Source: COLORADO STATE UNIVERSITY submitted to NRP
N-3 POLYUNSATURATED FATTY ACIDS AND HUMAN HEALTH AND DISEASE
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
Reporting Frequency
Annual
Accession No.
0231633
Grant No.
(N/A)
Cumulative Award Amt.
(N/A)
Proposal No.
(N/A)
Multistate No.
NC-1199
Project Start Date
Oct 1, 2012
Project End Date
Jan 26, 2017
Grant Year
(N/A)
Program Code
[(N/A)]- (N/A)
Recipient Organization
COLORADO STATE UNIVERSITY
(N/A)
FORT COLLINS,CO 80523
Performing Department
Food Science & Human Nutrition
Non Technical Summary
Two projects make up these studies. The first is a human clinical trial supplementing pregnant and breastfeeding mothers with omega-3 DHA to evaluate the effect on infant body fat and on breastmilk n-3 DHA levels and levels of obesity promoting and protective hormones in breastmilk. The second project will look at the effect of n-3 DHA on the inflammatory response to the Western diet (high fat, high sugar) or to a low fat diet. Both studies are interested in evaluating the requirement for preformed n-3 DHA or "fish oil fatty acid" in the diet, although technically it can be made by the body from a plant based n-3, linolenic acid (ALA). Conversion of ALA to n-3 DHA is believed to low in humans, but there is accumulating evidence that common gene mutations (known as "fads2 SNPs") have significant effects on the synthesis of n-3 DHA from ALA and therefore upon human requirements for dietary n-3 DHA and also on the ability to transport n-3 DHA to breastmilk and tissues.
Animal Health Component
50%
Research Effort Categories
Basic
50%
Applied
50%
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
7025010101050%
7025010104050%
Goals / Objectives
To determine the effects of omega-3 fatty acids on health-related outcomes in both human and rodent models. To define the mechanisms mediating the health promoting effects of omega-3 fatty acids. To evaluate the effect of an eXtension site on meeting the public's informational needs regarding omega-3 fatty acids.
Project Methods
Conduct and analyze a human clinical intervention trial of variable levels of n-3 DHA intake during pregnancy and throughout exclusive breastfeeding on infant body mass index (BMI) in the first year of life. DHA response will be evaluated by characterizing components of the mother's genome which may increase requirements for preformed DHA during pregnancy and breastfeeding. Maternal DHA stores and bresast milk DHA will e evaluated by gas chromatography. Adipogenic hormone levels, adiponectin and leptin, in breastmilk in response to DHA will be measured by enqyme linked immunoassay. A second project will elucidate the influence of systemic delta 6-desaturase (D6D) activity on cardiometabolic disease risk (glucose tolerance, hyperlipidemia, inflammation, etc.) in response to n-3 fatty acids and a standard low-fat diet or a high-fat/sucrose "Western" diet. This study will utilize animal models of cardiometabolic disease fed experimental diets with or without treatment with an orally active D6D inhibitor, and 2) recently developed a transgenic mouse with global overexpression of D6D (fads2). e are also interested in determining the extent to which effects of exogenous DHA (obtained through dietary supplementation) differ from those elicited by endogenously produced DHA (synthesized from ALA) on the pattern of incorporation into tissue phospholipids measured by liquid chromatography and gas liquid chromatography.

