INSULIN RECEPTORS AND THE GLUCOSE TRANSPORT SYSTEM

Summary

Principal Investigator: JERROLD MICHAEL OLEFSKY
Abstract: DESCRIPTION (provided by applicant): Obesity is the dominant cause of acquired insulin resistance and it is the epidemic of obesity in the United States which is driving the dramatically increasing incidence of Type 2 diabetes. The central theme of this proposal is that chronic low-grade tissue inflammation is an important underlying etiologic factor leading to decreased insulin sensitivity. Our previous work has shown that genetically disabling macrophage inflamma- tory pathways in knockout mice protects animals from obesity and high fat diet induced insulin resistance, lead- ing to the idea that the tissue macrophage can be an orchestrating or initiating cell type underlying this inflam- mation-induced insulin resistance. In this application, we propose a series of novel in vitro and in vivo studies to more fully understand the basic mechanisms of regulation of inflammation. Towards this end, the proposed studies capitalize on our new finding that GPR120, a lipid sensing GPCR expressed in proinflammatory macro- phages, functions as the omega 3 fatty acid receptor. Omega 3 fatty acids are potent anti-inflammatory mole- cules and our studies show that these anti-inflammatory effects are largely mediated through GPR120. Stud- ies are proposed to assess the mechanisms of GPR120 signaling to decipher precisely how signals from this receptor intersect with the inflammatory pathway. We will also conduct extensive in vivo phenotyping studies in GPR120 knockout. In a parallel effort, FOX01 is a well known insulin regulatable transcription factor and PPAR3 is a nuclear receptor mediating anti-inflammatory effects and insulin sensitization. We have made the novel finding that FOX01 can function as a direct transrepressor of PPAR3 activity through protein/protein in- teractions, independent of DNA binding. We propose a number of new studies to explore this finding by using Chip sequencing to define the global promoter binding sites (cistrome) of both FOX01 and PPAR3. We will also conduct in vivo studies using wild type and mutant FOX01 in a doxycycline inducible transgenic system to assess the effects of FOX01 repression of PPAR3 on overall in vivo insulin sensitivity TZD-responsiveness and glucose homeostasis. Finally, CD11c+ macrophage represents the majority of the macrophages recruited into obese adipose tissues. These cells are highly proinflammatory releasing large amounts of tissue cytokines which can cause insulin resistance through paracrine mechanisms. An improved understanding of the biology of these cells should provide new mechanistic insights into the etiology of inflammation/insulin resistance. To- wards this end, we have identified novel secretory and extracellular matrix proteins (biglycan and galectin 3) and a new GPCR (GPR105) which are differentially highly expressed in CD11c positive macrophages and have generated colonies of KO mice for new in vivo and in vitro studies. These results should identify relevant mechanisms where-by modification of inflammatory pathways in macrophages and in insulin target cells regu- lates systemic insulin resistance. This knowledge should lead to a better understanding of insulin resistance in Type 2 diabetes and could potentially lead to novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: Obesity is the dominant cause of acquired insulin resistance and the epidemic of obesity in the United States is driving the dramatic increase in incidence of Type 2 diabetes. Chronic low-grade tissue inflammation is a major cause of insulin resistance and the studies in this application will identify new mechanisms underlying the regulation of inflammation and how inflammation causes insulin resistance. These studies should lead to an improved understanding of the basic causes of Type 2 diabetes mellitus and hold the potential for new therapeutic modalities.
