Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11498-x
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Funding
- European Commission (Marie Curie Career Integration Grant) [320898]
- European Commission (ERC) [614847]
- Swiss National Science Foundation [310030_169966]
- Swiss Cancer League [KLS-3794-02-2016-R]
- Louis-Jeantet Foundation
- Fondation Pour Recherches Medicales of the University of Geneva
- Bo and Kerstin Hjelt Foundation for Diabetes Research
- Gertrude Von Meissner Foundation
- Swiss National Science Foundation (SNF) [310030_169966] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [614847] Funding Source: European Research Council (ERC)
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Tens of millions suffer from insulin deficiency (ID); a defect leading to severe metabolic imbalance and death. The only means for management of ID is insulin therapy; yet, this approach is sub-optimal and causes life-threatening hypoglycemia. Hence, ID represents a great medical and societal challenge. Here we report that S100A9, also known as Calgranulin B or Myeloid-Related Protein 14 (MRP14), is a leptin-induced circulating cue exerting beneficial anti-diabetic action. In murine models of ID, enhanced expression of S100A9 alone (i.e. without administered insulin and/or leptin) slightly improves hyperglycemia, and normalizes key metabolic defects (e.g. hyperketonemia, hypertriglyceridemia, and increased hepatic fatty acid oxidation; FAO), and extends lifespan by at least a factor of two. Mechanistically, we report that Toll-Like Receptor 4 (TLR4) is required, at least in part, for the metabolic-improving and pro-survival effects of S100A9. Thus, our data identify the S100A9/TLR4 axis as a putative target for ID care.
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