The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice.
Mice carrying a targeted disruption of the prostaglandin E2 (PGE2) E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet-induced obesity. Although no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3(-/-) mice gained more weight relative to EP3(+/+) mice. Overall, EP3(-/-) mice had increased epididymal fat mass and adipocyte size; paradoxically, a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3(-/-) mice. The EP3(-/-) mice had increased macrophage infiltration, TNF-α, monocyte chemoattractant protein-1, IL-6 expression, and necrosis in their epididymal fat pads as compared with EP3(+/+) animals. Adipocytes isolated from EP3(+/+) or EP3(-/-) mice were assayed for the effect of PGE2-evoked inhibition of lipolysis. Adipocytes isolated from EP3(-/-) mice lacked PGE2-evoked inhibition of isoproterenol stimulated lipolysis compared with EP3(+/+). EP3(-/-) mice fed HFD had exaggerated ectopic lipid accumulation in skeletal muscle and liver, with evidence of hepatic steatosis. Both blood glucose and plasma insulin levels were similar between genotypes on a control diet, but when fed HFD, EP3(-/-) mice became hyperglycemic and hyperinsulinemic when compared with EP3(+/+) fed HFD, demonstrating a more severe insulin resistance phenotype in EP3(-/-). These results demonstrate that when fed a HFD, EP3(-/-) mice have abnormal lipid distribution, developing excessive ectopic lipid accumulation and associated insulin resistance.
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Ryan P
RP
Ceddia
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
DaeKee
D
Lee
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Matthew F
MF
Maulis
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Bethany A
BA
Carboneau
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
David W
DW
Threadgill
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Greg
G
Poffenberger
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Ginger
G
Milne
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Kelli L
KL
Boyd
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Alvin C
AC
Powers
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Owen P
OP
McGuinness
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Maureen
M
Gannon
Department of Veterans Affairs (A.C.P., M.G., R.M.B.), Tennessee Valley Health Authority, and Department of Medicine (R.M.B.), Division of Nephrology and Hypertension; Departments of Pharmacology (R.P.C., G.M., R.M.B.) and Cell and Developmental Biology (D.L., D.W.T., M.G.); Department of Medicine (M.F.M., G.P., A.C.P., M.G.), Division of Diabetes, Endocrinology, and Metabolism; and Departments of Molecular Physiology and Biophysics (B.A.C., A.C.P., O.P.G., M.G.) and Pathology, Microbiology, and Immunology (K.L.B.), Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Richard M
RM
Breyer
D052436:Adipose Tissue, White / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050154:Adiposity; D000818:Animals; D048429:Cell Size; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000276:immunology; D059305:Diet, High-Fat / Q000009:adverse effects*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000276:immunology; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015434:Panniculitis / Q000209:etiology* / Q000276:immunology; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain
C545648:Ptger3 protein, mouse; D058308:Receptors, Prostaglandin E, EP3 Subtype