Funding Period: 1983-08-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity
    Yun Sok Lee
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Cell 157:1339-52. 2014
  2. pmc Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones
    Min Lu
    Department of Medicine, University of California San Diego UCSD, San Diego, California, USA
    Nat Med 17:618-22. 2011
  3. pmc The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice
    Yong Han Paik
    Department of Medicine, University of California San Diego, La Jolla, CA, USA
    Hepatology 53:1730-41. 2011
  4. pmc CRTC3 links catecholamine signalling to energy balance
    Youngsup Song
    The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 468:933-9. 2010
  5. pmc PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice
    Shweta Sharma
    Medical Research Service, VA San Diego Healthcare System, San Diego, California, USA
    Biol Reprod 84:466-75. 2011
  6. pmc FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages
    WuQiang Fan
    Division of Endocrinology Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093 0673, USA
    EMBO J 29:4223-36. 2010
  7. pmc Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats
    Gene Hsiao
    Department of Bioengineering, University of California, San Diego, CA, USA
    Am J Physiol Endocrinol Metab 300:E164-74. 2011
  8. pmc Genetic predictors of medically refractory ulcerative colitis
    Talin Haritunians
    Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    Inflamm Bowel Dis 16:1830-40. 2010
  9. pmc GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects
    Da Young Oh
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Cell 142:687-98. 2010
  10. pmc Common genetic determinants of vitamin D insufficiency: a genome-wide association study
    Thomas J Wang
    Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
    Lancet 376:180-8. 2010

Research Grants

Detail Information

Publications71

  1. pmc Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity
    Yun Sok Lee
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Cell 157:1339-52. 2014
    ..These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance. ..
  2. pmc Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones
    Min Lu
    Department of Medicine, University of California San Diego UCSD, San Diego, California, USA
    Nat Med 17:618-22. 2011
    ..Neuronal PPAR-γ signaling is also required for the hepatic insulin sensitizing effects of TZDs...
  3. pmc The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice
    Yong Han Paik
    Department of Medicine, University of California San Diego, La Jolla, CA, USA
    Hepatology 53:1730-41. 2011
    ..Both NOX1- and NOX2-deficient HSCs had decreased ROS generation and failed to up-regulate collagen α1(I) and transforming growth factor β in response to angiotensin II...
  4. pmc CRTC3 links catecholamine signalling to energy balance
    Youngsup Song
    The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 468:933-9. 2010
    ....
  5. pmc PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice
    Shweta Sharma
    Medical Research Service, VA San Diego Healthcare System, San Diego, California, USA
    Biol Reprod 84:466-75. 2011
    ..Taken together, our data support a direct role for PPARG in modulating pituitary function in vitro and in vivo...
  6. pmc FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages
    WuQiang Fan
    Division of Endocrinology Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093 0673, USA
    EMBO J 29:4223-36. 2010
    ....
  7. pmc Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats
    Gene Hsiao
    Department of Bioengineering, University of California, San Diego, CA, USA
    Am J Physiol Endocrinol Metab 300:E164-74. 2011
    ..Other PPARγ ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization...
  8. pmc Genetic predictors of medically refractory ulcerative colitis
    Talin Haritunians
    Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    Inflamm Bowel Dis 16:1830-40. 2010
    ..The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC...
  9. pmc GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects
    Da Young Oh
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Cell 142:687-98. 2010
    ..In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation...
  10. pmc Common genetic determinants of vitamin D insufficiency: a genome-wide association study
    Thomas J Wang
    Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
    Lancet 376:180-8. 2010
    ..We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency...
  11. pmc Genome-wide analysis of genetic loci associated with Alzheimer disease
    Sudha Seshadri
    Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
    JAMA 303:1832-40. 2010
    ..Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD)...
  12. pmc Inducible nitric oxide synthase deficiency in myeloid cells does not prevent diet-induced insulin resistance
    Min Lu
    Department of Medicine, University of California, San Diego, California 92093, USA
    Mol Endocrinol 24:1413-22. 2010
    ..In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance...
  13. pmc Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium
    Alanna C Morrison
    Atherosclerosis Risk in Communities Study University of Texas Health Science Center at Houston, Human Genetics Center, Houston, TX 77030, USA
    Circ Cardiovasc Genet 3:248-55. 2010
    ....
  14. pmc Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice
    Pingping Li
    Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093 0673, USA
    J Biol Chem 285:15333-45. 2010
    ....
  15. pmc Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium
    Nicholas L Smith
    Department of Epidemiology, University of Washington, Seattle, Wash 98101, USA
    Circulation 121:1382-92. 2010
    ..Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels...
