Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognizing that many circulating proteins are packaged in extracellular vesicles (EVs), we employed quantitative proteomic techniques to characterize the exercise-induced secretion of EV-contained proteins. Following a 1-hr bout of cycling exercise in healthy humans, we observed an increase in the circulation of over 300 proteins, with a notable enrichment of several classes of proteins that compose exosomes and small vesicles. Pulse-chase and intravital imaging experiments suggested EVs liberated by exercise have a propensity to localize in the liver and can transfer their protein cargo. Moreover, by employing arteriovenous balance studies across the contracting human limb, we identified several novel candidate myokines, released into circulation independently of classical secretion. These data identify a new paradigm by which tissue crosstalk during exercise can exert systemic biological effects.

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.Type 2 diabetes (T2D) is highly prevalent, with an estimated 370 million affected individuals worldwide, and this is predicted to double by 2030 1,2 . Despite the presence of several well-established drug classes for treating T2D, there is still a considerable unmet need for a drug that halts or reverses disease progression. The gp130 receptor cytokines IL-6 and CNTF modify food intake and body weight and improve insulin resistance in mice and humans [3][4][5][6] . Axokine, the human variant of CNTF, underwent human clinical trials for the treatment of amyotrophic lateral sclerosis, but the drug was repurposed to treat obesity and T2D 7-9 . After showing promise, the clinical development of Axokine was discontinued when some treated patients developed antibodies 9 , because of the fear that this could interfere with the neuroprotective action of endogenous CNTF. Although IL-6 protects against obesity and insulin resistance 10 , it is also pro-inflammatory owing-in part-to its 'trans-signalling' effects 11,12 , which limits its therapeutic utility.The gp130 cytokines signal by binding to the cytokine α-receptors, which are the IL-6 receptor (IL-6R) and CNTF receptor (CNTFR) for IL-6 and CNTF, respectively. Binding initiates the recruitment and dimerization of two transmembrane β-receptors: the IL-6-IL-6R complex binds two gp130 receptors as a homodimer, whereas the CNTF-CNTFR complex binds gp130 receptor and the LIF receptor (LIFR) as a heterodimer 13 . By transferring the LIFR-binding module from CNTF to IL-6, we engineered the chimeric protein IC7 14 , which predominantly consists of IL-6 residues, rendering it far less likely to induce an immune response compared with CNTF, because IL-6 circulates freely whereas CNTF is intracellular, and lacks a signal sequence peptide. Because IC7 is a chimaera with a unique sequence

It is well known that obesity is responsible, at least in part, for the increased incidence of chronic diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer. Despite public education programs emphasizing lifestyle modifications to arrest this global pandemic, it is now estimated that 10-15% of the world's population are overweight or obese. As a result, new therapeutic options for the treatment of obesity-related disorders are clearly warranted. Much of the benefit of physical activity has been attributed to several mechanisms including reduced adiposity, increased cardiorespiratory fitness, reduced circulating lipids and the maintenance of muscle mass. However, the observation that the gp130 receptor cytokine interleukin-6 (IL-6) was released from skeletal muscle during exercise to improve metabolic homeostasis altered our understanding of the health benefits of exercise and opened avenues for research into potential novel therapeutics to treat metabolic disease. One gp130 receptor cytokine in particular, ciliary neurotrophic factor (CNTF), a pluripotent neurocytokine, showed efficacy as a potential anti-obesogenic therapy. This review examines the potential of gp130 receptor ligands, with a focus on IL-6 and CNTF as therapeutic strategies to treat obesity-related disorders.

ObjectivesType 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatment without compromising all IL-1β-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic β cell death, thereby preventing the onset of T2D.MethodsDiabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic β cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention.ResultsMCC950 was a potent inhibitor of NLRP3-induced IL-1β in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1β.ConclusionsNLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.