The associations between sugar-sweetened beverage (SSB) consumption and the risk of stroke, depression, cancer, and cause-specific mortality have not been determined, and the quantitative aspects of this link remain unclear. This meta-analysis therefore conducted a systematic review and dose-response analysis to determine their causal links. The database searches were conducted in PubMed, Cochrane library, Embase, Web of Science up to 10 November 2021. The intervention effects were evaluated by relative risk (RR) with 95% confidences (CI). Thirty-two articles met the inclusion criteria. Higher levels of SSB consumption significantly increased the risk of stroke (RR 1.12, 95% CI 1.03–1.23), depression (1.25, 1.11–1.41), cancer (1.10, 1.03–1.17), and all-cause mortality (1.08, 1.05–1.11) compared with none or lower SSB intake. The associations were dose-dependent, with per 250 mL increment of SSB intake daily increasing the risk of stroke, depression, cancer, and all-cause mortality by RR 1.09 (1.03–1.15), 1.08 (1.06–1.10), 1.17 (1.04–1.32), and 1.07 (1.03–1.11), respectively. The link was curved for depression and cancer risk (p_non-linear < 0.05). Subgroup analysis suggested that higher SSB intake increased ischemic stroke by 10%, CVD-caused mortality by 13%, and cancer-caused mortality by 6.0% than none or lower SSB consumption. It is suggested that SSB accounts for a leading risk factor of stroke, depression, cancer, and mortality, and that the risk rises in parallel with the increment of SSB intake (and is affected by participant characteristics).

Persistent microglial inflammation is a detrimental contributor to the progression of Parkinson disease (PD) pathology and related issues such as impaired adult hippocampal neurogenesis (AHN) and cognition. We conducted a 10‐week exercise program with MPTP‐treated mice to determine whether neuroinflammation can be addressed by aerobic exercise and elucidate its underlying regulatory mechanisms. Ten weeks of exercise significantly reduced PD‐related pathology and enhanced AHN and memory. These changes were linked to a reduction in neuronal apoptosis, microglial inflammation, and NLRP3 inflammasome activation. In cultured microglia, fibril α‐synuclein reduced FNDC5/irisin protein levels and induced NLRP3 inflammasome formation and IL‐1β production, which could be diminished by recombinant irisin treatment. Interestingly, “runner serum” isolated from exercising rodents enhanced FNDC5/irisin expression and reduced NLRP3 inflammasome components and IL‐1β secretion in α‐synuclein‐treated microglia. These effects could be diminished by blocking irisin signaling with cyclo RGDyk or NLRP3 agonist, nigericin sodium salt. Exercise‐induced neuroprotective effects were weakened by treatment of MPTP‐treated mice with cyclo RGDyk. In contrast, systematic administration of irisin partially replicated the beneficial effects of exercise on PD pathology, AHN, and memory function. As a nonpharmacological strategy, aerobic exercise effectively addresses PD pathology and preserves adult neurogenesis and cognition by mitigating microglial inflammation via mediating irisin/NLRP3 inflammasome pathways.

Neuroinflammation is a major feature of type 2 diabetic mellitus (T2DM), adversely affecting hippocampal neurogenesis. However, the precise mechanism is not fully understood, and therapeutic approaches are currently lacking. Therefore, we determined the effects of exercise on neuroinflammation and hippocampal neurogenesis in T2DM mice, with a specific focus on understanding the role of the irisin and related cascade pathways in modulating the beneficial effects of exercise in these processes. Ten-week exercise significantly decreased T2DM-induced inflammation levels and markedly promoted hippocampal neurogenesis and memory function. However, these positive effects were reversed by 10 weeks of treatment with cyclo RGDyk, an inhibitor of irisin receptor signaling. Additionally, exercise helped reduce the M1 phenotype polarization of hippocampal microglia in diabetic mice; this effect could be reversed with cyclo RGDyk treatment. Moreover, exercise markedly increased the levels of fibronectin type III domain-containing protein 5 (FNDC5)/irisin protein while decreasing the expression of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and nuclear factor kappa-B (NF-κB) in the hippocampus of T2DM mice. However, blocking irisin receptor signaling counteracted the down-regulation of TLR4/MyD88/NF-κB in diabetic mice undergoing exercise intervention. Conclusively, exercise appears to be effective in reducing neuroinflammation and enhancing hippocampal neurogenesis and memory in diabetes mice. The positive effects are involved in the participation of the irisin/TLR4/MyD88/NF-κB signaling pathway, highlighting the potential of exercise in the management of diabetic-induced cognitive decline.

Insulin resistance is recognized as one major feature of metabolic syndrome, and frequently emerges as a difficult problem encountered during long-term pharmacological treatment of diabetes. Insulin resistance often causes organs or tissues, such as skeletal muscle, adipose, and liver, to become less responsive or resistant to insulin. Exercise can promote the physiological function of those organs and tissues and benefits insulin action via increasing insulin receptor sensitivity, glucose uptake, and mitochondrial function. This is done by decreasing adipose tissue deposition, inflammatory cytokines, and oxidative stress. However, understanding the mechanism that regulates the interaction between exercise and insulin function becomes a challenging task. As a novel myokine, irisin is activated by exercise, released from the muscle, and affects multi-organ functions. Recent evidence indicates that it can promote glucose uptake, improve mitochondrial function, alleviate obesity, and decrease inflammation, as a result leading to the improvement of insulin action. We here will review the current evidence concerning the signaling pathways by which irisin regulates the effect of exercise on the up-regulation of insulin action in humans and animals.

Purpose: Though exercise generates beneficial effects on diabetes‐associated cardiac damage, the underlying mechanism is largely unclear. Therefore, we prescribed a program of 8‐week treadmill training for type 2 diabetes mellitus (T2DM) rats and determined the role of irisin signaling, via interacting with AMP‐activated protein kinase (AMPK), in mediating the effects of exercise on myocardial injuries and mitochondrial fission.Methods: Forty 8‐week‐old male Wistar rats were randomly divided into groups of control (Con), diabetes mellitus (DM), diabetes plus exercise (Ex), and diabetes plus exercise and Cyclo RGDyk (ExRg). Ex and ExRg rats received 8 weeks of treadmill running, and the rats in the ExRg group additionally were treated with a twice weekly injection of Cyclo RGDyk, an irisin receptor‐αV/β5 antagonist. At the end of the experiment, murine blood samples and heart tissues were collected and analyzed with methods of ELISA, Western blot, real‐time quantitative polymerase chain reaction, as well as immunofluorescence staining.Results: Exercise effectively mitigated T2DM‐related hyperglycemia, hyperinsulinemia, lipid dysmetabolism, and inflammation, which could be diminished by Cyclo RGDyk treatment. Additionally, exercise alleviated T2DM‐induced myocardial injury and excessive mitochondrial fission, whereas the beneficial effects were blocked by the administration of Cyclo RGDyk. T2DM significantly decreased serum irisin concentrations and fibronectin type III domain‐containing protein 5 (FNDC5)/irisin gene and protein expression levels in the rat heart, whereas exercise could rescue T2DM‐reduced FNDC5/irisin expression. Blocking irisin receptor signaling diminished the exercise‐alleviated mitochondrial fission protein expression and elevated AMPK phosphorylation.Conclusion: Exercise is effective in mitigating diabetes‐related insulin resistance, metabolic dysfunction, and inflammation. Irisin signaling engages in exercise‐associated beneficial effects on myocardial injury and excessive mitochondrial fission in diabetes rats involving elevated AMPK phosphorylation.