  16. pmc Trans-resveratrol inhibits phosphorylation of Smad2/3 and represses FSHβ gene expression by a SirT1-independent pathway in LβT2 gonadotrope cells
    Debin Lan
    Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA
    Reprod Toxicol 32:85-92. 2011
    ..Taken together, our results suggest that resveratrol down-regulates Smad2/3 phosphorylation and suppresses FSHβ expression via a SirT1-independent pathway...
  17. pmc Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport
    Kazuaki Ohtsubo
    Center for Nanomedicine, Sanford Burnham Medical Research Institute, University of California Santa Barbara, Santa Barbara, California, USA
    Nat Med 17:1067-75. 2011
    ....
  18. pmc Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance
    Yun Sok Lee
    Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea
    Diabetes 60:2474-83. 2011
    ..However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions...
  19. pmc NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids
    Pingping Li
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
    Cell 155:200-14. 2013
    ..Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies. ..
  20. pmc Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects
    Kim Ravnskjaer
    J Clin Invest 123:4318-28. 2013
    ..Administration of a small-molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, suggesting that this enzyme may be a useful target for diabetes treatment...
  21. pmc Quantitative proteomic and functional analysis of liver mitochondria from high fat diet (HFD) diabetic mice
    Yurong Guo
    Department of Pharmacology, and
    Mol Cell Proteomics 12:3744-58. 2013
    ....
  22. pmc The fractalkine/CX3CR1 system regulates β cell function and insulin secretion
    Yun Sok Lee
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Cell 153:413-25. 2013
    ..Lastly, expression of FKN in islets was decreased by aging and high-fat diet/obesity, suggesting that decreased FKN/CX3CR1 signaling could be a mechanism underlying β cell dysfunction in type 2 diabetes...
  23. pmc Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues
    Min Lu
    Department of Medicine, University of California, San Diego, California 92093, USA
    J Biol Chem 288:10722-35. 2013
    ..Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet...
  24. ncbi The origins and drivers of insulin resistance
    Andrew M F Johnson
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0673, USA
    Cell 152:673-84. 2013
    ..Here, we offer a Perspective on the heterogeneous etiology of insulin resistance, focusing in particular on the role of inflammation, lipid metabolism, and the gastrointestinal microbiota...
  25. pmc Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3
    Jun Hee Lee
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA
    Cell Metab 16:311-21. 2012
    ..These results demonstrate an important homeostatic function for the stress-inducible Sestrin protein family in the control of mammalian lipid and glucose metabolism...
  26. pmc G protein-coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice
    Olivia Osborn
    Division of Endocrinology and Metabolism, Department of Medicine, UCSD, La Jolla, CA, USA
    J Clin Invest 122:2444-53. 2012
    ..Cumulatively, our data indicate that GPR21 has a critical function in coordinating macrophage proinflammatory activity in the context of obesity-induced insulin resistance...
  27. pmc Omega 3 fatty acids and GPR120
    Da Young Oh
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Cell Metab 15:564-5. 2012
    ..In addition, GPR120 KO mice develop obesity, increased inflammation, and insulin resistance, consistent with a role for GPR120 signaling in the metabolic syndrome and diabetes mellitus...
  28. pmc Regulation of chemokine and chemokine receptor expression by PPARγ in adipocytes and macrophages
    M T Audrey Nguyen
    Department of Medicine 0673, University of California San Diego, La Jolla, California, United States of America
    PLoS ONE 7:e34976. 2012
    ..However the underlying mechanisms are unclear...
  29. pmc A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis
    Johan W Jonker
    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 485:391-4. 2012
    ..The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization...
  30. pmc p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity
    Bernat Baeza-Raja
    Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 109:5838-43. 2012
    ..Our results identify p75(NTR) as a unique player in glucose metabolism and suggest that signaling from p75(NTR) to Rab5 family GTPases may represent a unique therapeutic target for insulin resistance and diabetes...
  31. pmc Increased macrophage migration into adipose tissue in obese mice
    Da Young Oh
    Department of Medicine, University of California, San Diego, La Jolla, California, USA
    Diabetes 61:346-54. 2012
    ..Monocytes from obese mice are not programmed to become inflammatory ATMs but rather the increased proinflammatory ATM accumulation in obesity is in response to tissue signals...
