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Davis, CA, United States

Hallenborg P.,Copenhagen University | Hallenborg P.,University of Southern Denmark | Petersen R.K.,Copenhagen University | Kouskoumvekaki I.,Technical University of Denmark | And 5 more authors.
Progress in Lipid Research

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the key decisive factor controlling the development of adipocytes. Ligand-mediated activation of PPARγ occurs early during adipogenesis and is thought to prime adipose conversion. Although several fatty acids and their derivatives are known to bind to and activate PPARγ, the identity of the ligand(s) responsible for initiating adipocyte differentiation is still a matter of debate. Here we review recent data on pathways involved in ligand production as well as possible endogenous, adipogenic PPARγ agonists. © 2015 Elsevier B.V. All rights reserved. Source

Walsh P.,Sutter Medical Center Sacramento | Behrens N.,University of California at Davis | Chaigneau F.R.C.,California Animal Health and Food Safety Laboratory | McEligot H.,University of California at Davis | And 5 more authors.

Background Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to the virus. RSV is accompanied by elevated prostaglandin E2 (PGE2) which is followed by neutrophil led inflammation in the lung. Ibuprofen is a prototypical nonsteroidal anti-inflammatory drug that decreases PGE2 levels by inhibiting cyclooxygenase. Hypotheses We hypothesized that treatment of RSV with ibuprofen would decrease PGE2 levels, modulate the immune response, decrease clinical illness, and decrease the histopathological lung changes in a bovine model of RSV. We further hypothesized that viral replication would be unaffected. Methods We performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, cyclooxygenase, lipoxygenase and endocannabinoid products in plasma and mediastinal lymph nodes and interleukin (Il)-4, Il-13, Il-17 and interferon-ã in mediastinal lymph nodes. RSV shedding was measured daily and nasal Il-6, Il-8 and Il-17 every other day. The calves were necropsied on Day 10 post inoculation and histology performed. Results One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Clinical scores (p<0.01) and weight gain (p = 0.08) seemed better in the ibuprofen group. Ibuprofen decreased cyclooxygenase, lipoxygenase, and cytochrome P450 products, and increased monoacylglycerols in lung lymph nodes. Ibuprofen modulated the immune response as measured by narrowed range of observed Il-13, Il-17 and IFN-ã gene expression in mediastinal lymph nodes. Lung histology was not different between groups, and viral shedding was increased in calves randomized to ibuprofen. Conclusions Ibuprofen decreased PGE2, modulated the immune response, and improved clinical outcomes. However lung histopathology was not affected and viral shedding was increased. Source

Duran A.T.,California State University, Fullerton | Gertz E.,Obesity and Metabolism Research Unit | Judelson D.A.,California State University, Fullerton | Haqq A.M.,University of Alberta | And 3 more authors.
Pediatric Exercise Science

Prader-Willi Syndrome (PWS), the best characterized form of syndromic obesity, presents with abnormally high fat mass. In children, obesity presents with low-grade systemic inflammation. This study evaluated if PWS and/or nonsyndromic obesity affected cytokine responses to intermittent aerobic exercise in children. Eleven children with PWS (11 ± 2 y, 45.4 ± 9.5% body fat), 12 children with obesity (OB) (9 ± 1 y, 39.9 ± 6.8% body fat), and 12 lean (LN) children (9 ± 1 y, 17.5 ± 4.6% body fat) participated. Children completed 10 2-min cycling bouts of vigorous intensity, separated by 1-min rest. Blood samples were collected preexercise (PRE), immediately postexercise (IP), and 15, 30, and 60 min into recovery to analyze possible changes in cytokines. In all groups, IL-6 and IL-8 concentrations were greater during recovery compared with PRE. PWS and OB exhibited higher IL-6 area under the curve (AUC) than LN (p < .01 for both). PWS demonstrated higher IL-8 AUC than LN (p < .04). IL-10, TNF-α, and IFN-γ did not change with exercise (p > .05 for all). Results indicate that children with PWS respond with increased Il-6 and IL-8 concentrations to acute exercise similarly to controls. Excess adiposity and epigenetic modifications may explain the greater integrated IL-6 and IL-8 responses in PWS compared with controls. © 2015 Human Kinetics, Inc. Source

Bedinger D.H.,XOMA | Bedinger D.H.,University of California at Davis | Goldfine I.D.,XOMA | Corbin J.A.,XOMA | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics

The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which activates the metabolic Akt kinase signaling pathway while having little or no effect on the mitogenic extracellular signal-regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the preferential signaling of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathwaybiased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation. Source

Mostaedi R.,University of California at Davis | Lackey D.E.,Obesity and Metabolism Research Unit | Adams S.H.,Obesity and Metabolism Research Unit | Adams S.H.,University of California at Davis | And 3 more authors.
Obesity Surgery

Background: Pharmacotherapy is considered the primary treatment modality for diabetes mellitus (DM), hypertension (HTN), and dyslipidemia (DYS). We sought to investigate the status of DM, HTN, and DYS in patients who seek bariatric surgery. Methods: Demographic and comorbidity history were prospectively collected on 1,508 patients referred for bariatric consultation at a single institution from February 2008 to March 2012. We utilized published consensus guidelines (GL) to benchmark the efficacy of standard pharmacotherapy for these metabolic diseases, and 881 patients met the study design criteria. Results: Most patients exhibited at least one form of metabolic dysregulation (pre-DM or DM, 75.8 %; pre-HTN or HTN, 91.1 %; pre-DYS or DYS, 84.0 %; metabolic syndrome, 76.0 %). The majority of patients either did not meet GL treatment goals (DM, 45.7 %; HTN, 39.5 %; DYS, 22.3 %) or were previously undiagnosed (DM, 15.8 %; HTN, 13.7 %; DYS, 41.7 %). Non-GL pharmacotherapy was significantly less effective than GL pharmacotherapy at achieving treatment goals for DM (31.8 vs 53.2 %, p < 0.001) and HTN (43.6 vs 63.2 %, p = 0.007). Patients with concurrent DM, HTN, and DYS (35.5 %) were less likely than patients with only one or two of these metabolic diseases to achieve GL treatment goals for HTN (38.1 vs 72.6 %, p < 0.001) and DYS (55.7 vs 73.8 %, p = 0.002). Only 8.0 % of these patients achieved treatment goals for all three metabolic comorbidities. Conclusions: In this patient group, DM, HTN, and DYS were poorly compensated, even when pharmacotherapy was consistent with published GL. This may be due to disease burden in bariatric surgery candidates or to inadequate medical management prior to presentation. © 2014 Springer Science+Business Media New York. Source

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