Potential role of adiponectin signaling in mediating physical exercise-induced hippocampal neurogenesis and antidepressant-like effects / y Ang Li

Abstract

Psychological depression is a multi-factorial prevailing mental disease that frequently coexists with other disabling maladies such as diabetes, together incurring inestimable burdens worldwide. A recently-proposed theory suggests that suppression of neurogenesis which originates neural progenitor cells in the hippocampal dentate gyrus could be the underlying etiology, while physical exercise as a long-recognized remedy against depression is capable of restoring this impairment by an unknown mechanism. Adiponectin is an adipocyte-secreted protein abundant in the circulation and resembles exercise in counteracting diabetes, inflammation and atherosclerosis. This molecule has also been found to be neuroprotective and possibly linked to depression, given that circulating adiponectin concentrations are reduced in depressive patients and reversed by antidepressants. Following these implications, my current study examined whether and how adiponectin would serve to mediate exercise-triggered anti-depressive benefits.

Voluntary wheel running and daily injections of corticosterone within the same designated period were adopted as the paradigm for exercise training and stress insult in adult male animals, respectively. The in vivo assays showed that under the basal condition, indices including behavioral despairs, general condition, locomotor function, anxiety state, short-term recognition memory, as well as hippocampal neurogenesis reflected by densities of newborn, proliferating, and immature neuronal populations were unexceptionally comparable between wild-type and adiponectin-knockout mice. Prolonged corticosterone administration that caused dysregulation of the hypothalamic-pituitary-adrenal axis suppressed hippocampal neurogenesis and elicited depression-like behaviors similarly in non-runners of both genotypes. However, running-induced enhancement of hippocampal neurogenesis and mitigation of depressive severity, either preventive or curative, were exclusively observed in wild-type mice. Adiponectin proved permeable through the blood-brain barrier. Running-elevated serum and hippocampal adiponectin levels concurrent with activation of the proneurogenic AMPK pathway were abolished upon adiponectin knockout. In contrast, hippocampal levels of BDNF and IGF-1, together with expressions of the adiponectin receptors and adaptor protein APPL1 were unaltered by any specified maneuver. Raising hippocampal adiponectin levels by the adenovirus-mediated overexpressing strategy in wild-type non-runners duplicated the beneficial effects of exercise, including promotion of hippocampal neurogenesis that was negatively correlated with depressive severity.

The proneurogenic effect of adiponectin was also verified in vitro. Adiponectin receptors and APPL1 were expressed comparably on neural progenitor cells isolated from wild-type and adiponectin-deficient mice. Applying adiponectin increased proliferation, but not neuronal differentiation in a concentration-dependent manner, with similar efficacies and potencies between these two cell preparations. This enhancement could be diminished by down-regulating adiponectin receptor 1, APPL1, or inhibiting AMPKαT172 phosphorylation. Corticosterone retarded cell proliferation possibly through an AMPK-independent pathway; in contrast, dorsomorphin that blocked AMPK phosphorylation could attenuate the rescue by adiponectin on corticosterone-evoked anti-proliferation.

Collectively, physical exercise could trigger the increase of circulating adiponectin, whose accumulation in the dentate gyrus after permeation through the blood-brain barrier enhances hippocampal neurogenesis by activating the adiponectin receptor 1/APPL1/AMPK cascade, subsequently alleviating depression. The antidepressant-like effects of adiponectin seem both prophylactic and therapeutic, and rely little on the direct interaction with the well-known neurotrophic factors BDNF and IGF-1; accordingly, modulating adiponectin signaling might be a novel strategy in preventing and treating neurological diseases involving neurogenesis deficits, such as depression.