We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

The canonical Wnt signaling pathway is ubiquitous throughout the body and influences a diverse array of physiological processes. Following the initial discovery of the Wnt signaling pathway during wing development in Drosophila melanogaster, it is now widely appreciated that active Wnt signaling in mammals is necessary for the development and growth of various tissues involved in whole-body metabolism, such as brain, liver, pancreas, muscle, and adipose. Moreover, elegant gain- and loss-of-function studies have dissected the tissue-specific roles of various downstream effector molecules in the regulation of energy homeostasis. This review attempts to highlight and summarize the contributions of the Wnt signaling pathway and its downstream effectors on whole-body metabolism and their influence on the development of metabolic diseases, such as diabetes and obesity. A better understanding of the Wnt signaling pathway in these tissues may aid in guiding the development of future therapeutics to treat metabolic diseases.

The scaffold protein 14-3-3ζ is an established regulator of adipogenesis and postnatal adiposity. We and others have demonstrated that the 14-3-3ζ interactome to be diverse and dynamic, and it can be examined to identify novel regulators of physiological processes, including adipogenesis. In the present study, we sought to determine if factors that influence adipogenesis could be identified in the 14-3-3ζ interactome found in white adipose tissue of lean or obese TAP-tagged-14-3-3ζ overexpressing mice. Using mass spectrometry, changes in the abundance of novel, as well as established, adipogenic factors within the 14-3-3ζ interactome could detected. One novel candidate is plakoglobin, the homolog of the known adipogenic inhibitor β-catenin, and herein, we report that plakoglobin is involved in adipocyte differentiation. Plakoglobin is expressed in murine 3T3-L1 cells and is primarily localized to the nucleus, where its abundance decreases during adipogenesis. Ectopic overexpression and siRNA-mediated depletion of plakoglobin had dual effects on inhibiting adipogenesis and reducing PPARγ2 expression. Plakoglobin depletion in human adipose-derived stem cells also impaired adipogenesis and reduced lipid accumulation post-differentiation. Transcriptional assays indicated that plakoglobin does not participate in Wnt/β-catenin signaling, as its depletion did not affect Wnt3a-mediated SUPERTOPFlash activity. Taken together, our results establish plakoglobin as a novel regulator of adipogenesis in vitro and highlights the ability of using the 14-3-3ζ interactome to discover undiscovered pro-obesogenic factors.