Source: MICHIGAN STATE UNIV submitted to NRP
OXIDIZED LINOLEIC ACID METABOLITES PRODUCED DURING LIPOLYSIS MODULATE ADIPOSE TISSUE METABOLIC FUNCTION IN PERIPARTURIENT DAIRY COWS
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
AFRI COMPETITIVE GRANT
Reporting Frequency
Annual
Accession No.
1018908
Grant No.
2019-67015-29443
Cumulative Award Amt.
$499,821.00
Proposal No.
2018-07094
Multistate No.
(N/A)
Project Start Date
May 1, 2019
Project End Date
Apr 30, 2024
Grant Year
2019
Program Code
[A1231]- Animal Health and Production and Animal Products: Improved Nutritional Performance, Growth, and Lactation of Animals
Recipient Organization
MICHIGAN STATE UNIV
(N/A)
EAST LANSING,MI 48824
Performing Department
LG ANML CLIN SCI
Non Technical Summary
During the periparturient period of dairy cows, adipose tissues (AT) breakdown of fat reserves (stored as triglycerides) fulfills, in part, energy deficits driven by calf growth and milk production.The breakdown of triglycerides into free fatty acids and glycerol is termed lipolysis. When lipolysis occurs, it induces changes in the structure of AT that are characterized by a moderate inflammatory response with infiltration of immune cells specially macrophages.Extended periods of lipolysis lead to excessive inflammation in AT and as a consequence cows have poor lactation performance and are predisposed to disease. Excessive inflammation in AT causes important economic losses to dairy producers and impacts negatively the wellbeing and health of dairy cows.During lipolysis fat cells, also known as adipocytes, secrete a type of molecules termed hydroxyl-octadecadienoic acids (HODEs) that are derived from linoleic acid. These HODEs are potent modulators of inflammation in AT and may directly increase lipolysis rate by reducing adipocyte response to insulin (the anti-lipolysis hormone). Our hypothesis is that lipolysis dysregulation increases the abundance of HODEs in AT which enhances AT macrophage infiltration and sustains AT inflammation. We will develop the hypothesis in two aims. Aim 1 will determine how HODEs synthesized during lipolysis in cows' AT modify macrophage inflammatory response and reduce the fat cells sensitivity to insulin. Aim 2 will determine the effect of lipolysis inhibition using niacin (a nutritional supplement) in periparturient dairy cows on HODEs and AT macrophage inflammatory responses.Upon completion of this project, we will be able to determine the role of HODEs in the vicious cycle of lipolysis dysregulation and chronic inflammation in AT. These findings will support the use of HODEs as diagnostic tool to detect AT inflammation. Also, results from this project will provide scientific bases for the use of nutritional or pharmacological compounds that inhibit lipolysis and will help producers control AT inflammation in their cows.
Animal Health Component
30%
Research Effort Categories
Basic
70%
Applied
30%
Developmental
0%
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
3023410102080%
3053410109020%
Knowledge Area
302 - Nutrient Utilization in Animals; 305 - Animal Physiological Processes;

Subject Of Investigation
3410 - Dairy cattle, live animal;

