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Antidepressant Effects of Exercise: A Role for the Adiponectin‐PGC‐1α‐kynurenine Triad?

It is well recognized that exercise improves mental health, for example, by decreasing depressive behaviors, improving hippocampal-dependent learning and neurogenesis, and increasing dendritic plasticity. Yet how exercise influences the brain at the molecular level is not clearly understood. Yau et al. (2014) recently reported that the antidepressant effects of physical exercise are mainly mediated by adiponectin, an adipocyte-secreted hormone (“adipocytokine”) with neuroprotective effects at the central nervous system level. Almost simultaneously, another recent investigation revealed that exercise-induced mental protection is mediated by reduced levels in the brain of kynurenine, a metabolite of tryptophan (Agudelo et al., 2014). Peripheral conversion of kynurenine to kynurenic acid by kynurenine aminotransferases (KATs) limits the availability of kynurenine to the brain, inasmuch as kynurenic acid is unable of penetrate the blood– brain barrier (Agudelo et al., 2014). The exercise-induced transcriptional coactivator “peroxisome proliferator-activated receptor a” (PGC-1a), induces the expression of KATs, thereby reducing brain levels of kynurenine (Agudelo et al., 2014). Interestingly, it has been recently shown that the tryptophan–kynurenine metabolism is deregulated in overweight/obese adults (Mangge et al., 2014). Blood adiponectin levels decrease with worsening obesity among children and adolescents (Weiss et al., 2004) whereas higher circulating levels of this adipocytokine are associated with lower risk of type 2 diabetes (Li et al., 2009). In this regard, adiponectin regulates PGC-1a through both Ca2þ and AMP-activated protein kinase (AMPK)/sirtuin (SIRT)-1 signaling pathways (Iwabu et al., 2010). It is also well known that exercise and weight loss increase adiponectin levels in humans (Kriketos et al., 2004), whereas muscle-specific adiponectin receptor 1 (AdipoR1)-deficient mice show low expression of PGC-1a (at bothmessenger RNA and protein levels), as well as low phosphorylation of AMPK and poor exercise capacity (Iwabu et al., 2010). Adiponectin acts as a coordinator of energy balance amongst white adipose tissue (WAT), skeletal muscle, and other tissues. Therefore, we hypothesize that exercise and weight loss may induce the secretion of adiponectin by WAT which, in turn, increases Ca2þ and AMPK/ SIRT1-dependent PGC-1a expression throughout the stimulation of AdipoR1 in skeletal muscle, and thus, circulating levels of KATs. Higher KATs levels may be ultimately involved in the antidepressant effects of exercise in obesity and other metabolic diseases. Moreover, activated AMPK and increased PGC-1a have been suggested to mediate the regulatory effects of adiponectin on