Orexin: A possible link between diabetes and depression?

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

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

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

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

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

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

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

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

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

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

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

Fig 1: OX1-R immunoreactive nerver fibers in normal and diabetic pancreatic cells

Fig 2: Receptor colocalization

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

Fig 4: Normal Wistar vs Goto Kakizakizaki(more intense for Ox1R)

Fig 5: Long term diabetes islet cells show more localization

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

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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

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

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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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!

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

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