Field Of Science
1090 - Immunology; 1020 - Physiology;
Goals / Objectives
Our central hypothesis is that lipolysis dysregulation increases the abundance of a select group of HODEs in AT in a non-enzymatic, ROS dependent manner. This increase enhances AT macrophage infiltration and sustains AT inflammation. We will test this hypothesis using in vitro and ex-vivo models of AT lipolysis, and in periparturient cows using a nutritional intervention for lipolysis modulation. We will pursue two aims:Aim 1: Determine how HODEs that are synthesized in bovine AT during lipolysis modify the macrophage phenotype and reduce the anti-lipolytic response of adipocytes to insulin.Aim 2: Determine how inhibiting lipolysis in periparturient dairy cows affects the non-enzymatic biosynthesis and profile of HODEs, and the AT macrophage phenotype.
Project Methods
Aim 1: Determine how HODEs that are synthesized in bovine AT during lipolysis modify the macrophage phenotype and reduce the anti-lipolytic response of adipocytes to insulin. In this aim we will address five questions surrounding the role of HODEs in modifying macrophage phenotypes and the anti-lipolytic response of adipocytes to insulin:1) How does lipolysis alter HODEs biosynthesis in AT?2) What is the role of hormone sensitive lipase in generating HODEs in adipocytes?3) How do reactive oxygen species contribute to producing 9-, 10-, and 12-HODE during lipolysis?4) How do HODEs affect the ATM inflammatory phenotype?5) How do HODEs derived from enzymatic versus non-enzymatic origins affect the anti-lipolytic response of adipocytes to insulin?To address this questions we will use cultured bovine adipocytes from omental and subcutaneous adipose tissues and bovine macrophages. To elucidate the mechanisms by which HODEs modulate lipolysis in adipocytes. we will use lipolytic agents (isoproterenol), antilipolytic compounts (niacin and CAY10499), HODEs, and pharmacological inhibitors of HODE targets in adipocytes.Evaluation: Based on a power analysis (>.90) conducted with our preliminary data, our study will include adipocytes and macrophages from 8 animals. To assure the repeatability and reproducibility of our results, we will run each assay in triplicate and blind the personnel that perform statistical analyses to treatments when possible. Variables will be analyzed by ANOVA (JMP software, SAS Inst.). Significance will be set at α=0.05.This aim will support 2 scholar publicatons and will be the central theme of a doctoral dissertationAim 2. Determine how inhibiting lipolysis in periparturient dairy cows affects the biosynthesis and profile of HODEs, AT macrophage phenotype, and AT response to insulin.To develop this aim we will use a cohort of periparturient cows to evaluate adipose tissue remodeling responses, focusing on how lipolysis modulation with niacin (NIA) affects HODE biosynthesis and the inflammatory phenotype of adipose tissue macrophages.We will select 30-40 gestating non-lactating multiparous Holstein cows 2 months before expected calving. The inclusion criteria are 1) pregnant, 2) 210 to 230 days of gestation, and 3) BCS between 3.25 and 3.75. Cows will be blocked by parity and BCS and then randomly assigned at close-up (d-21) to either the NIA (12g/d NiaShure™) or control (CON) group. At 12 g/d, rumen-protected NIA decreases lipolysis induced by negative energy balance.During the experiment we will evaluate:A) Metabolic function by assessing markers of energy, protein balance, liver function, and insulin using blood samples collected before morning feeding on days 30, 21, 14, and 7 before expected calving and 1, 7, 14, and 21 days after parturition.B) Adipose tisue inflammation and remodelling using samples collected from subcutaneous adipose tissue from the flank area at 21 days before expected calving and at 7 and 21 days after parturition and running well established assays to measure markers of these two processes.C) Biosynthesis of HODEs and other oxylipids. by extracting the lipid fraction of randomly selected subsamples of plasma collected on the day of biopsies and AT biopsies. In plasma samples, lipids will be further fractionated into triglycerides, cholesterol esters, phospholipids, and NEFA. Using this approach, we will be able to evaluate the effect of reducing lipolysis rates on HODEs and 60 other oxylipid targets in AT and provide for the first time a characterization of how oxylipids are transported and distributed in plasma.D) Insulin action during lipolysis inhibition with NIA using explants from the subcutaneous and omental AT biopsies. We will expose AT samples to insulin at two different concentrations, 5µU/mL (periparturient) and 20 µU (mid-lactation) with and without an acute lipolytic stimulus (ISO 1uM for 3 h). To emulate the chronic lipolytic stimulus experienced by the periparturient cow, we will perform an extended ISO exposure (12 h) using a recently developed chronic lipolysis protocol.Evaluation: All of the variables that we evaluate in a treatment and time-dependent manner will be analyzed as repeated measures using Proc MIXED of SAS (SAS Inst., Inc., Cary NC). Data will be presented as least square means ± standard error. Means will be separated by the Tukey-Kramer option in SAS. We will use the CORR procedure of SAS with the Pearson option to determine correlations among metabolic, inflammation and lipolysis markers and adipose tissue remodeling and adipose tissue macrophage polarization indicators.This aim will support 1 or 2 scholar publicatons and will be the central theme of a masters thesis or a doctoral dissertation

Progress 05/01/19 to 04/30/24

Outputs
Target Audience:Nutritionists, veterinarians, animal scientists, professional students (veterinary medicine), veterinary technicians, and undergraduate students (animal sciences and physiology). Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project supported, in part, the training of: 3 postdoctoral fellows, 3 PhD students, 3 visiting scholars (1 from Estonia and 2 from Colombia), and 6 undergraduate students. These trainees had the opportunity to learn new techniques, present their research at regional and national meetings, and support their future professional careers. How have the results been disseminated to communities of interest?Results from this project were presented at international, national, and regional scientific meetings. Results were also presented in Podcasts and lay articles to audiences that include dairy producers, industry partners, veterinarians, and animal scientists. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? Aim 1. We determined that lipolysis is a source of lipid mediators of inflammation, such as HODEs. These lipid mediators can modulate the inflammatory phenotype of macrophages, especially during the periparturient period. We demonstrated this by assessing the inflammatory phenotype of these cells using a transcriptomics approach (doi: 10.1186/s12864-020-07235-0; doi: 10.3168/jds.2023-23409), as well as by evaluating the histological changes and the expression of proteins that are biomarkers of macrophage infiltration, such as osteopontin (doi: 10.3168/jds.2023-23998). When adipose tissue macrophages change their inflammatory phenotype towards a pro-inflammatory state, the adipose tissue becomes insulin resistant, predisposing cows to ketosis and other metabolic diseases. Aim 2: Using different inhibitors of lipolysis, such as niacin, flunixin meglumine (doi: 10.1186/s12864-020-07235-0; doi: 10.3168/jds.2023-23409), and supplementation of oleic acid (doi: 10.3168/jds.2022-22402) and chromium (Parales et al., Abstract ADSA 2021, publication in preparation), we demonstrated that reducing lipolysis rates improves milk production, reduces the production of pro-inflammatory HODEs, and increases the synthesis of oxoODEs (anti-inflammatory linoleic acid metabolites). Reducing lipolysis rates may improve clinical ketosis recovery and enhance lactation and reproductive performance.

