Orexin: A possible link between diabetes and depression?

1. Orexin: A possible link between diabetes and depression?

2. Diabetes and depression amongst the leading causes of global disease burden Comorbid depression significantly worsens things -Non-depressed diabetes $55 M - Co-morbid $247 M The relationship can be bidirectional

3. Depressive phenotypes evoked by experimental diabetes are reversed by insulin -Lucki et al. 2011

4. Methods Two cohorts: First: For hippocampal cell proliferation - 2-month old males C57BL/6J males - Tests begin 2-3 Streptozotocin (STZ) and 1-2 weeks after insulin treatment - Elevated Zero Maze - Tail Suspension Test - Locomotor activity-movements/travelling

5. Methods Second: Second: For Intracranial self-stimulation (ICSS) - 4-month old males C57BL/6J males

6. Fig 1.- TST immobility increased by STZ. Reversed back by Insulin - Both diabetic and Insulin-treated ones showed decreased mobility

7. Fig 2 - Effects of diabetes and insulin treatment on ICSS performance

8. Fig 3: Longitudinal ICSS data from a single, representative STZ-diabetic mouse

9. Fig 4. Effect of diabetes and insulin treatment on hippocampal cell proliferation

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12. Main Points • EZM results: Experimental diabetes didn’t lead to anxiety • TST tests did depressive phenotypes which were reversed by insulin

13. Orexin-1 receptor colocalize with Pancreatic hormones and modulates STZ-induced Diabetes Mellitus Adeghate et al. 2008

14. Materials and Methods Streptozotocin induced DM (Type 1 diabetes) Goto-Kakizaki rats (Type-2 diabetes) Orexin deficient Immunohistochemistry of Pancreatic tissues from normal and diabetic rats - Antiserum of Orexin-1

15. Fig 1: OX1-R immunoreactivenerver fibers in normal and diabetic pancreatic cells

16. Fig 2: Receptor colocalization

17. Fig 3: Mean no. of pancreatic OX1-immunoreactive cells either with INS/Glu

18. Fig 4: Normal Wistar vs GotoKakizakizaki(more intense for Ox1R)

19. Fig 5: Long term diabetes islet cells show more localization

20. Fig 6: -Western blot of OX1R expression over a time period 2 & 4

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26. Conclusion • The no. of cells expressing OX1R increased in pancreatic islets after onset of diabetes • Expression intensity increases with latency of diabetes • The expression of OX1R is significantly lower in pancreas of Orexin knockout mice • STZ requires more orexins to cause diabtes

27. Hypothalamic orexin prevents hepatic insulin resistance induced by social defeat stress Tsuneki et al. 2013

28. Methods Animals: Orexin deficient, C57BL/6J male mice (WT) and ICR male mice (for causing Chronic social defeat stress) CSDS Glucose/Pyruvate/Insulin tolerance

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33. Conclusion • Central actions of orexin crucial for glucose homeostasis during depression • Basal to moderate activity of orexin neurons during defeat stress maybe sufficient to prevent impaired glucose regulation • Combined CSDS+Orexin deficiency promotes development of IR (increasing Akt phosphorylation) • Susceptible Orexin deficient mice increase leptin, increases hepatic IR • Hypothalamic Orexin system is required to prevent hepatic IR in a depressive state. Could also prevent persistent depression itself!

34. Take Home Depression may be caused due to diabetes Evidence of OX1R colocolization in diabetic pancreatic cells Social defeat stress (depression) possibly causes diabetes preventable by Orexin More study of Orexin as a link between diabetes and depression may lead to minimizing comorbidity of these two diseases

35. Thank you