Progress 10/01/12 to 01/26/17

Outputs
Target Audience:The target audience is women of childbearing age, obstetricians and dietetic practitioners. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?MS student project for thesis, How have the results been disseminated to communities of interest?Research presentations at scientific meetings, invited presentations, book chapter and published manuscripts. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? The Omega-Smart Baby follow-up study examined the relationship of DHA with lipocalin II, a ligand for small lipophilic substances (including arachidonic acid) and presumably participates in inflammatory processes. In conjunction with Concetta DiRussso (Nebraska Station), we previously demonstrated a seemingly paradoxical positive association between erythrocyte (RBC) n-3 DHA and lipocalin II in 85 pregnant women at 24 - 26 weeks of gestation. A follow up study of 27 of these participants at 1.5 - 2 y postpartum (mean age 35 +/- 3.7 y, BMI 24.6 +/- 3.5) supplemented with 0 or 300 mg DHA from week 26 of pregnancy through three months of lactation, reaffirmed the positive correlation between RBC-DHA (expressed as % total fatty acids) and lipocalin (r = .451, p = .018). RBC n-3 DHA and total dietary intake of DHA were positively correlated with the anti-inflammatory adipokine, resistin (p =.031) when corrected for BMI. RBC DHA was negatively correlated with the inflammatory mediator MCP-1 (r = -.427, p =.026). However, No effect of DHA supplementation or DHA status on body composition measured by DEXA was found. In conjunction with the University of Colorado, Division of Reproductive Medicine, we conducted a study with Alex Polotsky and Zain Al-safi, in 27 women (15 obese and 12 normal weight) on n-3 supplementation and gonadotrophins and ovarian reserve. Supplementation with 4 g Lovasa/day significantly reduced Il-1β and TNF-α in obese but not controls. Supplementation with n-3 fatty acids decreased serum FSH in hypogonadic normal weight women but not in obese women. The ratio of omega-6 to omega-3 PUFA was significantly reduced in plasma and red blood cell components for both groups after treatment (both P < .01). Omega-3 PUFA supplementation resulted in reduction of FSH and FSH response to GnRH by 17% on average (P = .06 and P = .03, respectively) in NW but not obese women. Serum levels of IL-1β and TNF-α were reduced after omega-3 PUFA supplementation (−72% for IL-1β; −56% for TNF-α; both, P < .05) in obese but not in NW women. This reduction, however, was not associated with a hormonal change in obese women. The Omega-Smart Baby follow-up study examined the relationship of DHA with in 27 women, who completed DEXA body composition testing and provided blood samples for analysis of inflammatory mediators and omega-3 docosahexaenoic acid (DHA) status. Red blood cell (RBC) DHA correlated well with dietary intake of DHA (r = .526 ( P= .005). Average dietary intake in DHA was 193.4±157.4 mg/day. Average amount of time postpartum was 31.9 ± 5.2 months fo r all women enrolled. Mean total months breastfeeding was 15.8 ± 9.6 months. Mean months since cessation of breastfeeding was 16.2 ± 10.1 months. Average amount of weight gain during pregnancy was 31.1 ± 8.7 lbs. Inflammatory markers, IL-1, IL-6, IL-8., TNFα were all highly correlated with one another. Weak negative associations of RBC DHA was (r =- .48, p = .011 with inflammatory marker, MCP-1 and weak positive associations with resistin (r = .54 , p = .004) and lipocalins, mixed proteins from a family of lipid transport molecules generally associated with inflammatory processes (r = .45, p = .018). DHA Intake and RBC DHA status were largely unrelated to body fat and bone density. Physical activity and RBC DHA together explained 40.3% of the variance in lumbar and pelvic BMC. Physical activity, reported as Only total METS of activity, reported questionnaire (PAQ) was consistent and positively associated with greater bone mineral density and lumbar bone mineral content 16 months to 2 years after cessation of breastfeeding. A negative correlation was seen between RBC DHA and bone mineral content at one of the sites (lumbar hip). These mixed findings are likely explained on the basis of the small sample size and relatively large standard deviations