Publications

  • Type: Journal Articles Status: Published Year Published: 2024 Citation: Bradford BJ, Contreras GA. Adipose Tissue Inflammation: Linking Physiological Stressors to Disease Susceptibility. Annu Rev Anim Biosci. 2024 Feb 15;12:261-281. doi: 10.1146/annurev-animal-021122-113212. Epub 2023 Dec 8. Review. PubMed PMID: 38064480.
  • Type: Journal Articles Status: Published Year Published: 2024 Citation: Chirivi M, Cortes D, Rendon CJ, Contreras GA. Lipolysis inhibition as a treatment of clinical ketosis in dairy cows: Effects on adipose tissue metabolic and immune responses. J Dairy Sci. 2024 Jan 24;. doi: 10.3168/jds.2023-23998. [Epub ahead of print] PubMed PMID: 38278290.
  • Type: Journal Articles Status: Published Year Published: 2023 Citation: Chirivi M, Cortes-Beltran D, Munsterman A, O'Connor A, Contreras GA. Lipolysis inhibition as a treatment of clinical ketosis in dairy cows: A randomized clinical trial. J Dairy Sci. 2023 Dec;106(12):9514-9531. doi: 10.3168/jds.2023-23409. Epub 2023 Sep 9. PubMed PMID: 37678786.
  • Type: Journal Articles Status: Published Year Published: 2024 Citation: Chirivi M, Contreras GA. Endotoxin-induced alterations of adipose tissue function: a pathway to bovine metabolic stress. J Anim Sci Biotechnol. 2024 Apr 6;15(1):53. doi: 10.1186/s40104-024-01013-8. Review. PubMed PMID: 38581064; PubMed Central PMCID: PMC10998405.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Abou-Rjeileh U, Lock AL, Contreras GA. Oleic acid promotes lipid accumulation and improves mitochondrial function in bovine adipocytes. American Dairy Science Association Annual Meeting, Ottawa, Ontario, Canada, June 25-28, 2023, 2110. National Milk Producers Federation Award First Place PhD Oral Presentation Competition.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Chirivi M, Worden L, Parales-Giron, Lock AL, Contreras GA. Endotoxemia induces lipolysis and alters adipose tissue function in dairy cows. American Dairy Science Association Annual Meeting, Ottawa, Ontario, Canada, June 25-28, 2023, 1023M.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Abou-Rjeileh U, Lock AL, Contreras GA. Mitochondrial uncoupling protein 1 expression is increased postpartum in adipose tissue of Holstein dairy cows. American Dairy Science Association Annual Meeting, Ottawa, Ontario, Canada, June 25-28, 2023, 1069M.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Contreras GA, 1Chirivi M, Gandy J, Tam Y, Zachut M. Lipolysis modulates the biosynthesis of palmitoyl- and oleaoyl-ethanolamines in bovine adipocytes. American Dairy Science Association Annual Meeting, Ottawa, Ontario, Canada, June 25-28, 2023, 1145M.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Chirivi M, Cortes D, Rendon J, Contreras GA. The effect of lipolysis inhibitors on adipose tissue function during clinical ketosis in dairy cows. American Dairy Science Association Annual Meeting, Ottawa, Ontario, Canada, June 25-28, 2023, 2240.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Myers MN, Chirivi M, Gandy J, Tam J, Zachut M, Contreras GA. Fatty acids alter endocannabinoid and lipid inflammatory mediator profile during lipolysis in cow adipocytes. Proceedings of the 2023 National Association of Veterinary Scholars Combined Degree Colloquium at the Puerto Rico Convention Center; August 2nd, 2023; San Juan, PR; p 46.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Abou-Rjeileh U, Lock AL, Contreras GA. Effects of oleic acid on lipid accumulation and mitochondrial function in bovine adipocytes. Phi Zeta Research Day, Michigan State University. August 10th, 2023. Pp11. First place PhD graduate student competition oral presentation.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Chirivi M, Cortes D, Rendon J, Contreras GA. Treating ketosis with lipolysis inhibitors improves adipose tissue function. Phi Zeta Research Day, Michigan State University. August 10th, 2023. Pp14.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2023 Citation: Myers MN, Chirivi M, Gandy J, Tam J, Zachut M, Contreras GA. Lipolysis pathways modulate endocannabinoid synthesis in dairy cow adipose tissue. Phi Zeta Research Day, Michigan State University. August 10th, 2023. Pp 20.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2024 Citation: Chirivi M, Worden L, Parales J, Lock AL., Contreras GA. Endotoxemia triggers lipolysis and modifies dairy cows adipose tissue function. CRWAD 2024, January 21-23, Chicago, IL. Pp 93.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2024 Citation: Myers MN, Chirivi M, Gandy J, Tam J, Zachut M, Contreras GA. Endocannabinoid synthesis is modulated by lipolysis pathways in dairy cows adipose tissue. CRWAD 2024, January 21-23, Chicago, IL. Pp 94.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2024 Citation: Abou-Rjeileh U, Lock AL, Contreras GA. Oleic acid enhances lipid accumulation and improves mitochondrial function in bovine adipocytes. CRWAD 2024, January 21-23, Chicago, IL. Pp 193.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2024 Citation: Chirivi M, Contreras GA. TLR4 activation by endotoxin activates lipolysis in bovine adipocytes. CRWAD 2024, January 21-23, Chicago, IL. Pp 250.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2024 Citation: Abou-Rjeileh U, Lock AL, Contreras GA. UCP1 expression in adipose tissue of Holstein dairy cows. CRWAD 2024, January 21-23, Chicago, IL. Pp 468.
  • Type: Conference Papers and Presentations Status: Accepted Year Published: 2024 Citation: Contreras GA, Chirivi M, Abou-Reijeleh U. Oxidized Linoleic Acid Metabolites Modulate Proliferation, Adipogenesis, and Lipogenesis in Bovine Adipocytes. American Dairy Science Association Annual Meeting, West Palm Beach, Florida, June 16-19, 2024.


