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 Statement The authors have declared no competing interest. * µCT : Micro computer tomography AgRP : Agouti-related protein AKT : Protein kinase B Apoa5 : Apolipoprotein A-V ATP : Adenosine triphosphate BAT : Brown adipose tissue BMDM : Bone marrow-derived macrophages Ccl3 : Chemokine (C-C motif) ligand 3 Ccl4 : Chemokine (C-C motif) ligand 4 CD : Control Diet CLS : Crown-like structures cNK : conventional NK cells Cxcl16 : Chemokine (C-X-C motif) ligand 16 DAG : Diacylglycerides DN : Double negative ECAR : Extracellular acidification rate OCR : Oxygen consumption rate ELISA : Enzyme-linked immunosorbent assay ERK : Extracellular signal-regulated kinases FFA : Free fatty acids GIR : Glucose infusion rate GTT : Glucose tolerance test HFD : High fat diet HGP : Hepatic glucose production HOMA-IR : Homeostasis model assessment- insulin resistance HSL : Hormone-sensitive lipase IFNγ : Interferon gamma IL : Interleukin ILC : Innate lymphoid cell ITT : Insulin tolerance test Lilra5 : Leukocyte immunoglobulin like receptor A5 Lpl : Lipoprotein lipase MAPK : Mitogen-activated protein kinase NCD : Normal chow diet NK cell : Natural killer cell OCR : Oxygen consumption rate OXPHOS : Oxidative phosphorylation P2Y6R : P2Y purinoreceptor 6 PGAT : Perigonodal adipose tissue pHSL : phosphorylated hormone-sensitive lipase PI3K : Phosphoinositide 3-kinase PKC : Protein kinase C Plin2 : Perilipin 2 RER : Respiratory exchange rate Rora : RAR-related orphan receptor alpha SEM : Standard error of the mean SKM : Skeletal muscle SVF : Stromal vascular fraction TG : Triglycerides TNFα : Tumor necrosis factor alpha TPM : Transcripts per million trNK : tissue-resident NK cells UDP : Uridine diphosphate uNK : uterine NK cells Xcl1 : Chemokine (C motif) ligand