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Dietary Fatty Acids and Cardiometabolic Risk: Influence on Lipoproteins, Insulin Resistance and Liver Fat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to investigate how dietary fatty acids affect the risk for cardiometabolic disease, i.e. cardiovascular disease (CVD), type 2 diabetes and obesity. The overall hypothesis was that unsaturated fatty acids and especially the predominant polyunsaturated fatty acid (PUFA) linoleic acid (LA), 18:2n-6, would decrease cardiometabolic risk compared with saturated fatty acids (SFAs), in line with current recommendations to partly replace dietary SFA with PUFA.

Papers I and V were observational studies based on the community-based cohort Uppsala Longitudinal Study of Adult Men (ULSAM). Adipose tissue fatty acid composition was determined as biomarker for dietary fat intake. Studies II, III and IV were randomised short-term interventions on human volunteers, in which different dietary fats were provided to the participants.

In 71-year-old men, adipose tissue LA and α-linolenic acid (18:3n-3) were associated with insulin sensitivity (euglycaemic clamp), although this association was diminished for LA after adjusting for lifestyle variables. Different SFA displayed divergent associations; only palmitic acid (16:0) was inversely associated with insulin sensitivity (Paper I). In Cox regression analyses, LA was modestly associated with decreased all-cause mortality, but not CVD mortality during 15 years follow-up (Paper V).

In a 3+3-week cross-over study on 20 weight-stable volunteers with dyslipidaemia, all foods were provided. A rapeseed oil-based diet distinctly lowered low-density lipoprotein cholesterol and triglycerides compared with a dairy-fat based diet (butter, cream and fatty cheese). Insulin sensitivity or coagulation factors were not affected (Paper II).

In a 10-week randomised trial on 67 abdominally obese participants, PUFA (mostly sunflower oil) decreased liver fat compared with SFA (mostly butter) under isocaloric conditions. In individuals considered highly compliant to study diets, lipoproteins were also decreased during the PUFA diet (Paper III).

In a 7-week double-blind randomised trial on 41 healthy volunteers, PUFA (sunflower oil) decreased the total:HDL cholesterol ratio compared with SFA (palm oil) during moderate weight gain (1.5 kg) (Paper IV).

In conclusion, LA (PUFA) intake is associated with decreased cardiometabolic risk compared with higher SFA intake, overall supporting a beneficial role of non-tropical vegetable oils in place of solid fats in preventing fatty liver and cardiometabolic disorders.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1111
Keyword [en]
Linoleic acid, Palmitic acid, PUFA, SFA, n-6 fatty acids
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-252066ISBN: 978-91-554-9264-9 (print)OAI: oai:DiVA.org:uu-252066DiVA: diva2:808545
Public defence
2015-08-21, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2015-05-29 Created: 2015-04-28 Last updated: 2015-07-07Bibliographically approved
List of papers
1. Adipose tissue fatty acids and insulin sensitivity in elderly men.
Open this publication in new window or tab >>Adipose tissue fatty acids and insulin sensitivity in elderly men.
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2010 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 53, no 5, 850-857 p.Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS

Dietary fatty acids may affect insulin sensitivity. Adipose tissue fatty acid composition partly reflects long-term dietary intake, but data from large studies regarding relationships with insulin sensitivity are lacking. We aimed to determine the association between adipose tissue fatty acids and insulin sensitivity in elderly Swedish men.

METHODS

In a cross-sectional analysis of the community-based Uppsala Longitudinal Study of Adult Men (n = 795, mean age 71 years), adipose tissue biopsies were obtained and fatty acid composition was determined by gas-liquid chromatography. Insulin sensitivity was measured directly by a euglycaemic clamp.

RESULTS

Palmitic acid (16:0), the major saturated fatty acid (SFA) in the diet and in adipose tissue, was negatively correlated with insulin sensitivity (r = -0.14), as were 16:1 n-7 (r = -0.15), 20:3 n-6 (r = -0.31), 20:4 n-6 (r = -0.38), 22:4 n-6 (r = -0.37) and 22:5 n-3 (r = -0.24; p < 0.001 for all). Some minor SFAs were positively correlated; 12:0 (r = 0.46), 14:0 (r = 0.32), 17:0 (r = 0.21) and 18:0 (r = 0.41; p < 0.001 for all), as were essential polyunsaturated fatty acids (PUFAs) 18:2 n-6 (r = 0.10, p < 0.01) and 18:3 n-3 (r = 0.16, p < 0.001). Docosahexaenoic acid (22:6 n-3) was negatively correlated (r = -0.11, p < 0.01), whereas eicosapentaenoic acid (20:5 n-3) was not (r = -0.02, NS). Most associations diminished or disappeared in lean individuals, indicating an effect of obesity.

CONCLUSIONS/INTERPRETATION

Adipose tissue enriched with palmitic acid and depleted of essential PUFAs is associated with insulin resistance. The positive association between minor SFAs and insulin sensitivity merits further investigation.