Progress 05/01/22 to 04/30/23

Outputs
Target Audience:Nutritionists, veterinarians, animal scientists, professional students (veterinary medicine), veterinary technicians, and undergraduate students (animal sciences and physiology). Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The following people are being trained as part of this project: 1. Madison Smith, PhD student 2. Ursula Abou-Rjeileh, PhD student 3. Miguel Chirivi, PhD Student 4. Stella Moline, undergraduate student How have the results been disseminated to communities of interest?Knowledge generated by this project was disseminated through a) peer review publications in high-impact journals, b) regional, national, and international conferences where graduate students and the PI actively participated presented the research as posters, oral abstracts, and keynote talks, c) two extension articles and 3 podcasts. What do you plan to do during the next reporting period to accomplish the goals?For aim 1: We are finalizing all the mechanistic experiments and this year these will be presented at regional, national, and international meetings. Publications are also being prepared. For aim 2: We are currently preparing publications

Impacts
What was accomplished under these goals? Aim 1: We demonstrate that HODEs had a diverse effect on adipogenesis and lipogenesis in bovine adipocytes. While 9- and 13-HODE promote lipogenesis, the non-enzymatically produced 12-HODE inhibits both process. None of the HODEs appear to have an effect on the formation of new adipocytes (adipogenesis). Aim 2: In a clinical trial evaluating the use of lipolysis inhibitors to treat clinical ketosis, we demonstrated that inhibitng lipolysis reduces the production of HODEs (9-, 13-, and 12-HODE) in cows that have lipolysis dysregulation. In healthy cows, the use of nutritional supplements that limit lipolysis such as chromium and oleic acid reduces the synthesis of HODEs, but at the same time, increases the production of their ketone derivatives (oxo-ODEs) these lipid mediators are potent anti-inflammatory products.