  32. pmc Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity
    Pingping Li
    Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
    Cell 147:815-26. 2011
    ....
  33. pmc Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction
    Simon Schenk
    Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0673, USA
    J Clin Invest 121:4281-8. 2011
    ..Thus, these data demonstrate that Sirt1 is an integral signaling node in skeletal muscle linking CR to improved insulin action, primarily via modulation of PI3K signaling...
  34. pmc Common variants in KCNN3 are associated with lone atrial fibrillation
    Patrick T Ellinor
    1 Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA 2 Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA 3 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA 4 These authors contributed equally to this work
    Nat Genet 42:240-4. 2010
    ..52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization...
  35. pmc A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats
    Min Lu
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0673, USA
    Am J Physiol Endocrinol Metab 298:E1036-48. 2010
    ..Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects...
  36. pmc Insulin sensitivity: modulation by nutrients and inflammation
    Simon Schenk
    Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California 92093, USA
    J Clin Invest 118:2992-3002. 2008
    ..Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity...
  37. pmc Beta-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic beta cells
    Noriyuki Sonoda
    Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 105:6614-9. 2008
    ..Taken together, these studies indicate that beta-arrestin-1 plays a role in GLP-1 signaling leading to insulin secretion, defining a previously undescribed mechanism for GLP-1 action...
  38. pmc Blockade of alpha4 integrin signaling ameliorates the metabolic consequences of high-fat diet-induced obesity
    Chloe C Feral
    Department of Medicine, University of California, San Diego, La Jolla, California, USA
    Diabetes 57:1842-51. 2008
    ..Thus, we hypothesized that mice bearing an alpha4(Y991A) mutation, which blocks signaling, would be protected from development of high-fat diet-induced insulin resistance...
  39. pmc Both preoperative perinuclear antineutrophil cytoplasmic antibody and anti-CBir1 expression in ulcerative colitis patients influence pouchitis development after ileal pouch-anal anastomosis
    Phillip Fleshner
    Division of Colon and Rectal Surgery, Inflammatory Bowel Disease Center, Cedars Sinai Medical Center, Los Angeles, California, USA
    Clin Gastroenterol Hepatol 6:561-8. 2008
    ..The aim of this study was to assess associations of preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti-CBir1 flagellin on AP or CP development...
  40. pmc Inflammation and insulin resistance
    Carl De Luca
    University of California at San Diego, Department of Medicine 0673, 225 Stein Clinical Research Building, 9500 Gilman Drive, La Jolla, CA 92093, USA
    FEBS Lett 582:97-105. 2008
    ....
  41. ncbi JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity
    Giovanni Solinas
    Department of Medicine, University of Fribourg, Chemin du Musee 5, CH 1700 Fribourg, Switzerland
    Cell Metab 6:386-97. 2007
    ..By contrast, Jnk1 removal from hematopoietic cells has no effect on adiposity but confers protection against HFD-induced insulin resistance by decreasing obesity-induced inflammation...
  42. pmc Selective modulation of promoter recruitment and transcriptional activity of PPARgamma
    DOROTHY D SEARS
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC0673, La Jolla, CA 92093, USA
    Biochem Biophys Res Commun 364:515-21. 2007
    ..Selective modulation of PPARgamma by TZDs resulted in distinct expression profiles and transcription kinetics which may be due to differential promoter activation and chromatin remodeling of target genes...
  43. ncbi A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways
    M T Audrey Nguyen
    Division of Endocrinology Metabolism, University of California, San Diego, La Jolla, California 92093, USA
    J Biol Chem 282:35279-92. 2007
    ..Together our results show that FFAs can activate CD11c(+) myeloid proinflammatory cells via TLR2/4 and JNK signaling pathways, thereby promoting inflammation and subsequent cellular insulin resistance...
  44. ncbi Tumor necrosis factor receptor-1 can function through a G alpha q/11-beta-arrestin-1 signaling complex
    Yuji Kawamata
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093 0673, USA
    J Biol Chem 282:28549-56. 2007
    ....
  45. pmc Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones
    Andrea L Hevener
    Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA
    J Clin Invest 117:1658-69. 2007
    ..These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs...
