Our past studies have indicated that alcohol abuse leads to a loss of docosahexaenoic acid (DHA), the major polyunsaturated fat in the nervous system. These losses contribute to deficits in dopaminergic neurotransmission, excesses in CRH neurotransmission and endocannabinoid hyperactivity, which are characteristic of states of chronic addiction. Nutritional inadequacies, particularly during early development, may also lead to such losses in this essential fatty acid. Residual developmental deficits include lower IQ, risk for ADHD and conduct disorders. This phenotypic profile is characteristic of an adverse developmental trajectory towards increased risk of substance abuse. However, tissue deficits of omega-3 highly unsaturated fats (n-3 HUFAs) may also be caused by excess dietary intakes of omega-6 fats in particular linoleic acid. In a portfolio of animal and human trials, we have evaluated the effects of lowering dietary intakes of the omega-6 fatty acid linoleic acid on elevating endogenous production of the long chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. During the 20th century dietary intakes of omega-6 fats increased dramatically; linoleic acid increased from approximately 1 % of energy to more than 8 % of energy. We posited that elevations in this omega-6 fat would elevate endogenous cannabinoids and induce obesity. We modeled these changes in animal studies and found that lowering linoleic acid intakes elevated omega-3 levels and reduced excessive levels of endogenous cannabinoid like molecules. We reversed obesity by reducing the linoleic acid intake to levels common in the US early in the 20th century, despite animals consuming a high fat diet (60 % en). In a separate study, we able to induce obesity even in low fat diets (12% en) by raising linoleic acid intakes. This study provides a critical framework for reducing excessive endocannabinoid activity by reducing dietary intake of their precursor omega-6 molecules as a means to both prevent and treat obesity. The efficacy of lowering dietary linoleic acid to below 2 en% is being evaluated in three human clinical intervention trials. 1)Among subjects with chronic daily headache, selective lowering of linoleic acid, and linoleic acid lowering in conjunction with elevating EPA and DHA intakes, reduced arachidonic acid in phospholipids and elevated EPA and DHA in serum. These changes caused a 50% reduction in headache severity and duration. 2) The Optimal Omega-3 trial is a collaboration with the DOD nutrition directorate, USARIEM. First, we translated the principle of linoleic lowering to the production of poultry meat (and eggs) enriched in omega-3 fats with significantly reduced omega-6 fats. These highly enriched food stuffs will replace standard commodity foods in recipes used in the US garrison food lines. 3) A third human protocol is active within the NIH Clinical Center to evaluate the effects of selective linoleic acid lowering on reducing adiposity among overweight women. The protocol will selectively lower intake to approximately 1 en%. These dietary changes are expected to reduce excessive endocannabinoid levels, improve satiety and results in weight and adipose loss. Elongation and desaturation of the omega-3 alpha linolenic acid (d5) to EPA and DHA will be quantified using steady state infusion and GC- MS/MS/MS quantification. Since linoleic acid is a polyunsaturated fat, it has been critical to determine if advice to reduce intake might be harmful or beneficial. The American Heart Association has specifically advised consumption of at least 5 to 10% of energy as omega-6 PUFAs substantially based on randomized controlled trials (RCTs) of mixed n-3/n-6 PUFAs and meta-analyses of their CHD outcomes. To better evaluate these recommendations we recovered data from two large randomized controlled trials conducted in the late 1060's to early 1970's that had not been fully published. The Sydney Diet Heart Study, conducted from 1966-1973 was unique as it was an intervention specifically with the n-6 polyunsaturated fat linoleic acid (LA) in place of saturated fats. Careful evaluation of recovered data from the Sydney Diet Heart Study show no indication of cardiovascular benefit from elevating dietary intake of LA above 6 en%. By contrast, there was a significant increased risk of death from coronary heart disease and all-cause mortality in the Sydney Diet Heart Study. Thus, from the available RCT data, increasing LA intakes above 6 en% appears likely to increase the risk of coronary heart disease and death. The Minnesota Coronary Experiment (MCE), an RCT designed to test whether replacement of saturated fat (SFA) with vegetable oil rich in linoleic acid (LA) reduces coronary heart disease and death by lowering serum cholesterol. We recovered (1) unpublished documents with completed analyses for the randomized cohort of 9,423 institutionalized women and men aged 20-97; (2) longitudinal serum cholesterol data for the 2,355 participants exposed to the study diets for 1 year; and (3) 149 completed autopsy files. The intervention was designed to lower serum cholesterol by replacing saturated fats with linoleic acid (LA, from corn oil and corn oil polyunsaturated margarine). Control participants consumed a diet high in SFA from animal fats, common margarines and shortenings. Outcome measures included (1) death from all causes; (2) association between changes in serum cholesterol and death; and (3) coronary atherosclerosis and myocardial infarcts at autopsy. We found that the intervention group had significant reductions in serum cholesterol compared to controls (mean change from baseline -13.8% v -1.0%; p<0.001). (1) We present unpublished Kaplan Meier graphs showing no mortality benefit for the intervention group in the full randomized cohort or any pre-specified subgroup. (2) There was a 22% higher risk of death for each 30 mg/dL reduction in serum cholesterol in covariate-adjusted Cox regression models (hazard ratio (HR) 1.22; 95% CI 1.14, 1.32; p<0.001). (3) The intervention group had no evidence of benefit for coronary atherosclerosis or myocardial infarcts. An updated meta-analysis of RCTs that lowered serum cholesterol by providing vegetable oils rich in LA in place of SFA showed no evidence of coronary (HR 1.12 (0.85 to 1.46)) or all-cause mortality benefit (HR 1.07 (0.92 to 1.23)). In meta-regression, there was no association between cholesterol lowering and coronary or all-cause mortality. MCE results do not provide support for the traditional diet-heart hypothesis. These findings add to growing evidence that incomplete publication has contributed to an overestimation of the benefits, and underestimation of the potential risks, of replacing SFA with vegetable oils rich in LA.

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37
Fiscal Year
2019
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National Institute on Alcohol Abuse and Alcoholism
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Strandjord, Sarah E; Lands, Bill; Hibbeln, Joseph R (2018) Validation of an equation predicting highly unsaturated fatty acid (HUFA) compositions of human blood fractions from dietary intakes of both HUFAs and their precursors. Prostaglandins Leukot Essent Fatty Acids 136:171-176
Lepsch, Jaqueline; Farias, Dayana Rodrigues; Eshriqui, Ilana et al. (2018) Serum fatty acids are positively associated with changes in systemic blood pressure throughout pregnancy. Pregnancy Hypertens 13:7-13
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Young, Andrew J; Marriott, Bernadette P; Champagne, Catherine M et al. (2017) Blood fatty acid changes in healthy young Americans in response to a 10-week diet that increased n-3 and reduced n-6 fatty acid consumption: a randomised controlled trial. Br J Nutr 117:1257-1269
Domenichiello, Anthony F; Wilhite, Breanne C; Keyes, Gregory S et al. (2017) A dose response study of the effect of prostaglandin E2 on thermal nociceptive sensitivity. Prostaglandins Leukot Essent Fatty Acids 126:20-24
Gallagher, A T; Byrne, F; Murray, I T et al. (2017) Lipids and polyunsaturated fatty acid levels in deliberate self-harm: a 10-year follow-up study. Ir J Psychol Med 34:117-126

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