Publications

  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Putman AK, Contreras GA. 15-F2t-Isoprostane Favors an Anti-Inflammatory Phenotype in RAW 264.7 Macrophages during Endotoxin Challenge. Antioxidants (Basel). 2022 Mar 19;11(3). doi: 10.3390/antiox11030586. PubMed PMID: 35326236; PubMed Central PMCID: PMC8945100
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Walker CCF, Sordillo LM, Contreras GA. Anandamide Alters Barrier Integrity of Bovine Vascular Endothelial Cells during Endotoxin Challenge. Antioxidants (Basel). 2022 Jul 27;11(8). doi: 10.3390/antiox11081461. PubMed PMID: 36009180; PubMed Central PMCID: PMC9405077
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Zachut M, Tam J, Contreras GA. Modulating immunometabolism in transition dairy cows: the role of inflammatory lipid mediators. Anim Front. 2022 Oct;12(5):37-45. doi: 10.1093/af/vfac062. eCollection 2022 Oct. PubMed PMID: 36268169; PubMed Central PMCID: PMC9564993
  • Type: Journal Articles Status: Published Year Published: 2023 Citation: Myers MN, Abou-Rjeileh U, Chirivi M, Parales J, Lock AL, Zachut M, Tam J, Contreras GA. Cannabinoid-1 receptor activation modulates lipid mobilization and adipogenesis in the adipose tissue of dairy cows. J Dairy Sci. 2023 Mar 10; doi: 10.3168/jds.2022-22556. [Epub ahead of print] PubMed PMID: 36907764.
  • Type: Journal Articles Status: Published Year Published: 2023 Citation: Abuelo A, Mann S, Contreras GA. Metabolic Factors at the Crossroads of Periparturient Immunity and Inflammation. Vet Clin North Am Food Anim Pract. 2023 Apr 7;. doi: 10.1016/j.cvfa.2023.02.012. [Epub ahead of print] Review. PubMed PMID: 37032303.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Myers MN, Abou-Rjeileh U, Chirivi M, Parales J, Lock A, Tam J, Zachut M, Contreras GA. Cannabinoid receptor 1 modulates adipose tissue lipid mobilization and adipogenesis in dairy cows. Proceedings of the 32nd Annual Phi Zeta Research Day at Michigan State University; Oct 14, 2022; East Lansing, MI; pp 4.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Chirivi M, Cortes D, OConnor A, Contreras GA. Targeting lipolysis dysregulation improves clinical ketosis recovery in dairy cows. Proceedings of the 32nd Annual Phi Zeta Research Day at Michigan State University; Oct 14, 2022; East Lansing, MI; pp 2.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Abou-Rjeileh U, Chirivi M, Parales-Giron J, Lock AL, Contreras GA. Chromium supplementation modulates insulin sensitivity in postpartum dairy cows' adipose tissue. Proceedings of the 32nd Annual Phi Zeta Research Day at Michigan State University; Oct 14, 2022; East Lansing, MI. pp 3
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Putman A, Contreras GA. 15-F2t-Isoprostane favors an anti-inflammatory macrophage phenotype during endotoxin challenge. American Dairy Science Association Annual Meeting, June 19-22, 2022, 2416V.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Chirivi M, Contreras GA. Endotoxin activates lipolysis through TLR4 signaling in bovine adipocytes. American Dairy Science Association Annual Meeting, June 19-22, 2022, 2285W.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA, Chirivi1, Abou-Rjeileh U, Gandy J, Parales J, Lock AL. Chromium and palmitic acid supplementations modulate oxidized linoleic acid metabolite biosynthesis in periparturient dairy cows. American Dairy Science Association Annual Meeting, June 19-22, 2022, 2072M.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA. Using NEFA and BHB for nutritional diagnostics in dairy herds. Conference: Importancia de los perfiles metab�licos y an�lisis de alimentos para el diagnostico nutricional del reba�o. Cooprisem Dairy Co-op. Osorno, Chile. November 3, 2022.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Chirivi M, Abou-Rjeileh U, Parales-Giron J, Lock AL, Contreras GA. Chromium and palmitic acid supplementation modulate adipose tissue insulin sensitivity in periparturient dairy cows. American Dairy Science Association Annual Meeting, June 19-22, 2022, 2286W.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA. Energy metabolism physiology in dairy cattle. Conference: Importancia de los perfiles metab�licos y an�lisis de alimentos para el diagnostico nutricional del reba�o. Cooprisem Dairy Co-op. Osorno, Chile. November 3, 2022.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA. Assessing and Managing Lipolysis and Inflammation in Adipose Tissues of Transition Dairy Cows. 11th Simposio Brasil Sul de Bovinocultura de Leite. Chapeco, Santa Catarina, Brazil. November 10, 2022
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA. Lipolysis and Inflammation in Adipose Tissues of Transition Dairy Cows. 11th Simposio Brasil Sul de Bovinocultura de Leite. Chapeco, Santa Catarina, Brazil. November 10. 2022.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA. Adipose tissue Inflammation influences metabolic and immune responses in periparturient dairy cows. China Platform Academic Forum 2022. Seminar "herd monitoring of the transition dairy cow." October 21, 2022. Virtual Conference. Organized by Northwest A&F University, Xianyang, China; Ghent University, Ghent, Belgium.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA, Pighetti G, Rezamand P. Inflammation in the transition cow - contributions of Dr. Lorraine Sordillo. American Dairy Science Association Annual Meeting 2022, Kansas City, MO, June 19-22, 2022. 30041NV.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2022 Citation: Contreras GA. Adipose tissue as an integrator of metabolic and inflammatory signals in periparturient cows. Pacific Northwest Animal Nutrition Conference 56th Annual Meeting. Boise Idaho. January 17-18, 2022. Pp138-144
  • Type: Websites Status: Published Year Published: 2022 Citation: Burch AM, Abou-Rjeileh U, Contreras GA, Lock AL. Harnessing fatty acids for transition cow management. Spartan Dairy Newsletter. Winter 2022. https://www.canr.msu.edu/news/harnessing-fatty-acids-for-transition-cow-management
  • Type: Websites Status: Published Year Published: 2022 Citation: Chirivi M, Contreras GA. Balchem Real Science Exchange. Lipolysis Inhibition Improves Clinical Outcomes in the Treatment of Ketosis in Dairy Cows: An Individually Randomized Multigroup Parallel Controlled Trial. https://balchem.com/animal-nutrition-health/resources/lipolysis-inhibition-improves-clinical-outcomes-in-the-treatment-of-ketosis-in-dairy-cows-an-individually-randomized-multigroup-parallel-controlled-trial/
  • Type: Websites Status: Published Year Published: 2022 Citation: Contreras GA. The Role of Fat Tissues on Lipid Mobilization, Inflammation, and Oxidative Stress During the Transition Period. September 14, 2022. http://www.fattyacidforum.com/the-role-of-fat-tissues-on-lipid-mobilization-inflammation-and-oxidative-stress-during-the-transition-period-dr-andres-contreras/
  • Type: Websites Status: Published Year Published: 2022 Citation: Contreras GA. #04 - Ketosis: still a concern with dairy cows? October, 2022. https://podcasts.apple.com/us/podcast/04-ketosis-still-a-concern-with-dairy-cows-dr/id1643773684?i=1000581472186


