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Nat Commun ; 10(1): 3545, 2019 08 07.
Article in English | MEDLINE | ID: mdl-31391467

ABSTRACT

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.


Subject(s)
Calgranulin B/metabolism , Diabetes Mellitus, Experimental/metabolism , Hyperglycemia/metabolism , Longevity/physiology , Toll-Like Receptor 4/metabolism , Animals , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/etiology , Diphtheria Toxin/toxicity , Fatty Acids/metabolism , Humans , Hyperglycemia/blood , Hyperglycemia/etiology , Insulin/deficiency , Leptin/administration & dosage , Liver/metabolism , Male , Mice , Mice, Knockout , Oxidation-Reduction , Signal Transduction/drug effects , Signal Transduction/physiology , Streptozocin/toxicity , Toll-Like Receptor 4/genetics
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