  46. pmc Myosin 5a is an insulin-stimulated Akt2 (protein kinase Bbeta) substrate modulating GLUT4 vesicle translocation
    Takeshi Yoshizaki
    Department of Medicine 0673, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093 0673, USA
    Mol Cell Biol 27:5172-83. 2007
    ..Taken together, these data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myosin 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface...
  47. ncbi Suppression of PPAR-gamma attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes
    Wei Liao
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Am J Physiol Endocrinol Metab 293:E219-27. 2007
    ....
  48. ncbi Impaired insulin secretion in a mouse model of ataxia telangiectasia
    Philip D Miles
    Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA, USA
    Am J Physiol Endocrinol Metab 293:E70-4. 2007
    ..Our findings support a role for ATM in metabolic function and point toward impaired insulin secretion as the primary cause of DM in A-T...
  49. ncbi Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance
    Lisa A Lesniewski
    Department of Endocrinology and Metabolism, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
    Nat Med 13:455-62. 2007
    ..These studies show that macrophages are an important cell type in the induction of insulin resistance and that Cap has a modulatory role in this function...
  50. ncbi Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects
    Gautam K Bandyopadhyay
    Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, 9500 Gilman Dr, La Jolla, 92093, USA
    Diabetes 55:2277-85. 2006
    ....
  51. pmc SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes
    Takeshi Yoshizaki
    Department of Medicine 0673, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92037 0673, USA
    Mol Cell Biol 29:1363-74. 2009
    ..Taken together, these data indicate that SIRT1 is a positive regulator of insulin signaling at least partially through the anti-inflammatory actions in 3T3-L1 adipocytes...
  52. pmc Genetic epistasis of IL23/IL17 pathway genes in Crohn's disease
    Dermot P B McGovern
    Medical Genetics Institute and Inflammatory Bowel Disease Center, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    Inflamm Bowel Dis 15:883-9. 2009
    ..Genetic variants in the IL23R and IL12B have been associated with CD susceptibility. We investigated 10 genes within the IL23/IL17 pathway in a case-control study of 763 CD cases and 254 healthy controls...
  53. pmc FOXO1 transrepresses peroxisome proliferator-activated receptor gamma transactivation, coordinating an insulin-induced feed-forward response in adipocytes
    WuQiang Fan
    Division of Endocrinology Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA
    J Biol Chem 284:12188-97. 2009
    ....
  54. ncbi Macrophages, inflammation, and insulin resistance
    Jerrold M Olefsky
    Department of Medicine, University of California San Diego, La Jolla, CA 92093 0651, USA
    Annu Rev Physiol 72:219-46. 2010
    ..Strategies focused on inhibiting the inflammation/insulin resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention...
  55. pmc Genome-wide association study of PR interval
    Arne Pfeufer
    Institute of Human Genetics, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich, Germany
    Nat Genet 42:153-9. 2010
    ..0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation...
  56. pmc A genome-wide association study of carotid atherosclerosis in HIV-infected men
    Sadeep Shrestha
    Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35294 0022, USA
    AIDS 24:583-92. 2010
    ..The role of host genetics in the development of subclinical atherosclerosis in the context of HIV-infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood...
  57. pmc SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity
    Takeshi Yoshizaki
    Department of Medicine, Univ of California, San Diego, La Jolla, 92037 0673, USA
    Am J Physiol Endocrinol Metab 298:E419-28. 2010
    ....
  58. pmc Candidate loci for insulin sensitivity and disposition index from a genome-wide association analysis of Hispanic participants in the Insulin Resistance Atherosclerosis (IRAS) Family Study
    N D Palmer
    Department of Biochemistry, Centers for Human Genomics and Diabetes Research, Wake Forest University School of Medicine, 1 Medical Center Blvd, Winston Salem, NC 27157, USA
    Diabetologia 53:281-9. 2010
    ....
  59. pmc Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice
    Maziyar Saberi
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA
    Cell Metab 10:419-29. 2009
    ..In summary, our results indicate that Tlr4 signaling in hematopoietic-derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice...
  60. pmc Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization
    D D Sears
    Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 106:18745-50. 2009
    ..We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness...