Progress 05/01/21 to 04/30/22

Outputs
Target Audience:Nutritionists, veterinarians, animal scientists, professional students (veterinary medicine), veterinary technicians, and undergraduate students (animal sciences and physiology). Changes/Problems:The in vitro experiments planned for Aim 1 continue to be delayed. During 2021 there were serious issues with tissue culutre supplies that were backordered due to supply chain disruptions. For example, 96 well plates and glycerol reagent were backordered nearly 7 months. Without these suplies we could not advance in our mechanistic experiments. What opportunities for training and professional development has the project provided?The following persons are being trainined as a part of this project: 1. Madison Smith, PhD Student 2. Ursula Abou-Rjeileh, PhD student 3. Miguel Chirivi, PhD Student 4. Jair Parales, PhD Student How have the results been disseminated to communities of interest?Knowledge generated by this project was disseminated through peer-reviewed publicatons in high impact factor journals and by presenting findings in regional, national, and international conferences where graduate students and the PIs participated. We also prepared one lay article that was published in MSU extension. What do you plan to do during the next reporting period to accomplish the goals?For aim 1: we will complete the mechanistic experiments that were delayed due to supply chain issues that limited the availability of tissue culture supplies that delayed our in vitro experiments For aim 2: we completed our in vivo experiments and this year we will analyze data and prepare publications.

Impacts
What was accomplished under these goals? Aim 1: We restarted the mechanistic experiments in adipocytes and macrophages. In adipocytes we are currently evaluatiing the effect of HODEs on adipogenesis, lipogenesis when these cells are cultured with supplemental fatty acids emulating our in vivo experiments. Aim 2: We demonstrated that reducing lipolysis and enhancing insulin sensitivity using supplementation of oleic acid reduces the biosynthesis of HODEs derived from non-enzymatic pathways.

Publications

  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Abou-Rjeileh U, Contreras GA. Redox Regulation of Lipid Mobilization in Adipose Tissues. Antioxidants (Basel). 2021 Jul 7;10(7). doi: 10.3390/antiox10071090. Review. PubMed PMID: 34356323; PubMed Central PMCID: PMC8301038
  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Chirivi M, Rendon CJ, Myers MN, Prom CM, Roy S, Sen A, Lock AL, Contreras GA. Lipopolysaccharide induces lipolysis and insulin resistance in adipose tissue from dairy cows. J Dairy Sci. 2022 Jan;105(1):842-855. doi: 10.3168/jds.2021-20855. Epub 2021 Oct 23. PubMed PMID: 34696909.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Zachut M, Contreras GA. Symposium review: Mechanistic insights into adipose tissue inflammation and oxidative stress in periparturient dairy cows. J Dairy Sci. 2022 Feb 9;. doi: 10.3168/jds.2021-21225. [Epub ahead of print] Review. PubMed PMID: 35151484.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Putman AK, Gandy JC, Contreras GA, Sordillo LM. Oxylipids are associated with higher disease risk in postpartum cows. J Dairy Sci. 2022 Mar;105(3):2531-2543. doi: 10.3168/jds.2021-21057. Epub 2022 Jan 25. PubMed PMID: 35086706
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Abou-Rjeileh U, Lock AL, Contreras GA. The effect of palmitic and oleic acids on lipogenesis in dairy cow adipocytes. 2021 Tri-State Dairy Nutrition Conference. Apr 19-21, pp 164. 1st place MS student competition.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Chirivi M, Rendon C, Myers M, Contreras GA. Lipopolysaccharide induces lipolysis and insulin resistance in adipose tissue from dairy cows. 2021 Tri-State Dairy Nutrition Conference, Apr 19-21. pp 166.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Myers MN, Rendon CJ, Zachut M, Tam J, Contreras GA. Cannabinoids modulate adipogenesis and lipogenesis in dairy cows. International Cannabinoid Research Society Annual Meeting. June 21-24, 2021, Jerusalem, Israel. Pp 167
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Myers MN, Rendon CJ, Zachut M, Tam J, Contreras GA. Adipogenesis and lipogenesis are modulated by cannabinoids in dairy cows. American Dairy Science Association Annual Meeting, July 11-14, 2021, SC138
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Abou-Rjeileh U, Lock AL, Contreras GA. Palmitic and oleic acids modulate lipogenesis in dairy cow adipocytes. American Dairy Science Association Annual Meeting, July 11-14, 2021, 264
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Abou-Rjeileh U, Chirivi M, Giron JP, Lock AL, Zachut M, Tam J, Contreras GA. Cannabinoids and adipose tissue lipolysis in periparturient dairy cows. American Dairy Science Association Annual Meeting, July 11-14, 2021 284
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Abou-Rjeileh U, Chirivi M, Parales-Giron J, Dos Santos Neto JM, Prom CM, Laguna J, Lock AL, Contreras GA. Oleic acid improves insulin sensitivity in adipose tissue of periparturient dairy cows. Phi Zeta Research Day, Michigan State University. October 1st 2021. pp13 1st place graduate student competition oral presentation
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Chirivi M, Contreras GA. Endotoxin Activates Lipolysis in Bovine Adipocytes. Phi Zeta Research Day, Michigan State University. October 1st 2021. pp15
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Abou-Rjeileh U, Chirivi M, Parales-Giron J, Prom CM, Laguna J, Lock AL, Contreras GA. Oleic acid improves insulin sensitivity in dairy cow adipose tissue through PPAR? and PLIN5. CRWAD 2021, December 5-7, Chicago, IL. Pp 33. Travel award recipient.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Contreras GA. Oxidative stress in the adipose tissue: Magnifying the risk for periparturient disease. Animal Health Symposium: Adipose Tissue in Transition Dairy Cows as an Integrator of Metabolic and Inflammatory Cues in Health and Disease. American Dairy Science Association Annual Meeting, July 11-14, 2021, S121
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Contreras GA, Putman A, Abuelo A, Sordillo LM. Lactational Biology Symposium: Metabolic transitions and lipid mediators as modulators of mammary gland inflammation and oxidative stress. American Dairy Science Association Annual Meeting 2021, Fall Seminars, W112.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Cortes D, Chirivi M, OConnor A, Contreras GA. Lipolysis Inhibition Improves Clinical Outcomes In The Treatment Of Ketosis In Dairy Cows. Phi Zeta Research Day, Michigan State University. October 1st 2021. pp15
  • Type: Conference Papers and Presentations Status: Published Year Published: 2021 Citation: Myers M, Chirivi M, Abou-Rjeileh U, Zachut M, Tam J, Contreras GA. Adipose Tissue Adipogenesis and Lipogenesis Are Modulated by Cannabinoids in Dairy Cows. Phi Zeta Research Day, Michigan State University. October 1st 2021. pp19 1st place graduate student competition poster presentation.


