Abstract
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.
Footnotes
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Abbreviations
- 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