Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15–GFRAL signalling might reduce acute anxiety.

Our study presents the novel findings that chronic peripheral BDNF injections result in regulation of APP processing enzymes and improved cognition to a similar extent as exercise training. These findings highlight the potential efficacy of using BDNF as a therapeutic intervention in the prevention of neurodegenerative diseases (i.e., Alzheimer’s disease). Furthermore, future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be of value for populations that are at risk of AD.

Interleukin-6 (IL-6) is a pleiotropic cytokine that can be released from the brain during prolonged exercise. In peripheral tissues, exercise induced IL-6 can result in GLUT4 translocation and increased glucose uptake through AMPK activation. GLUT4 is expressed in the brain and can be recruited to axonal plasma membranes with neuronal activity through AMPK activation. The aim of this study is to examine if IL-6 treatment: (1) results in AMPK activation in neuronal cells, (2) increases the activation of proteins involved in GLUT4 translocation, and (3) increases neuronal glucose uptake. Retinoic acid was used to differentiate SH-SY5Y neuronal cells. Treatment with 100 nM of insulin increased the phosphorylation of Akt and AS160 (p < 0.05). Treatment with 20 ng/mL of IL-6 resulted in the phosphorylation of STAT3 at Tyr705 (p ≤ 0.05) as well as AS160 (p < 0.05). Fluorescent Glut4GFP imaging revealed treatment with 20ng/mL of IL-6 resulted in a significant mobilization towards the plasma membrane after 5 min until 30 min. There was no difference in GLUT4 mobilization between the insulin and IL-6 treated groups. Importantly, IL-6 treatment increased glucose uptake. Our findings demonstrate that IL-6 and insulin can phosphorylate AS160 via different signaling pathways (AMPK and PI3K/Akt, respectively) and promote GLUT4 translocation towards the neuronal plasma membrane, resulting in increased neuronal glucose uptake in SH-SY5Y cells.

Sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) uncoupling in skeletal muscle and mitochondrial uncoupling via uncoupling protein 1 (UCP1) in brown/beige adipose tissue are two mechanisms implicated in energy expenditure. Here, we investigated the effects of glycogen synthase kinase 3 (GSK3) inhibition via lithium chloride (LiCl) treatment on SERCA uncoupling in skeletal muscle and UCP1 expression in adipose. C2C12 and 3T3-L1 cells treated with LiCl had increased SERCA uncoupling and UCP1 protein levels, respectively, ultimately raising cellular respiration; however, this was only observed when LiCl treatment occurred throughout differentiation. In vivo, LiCl treatment (10 mg/kg/day) increased food intake in chow-fed diet and high-fat diet (HFD; 60% kcal)–fed male mice without increasing body mass—a result attributed to elevated daily energy expenditure. In soleus muscle, we determined that LiCl treatment promoted SERCA uncoupling via increased expression of SERCA uncouplers, sarcolipin and/or neuronatin, under chow-fed and HFD-fed conditions. We attribute these effects to the GSK3 inhibition observed with LiCl treatment as partial muscle-specific GSK3 knockdown produced similar effects. In adipose, LiCl treatment inhibited GSK3 in inguinal white adipose tissue (iWAT) but not in brown adipose tissue under chow-fed conditions, which led to an increase in UCP1 in iWAT and a beiging-like effect with a multilocular phenotype. We did not observe this beiging-like effect and increase in UCP1 in mice fed a HFD, as LiCl could not overcome the ensuing overactivation of GSK3. Nonetheless, our study establishes novel regulatory links between GSK3 and SERCA uncoupling in muscle and GSK3 and UCP1 and beiging in iWAT.

We show that a 5:2 intermittent fasting regimen can increase lipid oxidation without altering body mass in lean mice. Therefore, repeated intermittent fasting can increase metabolic flexibility without the need for (or prior to) weight loss. Intermittent fasting did not increase lipid oxidation in mice with obesity and type 2 diabetes, highlighting that obesity and/or type 2 diabetes limit changes in metabolic flexibility and mitigate increased fatty acid oxidation without weight loss during intermittent fasting.

Neurodegenerative diseases such as Alzheimer’s disease (AD) are becoming more prevalent in our aging society. One specific neuropathological hallmark of this disease is the accumulation of amyloid-β (Aβ) peptides, which aggregate to form extraneuronal plaques. Increased Aβ peptides are often observed well before symptoms of AD develop, highlighting the importance of targeting Aβ-producing pathways early on in disease progression. Evidence indicates that exercise has the capacity to reduce Aβ peptide production in the brain; however, the mechanisms remain unknown. Exercise-induced signaling mediators could be the driving force behind some of the beneficial effects observed in the brain with exercise. The purpose of this study was to examine if postexercise serum and the factors it contains can alter neuronal amyloid precursor protein (APP) processing. Human SH-SY5Y neuronal cells were differentiated with retinoic acid for 5 days and treated with 10% pre- or postexercise serum from humans for 30 min. Cells were collected for analysis of acute (30 min; n = 6) or adaptive (24 h posttreatment; n = 6) responses. There were no statistical differences in a disintegrin and metalloproteinase 10 (ADAM10) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA or protein expression with postexercise serum treatment at either time point. However, there was an increase in the ratio of soluble amyloid precursor protein α (sAPPα) to soluble amyloid precursor protein β (sAPPβ) protein content (P = 0.05) after 30 min of postexercise serum treatment. In addition, 30 min of postexercise serum treatment increased ADAM10 (P = 0.01) and BACE1 (P = 0.02) activity. These findings suggest that postexercise serum modulates important enzymes involved in APP processing, potentially pushing the cascade toward the nonamyloidogenic arm.