GPR105 ablation prevents inflammation and improves insulin sensitivity in mice with diet-induced obesity.
GPR105, a G protein-coupled receptor for UDP-glucose, is highly expressed in several human tissues and participates in the innate immune response. Because inflammation has been implicated as a key initial trigger for type 2 diabetes, we hypothesized that GPR105 (official gene name: P2RY14) might play a role in the initiation of inflammation and insulin resistance in obesity. To this end, we investigated glucose metabolism in GPR105 knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD). We also examined whether GPR105 regulates macrophage recruitment to liver or adipose tissues by in vivo monocyte tracking and in vitro chemotaxis experiments, followed by transplantation of bone marrow from either KO or WT donors to WT recipients. Our data show that genetic deletion of GPR105 confers protection against HFD-induced insulin resistance, with reduced macrophage infiltration and inflammation in liver, and increased insulin-stimulated Akt phosphorylation in liver, muscle, and adipose tissue. By tracking monocytes from either KO or WT donors, we found that fewer KO monocytes were recruited to the liver of WT recipients. Furthermore, we observed that uridine 5-diphosphoglucose enhanced the in vitro migration of bone marrow-derived macrophages from WT but not KO mice, and that plasma uridine 5-diphosphoglucose levels were significantly higher in obese versus lean mice. Finally, we confirmed that insulin sensitivity improved in HFD mice with a myeloid cell-specific deletion of GPR105. These studies indicate that GPR105 ablation mitigates HFD-induced insulin resistance by inhibiting macrophage recruitment and tissue inflammation. Hence GPR105 provides a novel link between innate immunity and metabolism.
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Jianfeng
J
Xu
Hidetaka
H
Morinaga
Dayoung
D
Oh
Pingping
P
Li
Ai
A
Chen
Saswata
S
Talukdar
Yaël
Y
Mamane
Joseph A
JA
Mancini
Andrea R
AR
Nawrocki
Eduardo
E
Lazarowski
Jerrold M
JM
Olefsky
Jane J
JJ
Kim
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D059305:Diet, High-Fat / Q000009:adverse effects; D005434:Flow Cytometry; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007333:Insulin Resistance / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000276:immunology / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y; D020133:Reverse Transcriptase Polymerase Chain Reaction
C509795:P2ry14 protein, mouse; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y