Skeletal muscle PGC-1α1 and KAT enzymes at the intersection between depression and metabolic disease

• Depression and metabolic diseases are leading causes of disability and major contributors to socioeconomic burden worldwide. Physical activity exerts many beneficial effects that confer direct health improvement in individuals suffering from these disorders. However, the molecular mechanisms underlying the influence of different components of exercise interventions remain unknown. To isolate the impact of skeletal muscle conditioning on stress-induced depression, we used transgenic models that exhibit many of the chronic adaptations to aerobic exercise in skeletal muscle. Here, we show a mechanism by which skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. PGC-1α1 acts in concert with PPARα/δ transcription factors to induce the expression of kynurenine aminotransferases in skeletal muscle. The activity of this pathway diverts the metabolism of stress-induced kynurenine to kynurenic acid. Since kynurenic acid is unable to cross the blood brain barrier, this peripheral shift protects the brain from stress-induced accumulation of kynurenines. In addition, we further show that skeletal muscle PGC-1α1 and kynurenine aminotransferases are part of the physiological adaptations to aerobic exercise in both rodents and humans. Given that exercise-mediated activation of this pathway leads to peripheral accumulation of kynurenic acid, we evaluated the physiological role of this metabolite in modulating energy homeostasis. Here, we describe that kynurenic acid plays a role in systemic energy homeostasis through the regulation of adipose tissue function and inflammation. Kynurenic acid induces the expression of lipid metabolism, thermogenic and anti-inflammatory gene networks in the white adipose compartment. This reduces body-weight gain and improves glucose tolerance in animals fed a high-fat diet. Mechanistic studies in primary adipocytes show that kynurenic acid activates the G protein-coupled receptor 35. Downstream signaling of this activation is mediated through Ca2+, ERK, CREB and PGC-1α1 stabilization. Finally, activation of GPR35 by kynurenic acid induces the expression of RGS14, which sensitizes β-adrenergic response to specific agonists. In sum, this work uncovers a previously unknown function of PGC-1α1 in skeletal muscle and kynurenic acid in white adipose tissue. Targeting this metabolic node has great potential for the treatment of depression and metabolic diseases such as type-2 diabetes.

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