  61. pmc The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice
    Phuong T Hoang
    Division of Pediatric Endocrinology, Mattel Children s Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Metabolism 59:343-9. 2010
    ..This indicates that Humanin may be useful for islet protection and survival in a spectrum of diabetes-related therapeutics...
  62. pmc Susceptibility to Crohn's disease is mediated by KIR2DL2/KIR2DL3 heterozygosity and the HLA-C ligand
    Jill A Hollenbach
    Center for Genetics, Children s Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA
    Immunogenetics 61:663-71. 2009
    ..These results show for the first time that disease susceptibility may be related to heterozygosity at a specific KIR locus, and that HLA ligand genotype influences the relative effect of the KIR genotype...
  63. pmc Glucocorticoids and thiazolidinediones interfere with adipocyte-mediated macrophage chemotaxis and recruitment
    David Patsouris
    Division of Endocrinology Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA
    J Biol Chem 284:31223-35. 2009
    ....
  64. pmc Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes
    Maziyar Saberi
    Univ of California San Diego, Dept of Medicine, 9500 Gilman Dr, SCR225, La Jolla CA 92093, USA
    Am J Physiol Endocrinol Metab 297:E1137-46. 2009
    ..In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes...
  65. pmc Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry
    Emelia J Benjamin
    National Heart, Lung, and Blood Institute s Framingham Heart Study, Framingham, Massachusetts, USA
    Nat Genet 41:879-81. 2009
    ..19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15))...
  66. pmc Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data
    Ramachandran S Vasan
    Framingham Heart Study, 73 Mt Wayte Ave, Ste 2, Framingham, MA 01702 5827, USA
    JAMA 302:168-78. 2009
    ..Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease...
  67. pmc A genome-wide association scan for acute insulin response to glucose in Hispanic-Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS FS)
    S S Rich
    Center for Public Health Genomics, University of Virginia, 6111 West Complex, Charlottesville, VA 22908, USA
    Diabetologia 52:1326-33. 2009
    ....
  68. pmc Adipocyte CREB promotes insulin resistance in obesity
    Ling Qi
    Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
    Cell Metab 9:277-86. 2009
    ..These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes...
  69. ncbi Lentiviral short hairpin ribonucleic acid-mediated knockdown of GLUT4 in 3T3-L1 adipocytes
    Wei Liao
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, 92093, USA
    Endocrinology 147:2245-52. 2006
    ..These studies indicate that lentiviral shRNA constructs provide an excellent approach to deliver functional siRNAs into 3T3-L1 adipocytes for studying insulin signaling and adipocyte biology...

Research Grants30

  1. Metabolic Actions of Omega-3 Fatty Acids on Inflammation
    Michael Miller; Fiscal Year: 2013
    ..Favorable outcomes from this study could translate into a new approach to improve heart disease risk in men and women with the metabolic syndrome. ..
  2. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  3. Inflammation, Insulin Resistance, and Foxo factors
    Stephen M Hedrick; Fiscal Year: 2013
    ..These experiments will greatly enhance our knowledge of the interface between organismal metabolism and the immune system. ..
  4. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
    ....
  5. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  6. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  7. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  8. The Role of Substrate Metabolism and Macrophage Activation in Obesity
    Amy Johnson; Fiscal Year: 2013
    ....
  9. Function of the Myo-adipo Axis in Human Obesity and Type 2 Diabetes
    ROBERT ROY HENRY; Fiscal Year: 2013
    ..Results from this project will provide molecular mechanisms for metabolic dysfunction seen in vivo in obesity and T2D and identify possible targets for therapeutic interventions. ..
  10. Metabolic effects of adipose lipogenesis
    Timothy E McGraw; Fiscal Year: 2013
    ....
  11. GLYCOSYLTRANSFERASE FUNCTION IN DEVELOPMENT AND DISEASE
    JAMEY MARTH; Fiscal Year: 2013
    ..Combined, the proposed research is structured to achieve a more integrated understanding of the pathogenesis of diabetes and the molecular mechanisms governing metabolism, which could translate to more effective therapeutic approaches. ..
  12. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  13. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  14. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
    ..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
  15. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..