Progress 05/01/20 to 04/30/21

Outputs
Target Audience:Nutritionists, veterinarians, animal scientists, professional students (veterinary medicine), veterinary technicians, and undergraduate students (animal sciences and physiology). Changes/Problems:The in vitro experiments planned for Aim 1 were delayed because of COVID 19 pandemic. The access to our lab was limited during 5 months in 2020 (March-August) and thus we were not able to perform any in vitro research. Our ability to collect primary cells for experiments in Aim 1 was also very limited during 2020. This was due to the closing of abattoirs in June. Although abattoirs opened in July, our access to harvest cells was only granted back in January 2021. What opportunities for training and professional development has the project provided?The following persons are being trainined as a part of this project: 1. Madison Smith, PhD Student 2. Ursula Abou-Rjeileh, PhD student 3. Miguel Chirivi, PhD Student 4. Jair Parales, PhD Student How have the results been disseminated to communities of interest?Findings of this research were presented at the CRWAD 2020. Other conferences were cancelled due to the COVID-19 pandemic What do you plan to do during the next reporting period to accomplish the goals?Aim 1: Determine how HODEs that are synthesized in bovine AT during lipolysis modify the macrophage phenotype and reduce the anti-lipolytic response of adipocytes to insulin. We will evaluate the effects of HODEs on macrophage phenotype and will begin with mechanistics experiments. Aim 2: Determine how inhibiting lipolysis in periparturient dairy cows affects the non-enzymatic biosynthesis and profile of HODEs, and the AT macrophage phenotype. We completed an in vivo study in periparturient cows (n=24) that used two different treatments to inhibit lipolysis or promote lipogenesis. All samples were collected during the fall 2020 and the winter 2020-21. In 2021 and 2022 we will evaluate the effect of these treatments on HODEs biosynthesis and lipolysis regulation.

Impacts
What was accomplished under these goals? Aim 1: Determine how HODEs that are synthesized in bovine AT during lipolysis modify the macrophage phenotype and reduce the anti-lipolytic response of adipocytes to insulin. We determined new macrophage phenotype markers using RNAseq analyses of adipose tissue biopsies collected from periparturient dairy cows. These new targets will allow us to examine the effects of HODEs on adipose tissue macrophages in a more sensitive and specific manner. These findings were reported in BMC Genomics. 2020 Nov 23;21(1):824. Aim 2: Determine how inhibiting lipolysis in periparturient dairy cows affects the non-enzymatic biosynthesis and profile of HODEs, and the AT macrophage phenotype. We completed an in vivo study in periparturient cows (n=24) that used two different treatments to inhibit lipolysis or promote lipogenesis. As described in the project narrative, we will evaluate the effect of these treatments on HODEs biosynthesis and lipolysis regulation.