Publications

  • Type: Book Chapters Status: Published Year Published: 2016 Citation: Lammi-Keefe C and Harris, M. Chapter 5: Fish Consumption Recommendations for Pregnant and Lactating Women in Fish and Fish Oil in Health Promotion and Disease Prevention. S Ratz and D. Bibus eds., Elsevier, St. Loius, Mo.pages 49-60
  • Type: Conference Papers and Presentations Status: Published Year Published: 2015 Citation: Harris MA. Implementation of an evidenced based program to improve omega-3 fatty acids intake in pregnant women. Academy of Nutrition and Dietetics, Food and Nutrition Conference, Oct 6, 2015, Nashville, TN.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2016 Citation: Bauer J, Polotsky A, Bradford A, Harris M, Eckel R.Omega-3 fatty acid supplementation lowers FSH in hypogonadotrophic normal weight but not obese women. American Society for Reproductive Medicine
  • Type: Conference Papers and Presentations Status: Published Year Published: 2015 Citation: Harris MA, Pendleton W, Cox-York K. : N-3 Docosahexaenoic Acid (DHA) Status is Positively Associated with Plasma Lipocalin and Resistin and Inversely Associated MCP-1 in Post-partum Women Lipoids 2015 San Francisco Nov 30  Dec 3.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Pendleton W, Melby C and Harris M. Does N-3 Docosahexadenoic Acid Alter the Impact of Physical Activity on Bone Density in Postpartum Women? IORE Journal of Food and Nutrition v1.1 published online June 2016.
  • Type: Journal Articles Status: Under Review Year Published: 2016 Citation: Hunley, J., Clark, A., Harris, M., Baker, S. & Davalos, D. B. (submitted). Recommendations for and Benefits of Breastfeeding: a 1990-2012 Literature Review. Health Promotion Practice. Revisions Submitted
  • Type: Journal Articles Status: Awaiting Publication Year Published: 2016 Citation: Miller SM, Harris MA, Baker SS, Davalos DB, Clark AM, MGirr KA. Intake of Total Omega-3 Docosahexaenoic Acid is Associated with Increased Gestational Length and Improved Cognitive Performance at 1Year of Age. J Nutr Health Food Engineering. Accepted for Publication. Manuscript # JNHFE-16-RA-319
  • Type: Theses/Dissertations Status: Published Year Published: 2016 Citation: Pendleton, W. Effect of combined n-3 DHA and Physical Activity on Body composition and Bone Density in Postpartum Women. Colorado State University


Progress 10/01/14 to 09/30/15

Outputs
Target Audience:thiss is a multi-state project whose target audience is fatty acids and health of poeple in the United States. This project targets women of childbearing age. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest?Reported at Annual Society for Reproductive Medicine. What do you plan to do during the next reporting period to accomplish the goals?A new study will be initiated to determine whether n6:n3 ratios and FSH can be reduced in normal weight women followinghigh fat diets and recieving n-3 fatty acids suplements.

Impacts
What was accomplished under these goals? Evaluation of n-3 fatty acid supplementation in obese and non-obese women decreased serum FSH in hypogonadic normal weight women but not in obese women.The ratio of omega-6 to omega-3 PUFA was significantly reduced in plasma and red blood cell components for both groups after treatment (both P < .01). Omega-3 PUFA supplementation resulted in reduction of FSH and FSH response to GnRH by 17% on average (P = .06 and P = .03, respectively) in NW but not obese women. Serum levels of IL-1β and TNF-α were reduced after omega-3 PUFA supplementation (−72% for IL-1β; −56% for TNF-α; both, P < .05) in obese but not in NW women. This reduction, however, was not associated with a hormonal change in obese women.

Publications

  • Type: Conference Papers and Presentations Status: Published Year Published: 2015 Citation: Al-Safi Z, Polotsky A, Liu H, Chosich H, Bradford A, Carlson N, Harris M, Eckel R, Robledo, C. Omega-3 fatty acid supplementation lowers serum FSH in young normal weight women. 71st Annual Meeting American Society of Reproductive Medicine. Oct 17-21, Baltimore, MD
  • Type: Conference Papers and Presentations Status: Published Year Published: 2015 Citation: Al-Safi Z, Polotsky A, Liu H, Chosich H, Bradford A, Carlson N, Harris M, Eckel R, Robledo, C. N3 fatty acid supplementation does not improve relative hypogonadotrophic hypogonadism in obese women. 71st Annual Meeting American Society of Reproductive Medicine. Oct 17-21, Baltimore, MD
  • Type: Book Chapters Status: Awaiting Publication Year Published: 2016 Citation: Lammi-Keefe C and Harris, M. Chapter 5: Fish Consumption Recommendations for Pregnant and Lactating Women in Fish and Fish Oil in Health Promotion and Disease Prevention. S Ratz, ed., Elsevier, St. Loius, Mo.2015.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Harris MS, Reece MS, McGregor JA, Wilson JW, Burke SM, Wheeler M, Anderson JE, Auld GW, French JI, and Allen KGD. The effect of omega-3 docosahexaenoic acid (DHA) on gestational length: prenatal supplementation compared to nutrition education. Biomedical Science. Special Issues: prevention, Mechanism of Preterm Birth. 2015. doi: Manuscript doi www.hindawi.com/journals/bmri/aa/1230
  • Type: Conference Papers and Presentations Status: Published Year Published: 2015 Citation: Harris MS. Implementation of an evidenced based program to improve omega-3 fatty acids intake in pregnant women. Academy of Nutrition and Dietetics, Food and Nutrition Conference, Oct 6, 2015, Nashville, TN.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2015 Citation: Al-Safi Z, Polotsky A, Liu H, Chosich H, Bradford A, Carlson N, Harris M, Eckel R, Robledo, C.Omega-3 fatty acid Supplementation lowers FSH in normal weight but not obese women. Journal of Clinical Endocrinology and Metabolism. Nov 2, 2015. http://dx.doi.org/10.1210/jc.2015-2913


