P2Y6 receptor signaling in natural killer cells impairs insulin sensitivity in obesity

Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance and have previously been shown to up-regulate the expression of the P2Y purinoreceptor 6 (P2Y6R) upon high fat diet (HFD)-induced obesity. Here, we reveal that NK cell-specific inactivation of the P2Y6R gene improves insulin sensitivity in obese mice and reduces the expression of chemokines in adipose tissue infiltrating NK-cells. Obese mice lacking P2Y6R specifically in NK cells exhibited a reduction in adipose tissue inflammation, exhibited improved insulin-stimulated suppression of lipolysis in adipose tissue and a reduction in hepatic glucose production, leading to an overall improvement of systemic insulin sensitivity. In contrast, myeloid lineage specific P2Y6R inactivation does not affect energy or glucose homeostasis in obesity. Collectively, we show that P2Y6R signaling in NK cells contributes to the development of obesity-associated insulin resistance and thus might be a future target for the treatment of obesity-associated insulin resistance and type 2 diabetes.Competing Interest StatementThe authors have declared no competing interest.µCTMicro computer tomographyAgRPAgouti-related proteinAKTProtein kinase BApoa5Apolipoprotein A-VATPAdenosine triphosphateBATBrown adipose tissueBMDMBone marrow-derived macrophagesCcl3Chemokine (C-C motif) ligand 3Ccl4Chemokine (C-C motif) ligand 4CDControl DietCLSCrown-like structurescNKconventional NK cellsCxcl16Chemokine (C-X-C motif) ligand 16DAGDiacylglyceridesDNDouble negativeECARExtracellular acidification rateOCROxygen consumption rateELISAEnzyme-linked immunosorbent assayERKExtracellular signal-regulated kinasesFFAFree fatty acidsGIRGlucose infusion rateGTTGlucose tolerance testHFDHigh fat dietHGPHepatic glucose productionHOMA-IRHomeostasis model assessment- insulin resistanceHSLHormone-sensitive lipaseIFNγInterferon gammaILInterleukinILCInnate lymphoid cellITTInsulin tolerance testLilra5Leukocyte immunoglobulin like receptor A5LplLipoprotein lipaseMAPKMitogen-activated protein kinaseNCDNormal chow dietNK cellNatural killer cellOCROxygen consumption rateOXPHOSOxidative phosphorylationP2Y6RP2Y purinoreceptor 6PGATPerigonodal adipose tissuepHSLphosphorylated hormone-sensitive lipasePI3KPhosphoinositide 3-kinasePKCProtein kinase CPlin2Perilipin 2RERRespiratory exchange rateRoraRAR-related orphan receptor alphaSEMStandard error of the meanSKMSkeletal muscleSVFStromal vascular fractionTGTriglyceridesTNFαTumor necrosis factor alphaTPMTranscripts per milliontrNKtissue-resident NK cellsUDPUridine diphosphateuNKuterine NK cellsXcl1Chemokine (C motif) ligand