It's All Hormones: Study Identifies Molecular Diabetes-Depression Link
By Anette Breindl
Diabetic patients are two to three times as likely to be depressed as the general population. This week, scientists reported that they have identified a molecule that is low in both conditions, and may serve as a point of therapeutic intervention.
The molecule in question, adiponectin, is a signaling hormone that is produced by fat cells and regulates the breakdown of both glucose and fatty acids. Low levels of adiponectin are a risk factor for the development of Type II diabetes, and PPAR-gamma agonists such as Avandia (rosiglitazone, GlaxoSmithKline plc) and Actos (pioglitazone, Takeda Pharmaceutical Co. Ltd.) raise adiponectin levels, among other effects.
Adiponectin is "a circulating hormone, and it can get into the brain," Xin-Yun Lu told BioWorld Today. "But whether it affects our mood was not known." Lu is an associate professor of pharmacology at the University of Texas Health Sciences Center and the senior author of a paper describing adiponectin's effects in depression that appeared in the July 9, 2012, issue of the Proceedings of the National Academy of Sciences.
Previous studies had shown that adiponectin receptors are found in the brain, including areas that mediate emotion, and that the hormone can cross the blood-brain barrier. Lu and her team also had shown that adiponectin stimulates neural stem cells in the hippocampus. Making new neurons is thought to be a necessary step for antidepressants to have an effect.
So Lu and her team looked at both the natural adiponectin levels, and the effects of administering adiponectin, in mice that had been subjected to chronic stress and as a result, showed symptoms of depression.
The team first looked at the adiponectin levels in such animals, and researchers found that they correlated inversely with depression.
The lower a mouse's adiponectin levels were after several weeks of chronic stress, the more likely the animal was to show symptoms of depression. Specifically, the lower an animals' adiponectin levels were, the more likely they were to develop anhedonia, which is the inability to enjoy normally pleasant things in the case of lab mice, sugar water. The animals' weight did not change, meaning that the low adiponectin levels were not simply a consequence of the fact that there were fewer fat cells around to make them.
Lu and her team next looked at the opposite question, namely, whether animals whose levels of adiponectin were low to begin with were more sensitive to chronic stress. They compared animals with only one functional copy of the adiponectin gene, that is, about half of the normal level of adiponectin. In such animals, chronic social stress was more likely to lead to depressive symptoms than in their wild-type cousins. So were animals injected with an antibody to adiponectin, which would neutralize the hormone's effects.
Finally, when Lu and her team injected mice with adiponectin at the same time as exposing them to stress, those animals were protected, to a degree, from depressive symptoms.
Much remains unclear as to exactly how adiponectin affects depression on a cellular level. Lu and her colleagues found that one of the hormones' effects appears to be to shut off the so-called HPA axis, a signaling system which sets off the fight-or-flight response under acute stress and is hyperactive in depressed patients.
Lu and her team plan to look at adiponectin's effects on the HPA axis in more detail. They also want to investigate the relationship between the serotonin system, which is the target of currently marketed antidepressants, and adiponectin to see how the two intersect. Selective serotonin reuptake inhibitors raise the risk of Type II diabetes, suggesting there is perhaps a broader link between depression and metabolism.
They also hope to start a clinical trial with depressed patients both to see whether such patients have low levels of adiponectin to begin with, and whether administering adiponectin to them might help lift their moods.
If the work pans out, adiponectin, or treatments aimed at increasing its levels or its effectiveness, may become an alternative depression treatment for people who do not respond to serotonin-targeting drugs, or who have too many side effects to take them.
Adiponectin "can pass the blood-brain barrier," Lu noted. "It may serve as a therapeutic approach for such patients."
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