Keyword
Adipose tissue, Dietary fatty acids, Fatty acid composition, Insulin resistance, Insulin sensitivity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-122778 (URN)10.1007/s00125-010-1669-0 (DOI)000276424300007 ()20127308 (PubMedID)
Available from: 2010-04-19 Created: 2010-04-19 Last updated: 2017-12-12Bibliographically approved
2. Replacing dairy fat with rapeseed oil causes rapid improvement of hyperlipidaemia: a randomized controlled study
Open this publication in new window or tab >>Replacing dairy fat with rapeseed oil causes rapid improvement of hyperlipidaemia: a randomized controlled study
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2011 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, no 4, 356-364 p.Article in journal (Refereed) Published
Abstract [en]

Background. Rapeseed oil (RO), also known as canola oil, principally contains the unsaturated fatty acids 18:1n-9, 18:2n-6 and 18:3n-3 and may promote cardiometabolic health.

Objective. To investigate the effects on lipoprotein profile, factors of coagulation and insulin sensitivity of replacing a diet rich in saturated fat from dairy foods (DF diet) with a diet including RO-based fat (RO diet).

Design. During a 2 x 3-week randomized, controlled, cross-over trial, 20 free-living hyperlipidaemic subjects were provided with isocaloric test diets that differed in fat composition alone. Blood lipoprotein profile, coagulation and fibrinolytic factors and insulin sensitivity (euglycaemic clamp) were determined before and after the dietary intervention.

Results. All subjects completed the study, and compliance was high according to changes in serum fatty acids. The RO diet, but not the DF diet, reduced the levels of serum cholesterol (-17%), triglycerides (-20%) and low-density lipoprotein cholesterol (-17%), cholesterol/high-density lipoprotein (HDL) cholesterol ratio (-21%), apolipoprotein (apo) B/apo A-I ratio (-4%) and factor VII coagulant activity (FVIIc) (-5%) from baseline. These changes were significantly different between the diets (P = 0.05 to P < 0.0001), except for FVIIc (P = 0.1). The RO diet, but not the DF diet, modestly increased serum lipoprotein( a) (+6%) and tended to increase the glucose disappearance rate (K-value, +33%). HDL cholesterol, insulin sensitivity, fibrinogen and tissue plasminogen activator inhibitor-1 levels did not change from baseline or differ between the two diets.

Conclusions. In a diet moderately high in total fat, replacing dairy fat with RO causes a rapid and clinically relevant improvement in serum lipoprotein profile including lowering of triglycerides in hyperlipidaemic individuals.

Keyword
cholesterol, coagulation, diet, fatty acids, lipoproteins
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-160127 (URN)10.1111/j.1365-2796.2011.02383.x (DOI)000295096600009 ()
Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2017-12-08Bibliographically approved
3. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial
Open this publication in new window or tab >>Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial
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2012 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 95, no 5, 1003-1012 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Replacing SFAs with vegetable PUFAs has cardiometabolic benefits, but the effects on liver fat are unknown. Increased dietary n-6 PUFAs have, however, also been proposed to promote inflammation-a yet unproven theory.

OBJECTIVE:

We investigated the effects of PUFAs on liver fat, systemic inflammation, and metabolic disorders.

DESIGN:

We randomly assigned 67 abdominally obese subjects (15% had type 2 diabetes) to a 10-wk isocaloric diet high in vegetable n-6 PUFA (PUFA diet) or SFA mainly from butter (SFA diet), without altering the macronutrient intake. Liver fat was assessed by MRI and magnetic resonance proton (1H) spectroscopy (MRS). Proprotein convertase subtilisin/kexin type-9 (PCSK9, a hepatic LDL-receptor regulator), inflammation, and adipose tissue expression of inflammatory and lipogenic genes were determined.

RESULTS:

A total of 61 subjects completed the study. Body weight modestly increased but was not different between groups. Liver fat was lower during the PUFA diet than during the SFA diet [between-group difference in relative change from baseline; 16% (MRI; P < 0.001), 34% (MRS; P = 0.02)]. PCSK9 (P = 0.001), TNF receptor-2 (P < 0.01), and IL-1 receptor antagonist (P = 0.02) concentrations were lower during the PUFA diet, whereas insulin (P = 0.06) tended to be higher during the SFA diet. In compliant subjects (defined as change in serum linoleic acid), insulin, total/HDL-cholesterol ratio, LDL cholesterol, and triglycerides were lower during the PUFA diet than during the SFA diet (P < 0.05). Adipose tissue gene expression was unchanged.

CONCLUSIONS:

Compared with SFA intake, n-6 PUFAs reduce liver fat and modestly improve metabolic status, without weight loss. A high n-6 PUFA intake does not cause any signs of inflammation or oxidative stress. Downregulation of PCSK9 could be a novel mechanism behind the cholesterol-lowering effects of PUFAs.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-172856 (URN)10.3945/ajcn.111.030114 (DOI)000303140700004 ()22492369 (PubMedID)
Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2017-12-07Bibliographically approved
4. Role of Dietary Fats in Modulating Cardiometabolic Risk During Moderate Weight Gain: A Randomized Double-Blind Overfeeding Trial (LIPOGAIN Study)
Open this publication in new window or tab >>Role of Dietary Fats in Modulating Cardiometabolic Risk During Moderate Weight Gain: A Randomized Double-Blind Overfeeding Trial (LIPOGAIN Study)
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2014 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 3, no 5, e001095Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Whether the type of dietary fat could alter cardiometabolic responses to a hypercaloric diet is unknown. In addition, subclinical cardiometabolic consequences of moderate weight gain require further study.