Publications

  • Type: Journal Articles Status: Published Year Published: 2020 Citation: Salcedo-Tacuma D, Parales-Giron J, Prom C, Chirivi M, Laguna J, Lock AL, Contreras GA. Transcriptomic profiling of adipose tissue inflammation, remodeling, and lipid metabolism in periparturient dairy cows (Bos taurus). BMC Genomics. 2020 Nov 23;21(1):824. doi: 10.1186/s12864-020-07235-0. PubMed PMID: 33228532; PubMed Central PMCID: PMC7686742.
  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Putman AK, Contreras GA, Sordillo LM. Isoprostanes in Veterinary Medicine: Beyond a Biomarker. Antioxidants (Basel). 2021 Jan 20;10(2):145. doi: 10.3390/antiox10020145. PMID: 33498324; PMCID: PMC7909258.
  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Myers MN, Zachut M, Tam J, Contreras GA. A proposed modulatory role of the endocannabinoid system on adipose tissue metabolism and appetite in periparturient dairy cows. J Anim Sci Biotechnol. 2021 Mar 5;12(1):21. doi: 10.1186/s40104-021-00549-3. PMID: 33663611; PMCID: PMC7934391.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2020 Citation: Chirivi M, Myers MN, Rendon CJ, Runin M, Contreras GA. Endotoxin enhances lipolytic responses and impairs insulin sensitivity in bovine adipose tissue. CRWAD 2020. 273-pp182
  • Type: Conference Papers and Presentations Status: Published Year Published: 2020 Citation: Salcedo-Tacuma D, Parales-Giron J, Prom C, Chirivi M, Laguna J, Lock AL, Contreras GA. Effect of parturition and lactation on adipose tissue transcriptomic profiles in dairy cows. CRWAD 2020. 349-pp252


Progress 05/01/19 to 04/30/20

Outputs
Target Audience:Nutritionists, veterinarians, animal scientists, professional students (veterinary medicine), veterinary technicians, and undergraduate students (animal sciences and physiology). Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The following persons have been trainined as a part of this project: 1. Madison Smith, MS student 2. Ursula Abou-Rjeileh, Undergraduate student Animal Science 3. Josh Geldersma, Undergraduate student Biochemistry 4. Maxim Runin, International Scholar, Estonian Life Sciences University 5. Miguel Chirivi, PhD Student 6. Jair Parales, PhD Student 7. Javier Rendon, PhD Student How have the results been disseminated to communities of interest?Findings of this research have been presented at the American Dairy Science Annual meeting 2019, CRWAD 2019, Phi Zeta Research Day CVM MSU 2019, Discover Conference October 2019 What do you plan to do during the next reporting period to accomplish the goals?Aim 1: Determine how HODEs that are synthesized in bovine AT during lipolysis modify the macrophage phenotype and reduce the anti-lipolytic response of adipocytes to insulin. We will evaluate the effects of HODEs on macrophage phenotype and will begin with mechanistics experiments. Aim 2: Determine how inhibiting lipolysis in periparturient dairy cows affects the non-enzymatic biosynthesis and profile of HODEs, and the AT macrophage phenotype. In vivo studies will start in the Fall 2020

Impacts
What was accomplished under these goals? Aim 1: Determine how HODEs that are synthesized in bovine AT during lipolysis modify the macrophage phenotype and reduce the anti-lipolytic response of adipocytes to insulin. We have determined the direct effects of lipolytic activity of hormone sensitive lipase (HSL) on the biosynthesis of HODE. When HSL becomes active it provides linoleic acid as a substrate for HODE biosynthesis. When we inhibited HSL, HODE bosyntheis was reduced by over 50%. In healthy cows production of HODE during the first week of lactation does not increase oxidative stress. However, by three weeks in lactation the adipose tissue concentrations of Isoprostanes started to increase, probably because antioxidant potential of adipose tissue starts to be depleted. These findings were reported in doi: 10.3168/jds.2019-17256. We determined that HODEs do not inhibit the adipogenesis process in bovine preadipocytes.

Publications

  • Type: Journal Articles Status: Published Year Published: 2020 Citation: Contreras GA, De Koster J, de Souza J, Laguna J, Mavangira V, Nelli RK, Gandy J, Lock AL, Sordillo LM. Lipolysis modulates the biosynthesis of inflammatory lipid mediators derived from linoleic acid in adipose tissue of periparturient dairy cows. J Dairy Sci. 2019 Nov 20;. doi: 10.3168/jds.2019-17256. [Epub ahead of print] PubMed PMID: 31759597.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Chirivi M, Parales JE, Laguna J. Worden L, Prom C, Lock A, Contreras GA. LPS enhances lipolytic responses and reduces insulin sensitivity in adipose tissue from transition dairy cows. Conference of Research Workers in Animal Diseases Annual Meeting, November 2-5, 2019, Chicago, IL. P084.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Chirivi M, Laguna J. Worden L, Prom C, Lock A, Contreras GA. Lipopolysaccharide induces lipolysis and reduces insulin sensitivity in subcutaneous adipose tissue from transition dairy cows. American Dairy Science Association Annual Meeting, June 23-26, 2019, Cincinnati, OH.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Geldersma J. Laguna J, Lock A, Contreras GA. Lipogenic effects of trans-10,cis-12 and cis-9,trans-11 conjugated linoleic acids on 3D cultured omental and subcutaneous adipocytes derived from lactating dairy cows. American Dairy Science Association Annual Meeting, June 23-26, 2019, Cincinnati, OH. W80.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Laguna J, Chirivi M, Prom C, Lock A, Contreras GA. Oleic acid supplementation alters adipose tissue lipolytic responses and insulin sensitivity in early-lactation dairy cows. American Dairy Science Association Annual Meeting, June 23-26, 2019, Cincinnati, OH. W125.