Progress 10/01/13 to 09/30/14

Outputs
Target Audience: The target audience for the Omega-Smart Baby Project in Dr. Harris' laboratory is pregnnant and breastfeeding women and their infants. The target audience for animal studies in Dr. Chiccos laboratory is adults with cardiometabolic disease. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Doctoral dissertation research. How have the results been disseminated to communities of interest? Results disseminated to target audiences (nurses, breastfeeding professionals and obstetricians) at: Annual Breastfeeding Conference, St. Luke's Presbyterian Hospital, (August 6, 2013, Denver, CO) Society for Maternal Fetal Medicine (Feb 6, 2104, New Orleans, LA) What do you plan to do during the next reporting period to accomplish the goals? Dr Chicco's laboratoryplans tomonitoring the metabolic health of offspring out into adulthood following maternal n3-PUFA supplementation and continue studies through a newly awarded NIFA grant to sttudy effects of western diet and over and underexpression of the FADS2 gene on cardiomatabolic profiles and inflammation.

Impacts
What was accomplished under these goals? The specific objectives of this study are to: 1) determine level of n-3 DHA intake throughout the third trimester of pregnancy and breastfeeding which promotes optimal breastmilk DHA and infant fetal and post natal growth and healthy BMI and 2) determine the level of n-3 DHA intake throughout the third trimester of pregnancy and breastfeeding which promotes optimal neurocognitive development (objective of the USDA/AFRI funded study to which this study will link). 3) determine the effect of n-3 DHA and breastfeeding duration on IQ and BMI as a function of maternal genotype for 3 genes associated with the ability to convert dietary n-3 ALA to DHA and express DHA in breastmilk. The Omega Smart Baby Project (OSBP) Pregnancy and Breastfeeding Coaching program was completed to examine the effect of DHA on infant growth and cognitive development. 115 pregnant women were supplemented with 300 mg DHA or placebo from 24-26 weeks of gestation through the first 3 months of breastfeeding. Total intake from supplements and food were combined and analyzed by tertile. DHA supplementation resulted in a 1 wk increase in gestation with a significant (p<.03) 8 d increase in gestational length comparing the highest intake of DHA( > 600 mg/d) to the lowest (< 300 mg/d). Bayley's Scores of Human Development cognitive and language scales were measured at 12 months of age. . At 12 months of age, Bayley's cognitive scales were each 10 points higher in babies born to mothers with total intake of DHA > 600 mg/day compared to < 300 mg/d (p<.02). Two single nucleotide polymorphisms in the fatty acid desaturase cluster (rs174575 and rs 174561) were evaluated. Plasma n-3 DHA and breastmilk DHA (% fatty acids) were significantly increased as intake of DHA (supplement plus dietary intake) increased from <300 mg/day to 600 mg/day and significantly lower (p <.002) in heterozygotes for the rs174575 allele of the Fads1 gene. Weight/age and recumbent length/age z-scores were calculated in 54 infants born to mothers in the control group and 62 babies born to mothers in the DHA supplemented group. There were no significant effects of DHA supplementation, nor BM DHA, on infant wt/age or wt/length Z-scores at 2 or 4months of age. There was a consistent trend for lower wt/age and wt/ht scores at birth, 2 and 4 months as mother's intake of n-3 DHA increased from <300 mg/d to > 600 mg/d, and as breast milk DHA increased, but these trends did not reach statistical significance. Studies in Dr. Chicco's laboratory are investigating role of Fads2 expression on dietary ALA (18:3n3) conversion to DHA in pregnant mice and their offspring, with a focus on inflammatory outcomes and metabolic health, using a novel transgenic mouse model. We have completed the first half of the proposed experiments for the CO AES-funded project involving the effects of maternal dietary supplementation with n3-PUFA during pregnancy on the phenotype of their offspring prior to weaning (14 day old pups from Fads2-TG (overexpressor) or WT dams +/- n3-PUFA supplementation; phase 1 of 2). Lipid analyses are still pending, but there were no overt differences in body or organ weights at this time point, which was not unexpected. Upon completing our analyses of the tissues harvested, we will determine the main and interaction effects of dietary n3-PUFA status and Fads2 expression on organ phospholipid composition and eicosanoid profiles, which will inform the hypothesized effects of maternal diet on offspring phenotype at 2 and 4 months of age (phase 2; studies currently in progress).

