Chronic dietary energy stress on white adipose tissue (WAT) promotes fat deposition in peripheral tissues, whichacceleratesinsulinresistanceandtype2diabetesmellitus(T2DM).RestoringthecapacityofWATto safelysequesterexcessenergypromotesinsulinsensitivityinthefaceofdiet-inducedobesity.Tothisend,we discovered that the microRNA miR-30a exhibits reduced expression in subcutaneous fat from diabetic mice andhumanscomparedtonormalcontrols.OurpreliminarystudiesestablishthatmiR-30aconfersuponWAT theabilitytowithstandthepressureofhighfatdietandpreventtheco-morbiditiesofobesity.Thesechanges result in improved whole-body insulin sensitivity coupled with muted WAT inflammation and reduced hepatic steatosis.TheeffectofmiR-30aonWATfunctioncoincideswithcompleteblockadeofSTAT1signaling,which is a key transducer of obesity-linked inflammatory cytokines. These exciting studies support the hypothesis that systemic insulin sensitivity is preserved by miR-30a repression of STAT1-mediated inflammation in adipocytes.Intriguingly,miR-30aconfersbeneficialeffectsonglucoseandlipidhomeostasiswithoutreducing body weight. The goal of this proposal is to critically test our hypothesis by challenging our genetic mouse models of miR-30a and STAT1 expression with diet-induced obesity.
In Aim 1, we will define the basis underpinningthemetaboliceffectsofmiR-30atransgenicexpressioninWAT.
Aim2 willevaluatetheroleof the inflammatory transcription factor STAT1 in mediating the metabolic effects of miR-30a expression in subcutaneous WAT. Lastly, Aim 3 will establish the mechanisms governing the transcriptional regulation of miR-30a.OurinvestigationofthebasisbywhichmiR-30acontrolsWATfunctionissignificantbecauseitwill expand our understanding of mechanisms that connect obesity with T2DM. At the completion of our studies, we will have identified mechanisms that might be exploited in therapies to manage insulin resistance and T2DM.
Insulin resistance and T2DM are chronic health problems in the United States. Mechanisms that improve insulin sensitivity by restoring proper fat storage mechanisms representnewparadigmsforclinicalmanagementofobesity.
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