One such 'time-keeper' is cryptochrome 1 (CRY1). An important signaling molecule called AMPK is known to make changes to CRY1 (add a phosphate group on its surface), which will tag CRY1 for removal and help keep cellular timing. A major discovery was that CRY1 stops liver cells from making more sugar than it needs. Therefore, it is predicted that having more CRY1 will lower blood sugar and stop diabetes. New results suggest that autophagy, a pathway that keeps cells clean by eliminating unnecessary/broken cell parts, helps to remove CRY1 from cells by breaking it down, and mice with no autophagy have more CRY1 and lower blood sugar. This has led to the idea that autophagy is a new way by which cells remove CRY1, and individuals who are diabetic remove CRY1 faster by autophagy than those who are not. This study has three major Aims: Aim1 will test if CRY1, and other 'time-keepers', are removed from cells by autophagy, and if obese mice remove CRY1 faster than lean mice. Aim2 will test how autophagy removes CRY1 from cells, and what changes in CRY1 (addition of a phosphate group) will make CRY1 easier to remove. Aim3, will find out how obesity in mice changes CRY1, and which signaling molecules, for example AMPK, can bring about these changes. This study will find ways to stop cells from making more sugar and stop diabetes.