Abstract
Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.
Highlights
Major depression is a mood disorder with multifactorial origins, which affects about 350 million people worldwide
Daily administration of AdipoRon during the last three weeks limited the corticosterone-induced increases of weight gain, epididymal mass, and adipocyte surface area, without any significant effect on control mice (Fig. 1b-e)
The plasma concentrations of ApN and leptin were increased in cortico-treated mice compared to that of control group, but chronic administration of AdipoRon did not counteract this cortico-induced effect (Fig. 1h)
Summary
Major depression is a mood disorder with multifactorial origins, which affects about 350 million people worldwide. The symptomology is complex and characterized by sadness, low self-esteem, social withdrawal, loss of interest and pleasure, despair for several consecutive weeks, amongst other symptoms. Major depression can occur as a transient and isolated episode or in a chronic fashion. Current treatments are mainly based on monoaminergic system regulation such as selective serotonin reuptake inhibitors (SSRIs), and are readily available and efficient. About 30% of patients with depressive disorders are partially or completely resistant to treatments. There is an urgent need for novel therapeutic targets for the treatment of depression
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