Publications

  • Type: Conference Papers and Presentations Status: Published Year Published: 2014 Citation: Breastfeeding support increases breastfeeding duration among middle- to high-income women. Alena Clark, Susan Baker, Katie McGirr and Mary Harris. Experimental Biology, 2014. Abstract #1017.6


Progress 10/01/12 to 09/30/13

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Ongoing PhD and MS graduate student participation in human clinical studies, animal research, training in lipid analytical methods and measurement of body composition and blood analyses including adipokines and hormones. How have the results been disseminated to communities of interest? Abstracts submitted to experimental biology 2014 by Harris and Chicco. What do you plan to do during the next reporting period to accomplish the goals? --Harris in collaboration with Concetta DiRusso, Univ of Nebraka, NC1199. Complete Omega-3 Project on post-natal body composition changes. --Chicco in collaboration with Mani Nakamura, NC1199. Complete studies with Fads2genetic mouse models on aspects ofcardiometabolic risk.

Impacts
What was accomplished under these goals? The Omega Smart Baby Project (OSBP) Pregnancy and Breastfeeding Coaching program was examined the effect of DHA on infant growth and cognitive development. 115 pregnant women were supplemented with 300 mg DHA or placebo from 24-26 weeks of gestation through the first 3 months of breastfeeding. Total intake from supplements and food were combined and analyzed by tertile. DHA supplementation resulted in a 1 wk increase in gestation with a significant (p<.03) 8 d increase in gestational length comparing the highest intake of DHA( > 600 mg/d) to the lowest (< 300 mg/d). Bayley’s Scores of Human Development cognitive and language scales were measured at 4 and 12 months of age. Two single nucleotide polymorphisms in the fatty acid desaturase cluster (rs174575 and rs 174561) were evaluated. Plasma n-3 DHA and breastmilk DHA (% fatty acids) were significantly increased as intake of DHA (supplement plus dietary intake ) increased from <300 mg/day to 600 mg/day or more (p <.05) in those with major allele (wild type) but not in carriers or homozygotes of the minor rs174575 allelle. At 12 months of age, Bayleys cognitive and language scores were 10 points higher in babies born to mothers with total intake of DHA > 600 mg/day compared to < 300 mg/day (p<.05). This effect was examined in relationship to the presence of the minor alleles of the desaturase genes. The effect of DHA intake on Bayley’s scores was only significant in babies born to mothers with the wildtype phenotype. There was no association with breastmilk arachidonic levels by genotype nor upon the measures of neurocognitive development. Leptin significantly decreased from 27.16 to 9.64 pg/ml and Lipocalin II increased from0.63 to 2.65 pg/ml as DHA increased from the fist to the third tertile. These relationships along with other adipokines and regulators of adipose tissue metabolism and maternal body composition are continuing to be explored. Regarding our animals studies, we have completed the first half of the proposed experiments for our AES-funded project involving the effects of maternal dietary supplementation with n3-PUFA during pregnancy on the phenotype of their offspring prior to weaning (14 day old pups from Fads2++ or WT dams +/- n3-PUFA supplementation; phase 1 of 2). Lipid analyses are still pending, but there were no overt differences in body or organ weights at this time point, which was not unexpected. Upon completing our analyses of the tissues harvested, we will determine the main and interaction effects of dietary n3-PUFA status and Fads2 expression on organ phospholipid composition and eicosanoid proviles, which will inform the hypothesized effects of maternal diet on offspring phenotype at 2 and 4 months of age (phase 2; studies currently in progress). We plan to have the second phase of experiments completed by this summer, which involves monitoring the metabolic health of offspring out into adulthood following maternal n3-PUFA supplementation.

Publications