Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin - PubMed (original) (raw)

Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin

Suk Yu Yau et al. Proc Natl Acad Sci U S A. 2014.

Abstract

Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood-brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exercise-induced reduction in depression-like behaviors was abrogated in ADN-deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression.

Keywords: adiponectin; adiponectin receptor; depression-like behavior; hippocampal neurogenesis; physical exercise.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Elevation of adiponectin levels in the brain reduced depressive phenotype in mice. (A) Experimental timeline for administration of recombinant adenovirus and behavioral tests. C57BL/6J mice with i.c.v. injection of recombinant Ad-Adn or control Ad-Luc received the nonrunning treatment for 2 wk, followed by behavioral tests. (B) The tail TST and (C) the FST assessed the duration of immobility that parallels depressive severity. (D) The SPT examined the loss of preference to sucrose (anhedonia), a core symptom in depression. (E) Cell proliferation in the hippocampal dentate gyrus was determined by measuring the density of Ki67+ cells. *P < 0.05, **P < 0.005; n = 8 mice per group. (F and G) The immobility time of TST and FST was negatively correlated with the density of hippocampal Ki67+ cells. (H) Trimeric adiponectin (ADN, 20 μg) administered through the tail vein became detectable in CSF in _adipo_−/− mice at 3 h after injection. VEH, PBS as vehicle. **P < 0.005; n = 4 mice per group.

Fig. 2.

Fig. 2.

Depressive phenotype of WT and adipo −/− mice after the 2-wk running. (A) Experimental timeline for behavioral tests and sample collections. WT or adipo −/− mice received the 2-wk nonrunning or running treatment, followed by behavioral tests, including FST (B), TST (C), and SPT (D). Depression-like behaviors were significantly reduced by running in WT, but not adipo −/− mice. *P < 0.05 and **P < 0.005 vs. WT nonrunners; n = 8–10 mice per group.

Fig. 3.

Fig. 3.

Cellular changes in the hippocampus of WT and adipo −/− mice after exercise. (A) Experimental timeline for the running or nonrunning treatment, FST, and immunohistochemical analyses. WT and adipo −/− mice receiving the nonrunning or running treatment were daily injected with BrdU to label newborn cells during the last 5 consecutive days of the 2-wk training period. (B) Representative images of newborn (BrdU+) cells in the hippocampal dentate gyrus. (Scale bars, 100 µm.) (C and D) Running-enhanced hippocampal cell proliferation, reflected by the density of BrdU+ or Ki67+ population, was observed in WT but not adipo −/− mice. (E) Adiponectin knockout also diminished the effect of running on increasing the number of immature neurons (DCX+), without affecting the baseline. *P < 0.005 vs. WT nonrunners. (F) Neuronal differentiation estimated by the colabeling ratio of BrdU and DCX was comparable between WT and adipo −/− mice receiving the same treatments. *P < 0.05 vs. WT nonrunners, **P < 0.01 vs. adipo −/− nonrunners; n = 5–6 mice per group.

Fig. 4.

Fig. 4.

Effects of running on neurotrophic factors. The brain samples collected from adipo −/− mice or WT littermates receiving the 2-wk running or nonrunning treatment as described in Fig. 2_A_ were homogenized and subjected to immunoassays. (A and B) Running significantly increased the hippocampal but not circulating adiponectin levels in WT mice. *P < 0.05 vs. WT nonrunners. Note that adiponectin was undetectable in either the serum or hippocampal lysate of Adipo−/− mice. (C and D) The levels of BDNF in the whole hippocampus were unaffected by either exercise or adiponectin knockout. Running raised the BDNF levels specifically in the dentate gyrus of WT and adipo −/− mice essentially to the same extent. (E and F) adipo −/− mice showed lower protein levels of IGF-1 in the whole hippocampus compared with WT animals (*main effect of genotype: P < 0.001), whereas IGF-1 levels in the dentate region remained comparable in all four groups. n = 4–6 mice per group.

Fig. 5.

Fig. 5.

Effects of running and adiponectin on several signaling pathways in the hippocampus. The homogenates of hippocampal tissues collected from adipo −/− mice or WT littermates receiving the 2-wk running or nonrunning treatment as described in Fig. 2_A_ were subjected to Western blot analysis. (A) Representative immunoblotting images for phospho-AMPK (T172), total AMPK, phospho-Akt (S473), total Akt, phospho-Erk1/2 (T202/Y204), total Erk1/2, phospho-p38MAPK (T180/Y182), total p38MAPK, and the loading control β-actin. (B–E) Semiquantitative analysis for phosphor-AMPK (T172), phospho-Akt (S473), phospho-Erk1/2 (T202/Y204), and phospho-p38MAPK (T180/Y182). The data were expressed as fold changes over WT nonrunners. *P < 0.005 vs. WT nonrunners. n = 9 mice per group.

Fig. 6.

Fig. 6.

Adiponectin-induced enhancement of cell proliferation was mediated by ADNR1. The N2a cell line as well as the primary NPCs isolated from WT (WT NPC) and adipo −/− mice (KO NPC) were incubated with different concentrations of trimeric adiponectin and measured for proliferation using MTT (A and C, Left) and CyQuant assays (B and C, Right). *P < 0.05 vs. control cells without adiponectin treatment. (C) The concentration-dependent curves replotted using the data from A and B show the comparable responses to adiponectin in these three cell preparations. (D) Down-regulating ADNR1 but not ADNR2 in N2a cells with siRNA abolished adiponectin-enhanced proliferation. *P < 0.05 vs. Scramble siRNA-transfected cells (SC) without adiponectin treatment. n = 4–5 independent experiments for each assay. Numbers enclosed in the bracelets indicate the concentrations of the trimeric adiponectin applied. CT, combined transfection of si-Adnr1 and si-Adnr2.

Comment in

Similar articles

Cited by

References

    1. Rimer J, et al. Exercise for depression. Cochrane Database Syst Rev. 2012;7:CD004366. - PubMed
    1. Déry N, et al. Adult hippocampal neurogenesis reduces memory interference in humans: Opposing effects of aerobic exercise and depression. Front Neurosci. 2013;7:66. - PMC - PubMed
    1. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA. 1999;96(23):13427–13431. - PMC - PubMed
    1. Eadie BD, Redila VA, Christie BR. Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J Comp Neurol. 2005;486(1):39–47. - PubMed
    1. Yau SY, et al. Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats. PLoS One. 2011;6(9):e24263. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources