Publications by authors named "Pedro A Perez"

7 Publications

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A high docosahexaenoic acid diet alters lung inflammation and recovery following repetitive exposure to aqueous organic dust extracts.

J Nutr Biochem 2021 Jun 12;97:108797. Epub 2021 Jun 12.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA; Pulmonary, Critical Care, Sleep and Allergy Division, University of Nebraska Medical Center, Omaha, Nebraska, USA. Electronic address:

Agricultural workers, especially those who work in swine confinement facilities, are at increased risk for developing pulmonary diseases including asthma, chronic obstructive pulmonary disease, and chronic bronchitis due to exposures to fumes, vapors, and organic dust. Repetitive exposure to agricultural dust leads to unresolved inflammation, a common underlying mechanism that worsens lung disease. Besides occupational exposure to dusts, diet also significantly contributes to inflammation and disease progression. Since DHA (docosahexaenoic acid), a polyunsaturated omega-3 fatty acid and its bioactive metabolites have key roles in inflammation resolution, we rationalized that individuals chronically exposed to organic dusts can benefit from dietary modifications. Here, we evaluated the role of DHA in modifying airway inflammation in a murine model of repetitive exposure to an aqueous extract of agricultural dust (three-week exposure to swine confinement dust extract, HDE) and after a one-week resolution/recovery period. We found that mice fed a high DHA diet had significantly increased bronchoalveolar lavage fluid (BALF) levels of DHA-derived resolvins and lower TNFα along with altered plasma levels of endocannabinoids and related lipid mediators. Following the one-week recovery we identified significantly reduced BALF cellularity and cytokine/chemokine release along with increased BALF amphiregulin and resolvins in DHA diet-fed versus control diet-fed mice challenged with HDE. We further report observations on the effects of repetitive HDE exposure on lung Ym1+ and Arg-1+ macrophages. Overall, our findings support a protective role for DHA and identify DHA-derived resolvins and endocannabinoids among the potential mediators of DHA in altering airway inflammation in chronic agricultural dust exposure.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108797DOI Listing
June 2021

Maternal transfer of environmentally relevant polybrominated diphenyl ethers (PBDEs) produces a diabetic phenotype and disrupts glucoregulatory hormones and hepatic endocannabinoids in adult mouse female offspring.

Sci Rep 2020 10 22;10(1):18102. Epub 2020 Oct 22.

Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA.

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.
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http://dx.doi.org/10.1038/s41598-020-74853-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582149PMC
October 2020

Cannabinoid CB Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice.

Nutrients 2020 Sep 20;12(9). Epub 2020 Sep 20.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA.

The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut-brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CBRs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CBR antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CBR-deficient mice (IntCB-/-) to investigate if intestinal CBRs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB-/- mice when compared to control mice for up to 6 h. Together, these data suggest that CBRs in the murine intestinal epithelium are required for acute WD preferences.
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http://dx.doi.org/10.3390/nu12092874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551422PMC
September 2020

Bile acid composition regulates GPR119-dependent intestinal lipid sensing and food intake regulation in mice.

Gut 2020 09 28;69(9):1620-1628. Epub 2020 Feb 28.

Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA

Objectives: Lipid mediators in the GI tract regulate satiation and satiety. Bile acids (BAs) regulate the absorption and metabolism of dietary lipid in the intestine, but their effects on lipid-regulated satiation and satiety are completely unknown. Investigating this is challenging because introducing excessive BAs or eliminating BAs strongly impacts GI functions. We used a mouse model (Cyp8b1 mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation.

Design: We evaluated OEA levels, gastric emptying and food intake in wild-type and Cyp8b1 mice. We assessed the role of the fat receptor GPR119 in these effects using Gpr119 mice.

Results: Cyp8b1 mice on a chow diet showed mild hypophagia. Jejunal OEA production was blunted in Cyp8b1 mice, thus these data do not support a role for this pathway in the hypophagia of Cyp8b1 mice. On the other hand, Cyp8b1 deficiency decreased gastric emptying, and this was dependent on dietary fat. GPR119 deficiency normalised the gastric emptying, gut hormone levels, food intake and body weight of Cyp8b1 mice.

Conclusion: BAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.
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http://dx.doi.org/10.1136/gutjnl-2019-319693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423635PMC
September 2020

Cannabinoid CB Receptors Inhibit Gut-Brain Satiation Signaling in Diet-Induced Obesity.

Front Physiol 2019 11;10:704. Epub 2019 Jun 11.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States.

Gut-brain signaling controls feeding behavior and energy homeostasis; however, the underlying molecular mechanisms and impact of diet-induced obesity (DIO) on these pathways are poorly defined. We tested the hypothesis that elevated endocannabinoid activity at cannabinoid CB receptor (CBRs) in the gut of mice rendered DIO by chronic access to a high fat and sucrose diet for 60 days inhibits nutrient-induced release of satiation peptides and promotes overeating. Immunoreactivity for CBRs was present in enteroendocrine cells in the mouse's upper small-intestinal epithelium that produce and secrete the satiation peptide, cholecystokinin (CCK), and expression of mRNA for CBRs was greater in these cells when compared to non-CCK producing cells. Oral gavage of corn oil increased levels of bioactive CCK (CCK-8) in plasma from mice fed a low fat no-sucrose diet. Pretreatment with the cannabinoid receptor agonist, WIN55,212-2, blocked this response, which was reversed by co-administration with the peripherally-restricted CBR neutral antagonist, AM6545. Furthermore, monoacylglycerol metabolic enzyme function was dysregulated in the upper small-intestinal epithelium from DIO mice, which was met with increased levels of a variety of monoacylglycerols including the endocannabinoid, 2-arachidonoyl--glycerol. Corn oil failed to affect levels of CCK in DIO mouse plasma; however, pretreatment with AM6545 restored the ability for corn oil to stimulate increases in levels of CCK, which suggests that elevated endocannabinoid signaling at small intestinal CBRs in DIO mice inhibits nutrient-induced CCK release. Moreover, the hypophagic effect of AM6545 in DIO mice was reversed by co-administration with the CCK receptor antagonist, devazepide. Collectively, these results provide evidence that hyperphagia associated with DIO is driven by a mechanism that includes CBR-mediated inhibition of gut-brain satiation signaling.
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http://dx.doi.org/10.3389/fphys.2019.00704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597959PMC
June 2019

Impact of maternal western diet-induced obesity on offspring mortality and peripheral endocannabinoid system in mice.

PLoS One 2018 1;13(10):e0205021. Epub 2018 Oct 1.

University of California Riverside, School of Medicine, Division of Biomedical Sciences, Riverside CA, United States of America.

Over two-thirds of adults in the United States are obese or overweight, which is largely due to chronic overconsumption of diets high in fats and sugars (i.e., Western diet). Recent studies reveal that maternal obesity may predispose offspring to development of obesity and other metabolic diseases; however, the molecular underpinnings of these outcomes are largely unknown. The endocannabinoid system is an important signaling pathway that controls feeding behavior and energy homeostasis, and its activity becomes upregulated in the upper small intestinal epithelium of Western diet-induced obese mice, which drives overeating. In the current investigation, we examined the impact of chronic maternal consumption of Western diet on the expression and function of the endocannabinoid system in several peripheral organs important for food intake and energy homeostasis in offspring. Female C57BL/6Tac mice were fed a Western diet or low-fat/no-sucrose control chow for 10 weeks, then males were introduced for mating. Dams were maintained on their respective diets through weaning of pups, at which time pups were maintained on low-fat/no-sucrose chow for 10 weeks. Neonates born from dams fed Western diet, when compared to those born from mice fed control chow, unexpectedly displayed increases in mortality that occurred exclusively within six days following birth (greater than 50% mortality). Males comprised a larger fraction of surviving offspring from obese dams. Furthermore, surviving offspring displayed transient increases in body mass for first two days post weaning, and no marked changes in feeding patterns and endocannabinoid levels in upper small intestinal epithelium, pancreas, and plasma, or in expression of key endocannabinoid system genes in the upper small intestinal epithelium and pancreas at 10 weeks post-weaning. Collectively, these results suggest that maternal diet composition greatly influences survival of neonate C57BL/6Tac mice, and that surviving offspring from dams chronically fed a Western diet do not display marked changes in body mass, eating patterns, or expression and function of the endocannabinoid system in several peripheral organs important for feeding behavior and energy homeostasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166980PMC
March 2019

The effect of undissolved air on isochoric freezing.

Cryobiology 2016 Jun 10;72(3):225-31. Epub 2016 Apr 10.

Department of Mechanical Engineering, University of California at Berkeley, Berkeley, CA 94720, USA.

This study evaluates the effect of undissolved air on isochoric freezing of aqueous solutions. Isochoric freezing is concerned with freezing in a constant volume thermodynamic system. A possible advantage of the process is that it substantially reduces the percentage of ice in the system at every subzero temperature, relative to atmospheric freezing. At the pressures generated by isochoric freezing, or high pressure isobaric freezing, air cannot be considered an incompressible substance and the presence of undissolved air substantially increases the amount of ice that forms at any subfreezing temperature. This effect is measurable at air volumes as low as 1%. Therefore eliminating the undissolved air, or any separate gaseous phase, from the system is essential for retaining the properties of isochoric freezing.
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http://dx.doi.org/10.1016/j.cryobiol.2016.04.002DOI Listing
June 2016