METHODS AND RESULTS: In a 7-week, double-blind, parallel-group, randomized controlled trial, 39 healthy, lean individuals (mean age of 27±4) consumed muffins (51% of energy [%E] from fat and 44%E refined carbohydrates) providing 750 kcal/day added to their habitual diets. All muffins had identical contents, except for type of fat; sunflower oil rich in polyunsaturated fatty acids (PUFA diet) or palm oil rich in saturated fatty acids (SFA diet). Despite comparable weight gain in the 2 groups, total: high-density lipoprotein (HDL) cholesterol, low-density lipoprotein:HDL cholesterol, and apolipoprotein B:AI ratios decreased during the PUFA versus the SFA diet (-0.37±0.59 versus +0.07±0.29, -0.31±0.49 versus +0.05±0.28, and -0.07±0.11 versus +0.01±0.07, P=0.003, P=0.007, and P=0.01 for between-group differences), whereas no significant differences were observed for other cardiometabolic risk markers. In the whole group (ie, independently of fat type), body weight increased (+2.2%, P<0.001) together with increased plasma proinsulin (+21%, P=0.007), insulin (+17%, P=0.003), proprotein convertase subtilisin/kexin type 9, (+9%, P=0.008) fibroblast growth factor-21 (+31%, P=0.04), endothelial markers vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin (+9, +5, and +10%, respectively, P<0.01 for all), whereas nonesterified fatty acids decreased (-28%, P=0.001).

CONCLUSIONS: Excess energy from PUFA versus SFA reduces atherogenic lipoproteins. Modest weight gain in young individuals induces hyperproinsulinemia and increases biomarkers of endothelial dysfunction, effects that may be partly outweighed by the lipid-lowering effects of PUFA.

CLINICAL TRIAL REGISTRATION URL: http://ClinicalTrials.gov. Unique identifier: NCT01427140.

National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-234939 (URN)10.1161/JAHA.114.001095 (DOI)000357396800016 ()25319187 (PubMedID)
Funder
Swedish Research Council, K2012-55X-22081-01-3, K2013-55X-15075-10-3Swedish Heart Lung FoundationSwedish Diabetes Association
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-12-05Bibliographically approved
5. Adipose tissue fatty acids and cardiovascular and all-cause mortality in elderly men: a prospective cohort study
Open this publication in new window or tab >>Adipose tissue fatty acids and cardiovascular and all-cause mortality in elderly men: a prospective cohort study
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: For several fatty acids, adipose tissue reflects long-term dietary intake and may provide more objective information than self-reported intake. No prospective studies have examined whether adipose tissue fatty acids predict cardiovascular and all-cause mortality.

Objective: To investigate associations between adipose tissue fatty acids and cardiovascular and overall mortality in a cohort of elderly men. We hypothesized that polyunsaturated fatty acids (PUFA) could be inversely associated with cardiovascular and all-cause mortality.

Methods: In the Swedish community-based cohort study ULSAM, adipose tissue biopsies were taken from the buttocks of 853 men at age 71. Cox regression analyses were performed primarily for four PUFA that were considered to reflect dietary intake (linoleic acid, 18:2n-6, alpha-linolenic acid, 18:3n-3, eicosapentaenoic acid, 20:5n-3, and docosahexaenoic acid, 22:6n-3), and for all other available fatty acids (secondary analyses) analyzed by gas-liquid chromatography.

Results: During 20-year follow-up, 605 individuals died of which 251 were cardiovascular deaths. After adjusting for risk factors, none of the four primary fatty acids were associated with cardiovascular mortality (hazard ratios (HR)=0.92-1.05 for each SD increase, P≥0.27). Linoleic acid was inversely associated with mortality (HR=0.90, 95% confidence interval (CI) 0.82-0.99, P=0.03). In secondary analyses, palmitoleic acid, 16:1n-7, (HR=1.11, 95% CI 1.02-1.21, P=0.01), and arachidonic acid, 20:4n-6, (HR=1.09, 95% CI 1.00-1.19, P=0.05) were associated with increased mortality, whereas heptadecanoic acid, 17:0, was inversely associated with mortality (HR=0.89, 95% CI 0.79-1.00, P=0.05).

Conclusions: Adipose tissue PUFA was inversely associated with total mortality, but not cardiovascular mortality in elderly men. The mechanisms behind adipose tissue PUFA and longevity warrant further investigation.

Keyword
Dietary fat, adipose tissue, linoleic acid, PUFA, mortality
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-252065 (URN)
Available from: 2015-04-28 Created: 2015-04-28 Last updated: 2015-12-28

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