Linoleic acid (LA; 18:2n–6) has been considered to promote low-grade chronic inflammation and adiposity. Studies show adiposity and inflammation are inversely associated with bone mass.
This study ...tested the hypothesis that decreasing the dietary ratio of LA to α-linolenic acid (ALA, 18:3n–3), while keeping ALA constant, mitigates high-fat diet (HF)-induced adiposity and bone loss.
Male C57BL/6 mice at 6 wk old were assigned to 4 treatment groups and fed 1 of the following diets ad libitum for 6 mo: a normal-fat diet (NF; 3.85 kcal/g and 10% energy as fat) with the ratio of the PUFAs LA to ALA at 6; or HFs (4.73 kcal/g and 45% energy as fat) with the ratio of LA to ALA at 10:1, 7:1, or 4:1, respectively. ALA content in the diets was kept the same for all groups at 1% energy. Bone structure, body composition, bone-related cytokines in serum, and gene expression in bone were measured. Data were analyzed using 1-factor ANOVA.
Compared with those fed the NF, mice fed the HFs had 19.6% higher fat mass (P < 0.01) and 13.5% higher concentration of serum tartrate-resistant acid phosphatase (TRAP) (P < 0.05), a bone resorption cytokine. Mice fed the HFs had 19.5% and 12.2% lower tibial and second lumbar vertebral bone mass, respectively (P < 0.01). Decreasing the dietary ratio of LA to ALA from 10 to 4 did not affect body mass, fat mass, serum TRAP and TNF-α, or any bone structural parameters.
These data indicate that decreasing the dietary ratio of LA to ALA from 10 to 4 by simply reducing LA intake does not prevent adiposity or improve bone structure in obese mice.
The nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that responds to oxidative stress by binding to the antioxidant response element (ARE) in the promoter of genes coding for ...antioxidant enzymes like NAD(P)H:quinone oxidoreductase 1 and proteins for glutathione synthesis. The Nrf2/ARE pathway has nutritional interest owing to its activation by phytochemicals such as sulforaphane. Recently, the Nrf2 pathway was identified as having regulatory functions in mitochondrial biogenesis, adipocyte differentiation and liver energy metabolism. Activation of Nrf2 increases energy metabolism and conversely suppresses lipid synthesis. Lard-based, but not soybean oil-based, high-fat diets reduce mRNA expression of Nrf2 and its downstream targets, suggesting a macronutrient influence on the activation of the Nrf2 pathway and susceptibility to oxidative stress. This review examines data revealing the Nrf2 pathway's regulatory role in energy metabolism at the molecular, cellular and whole animal levels. Understanding the relationship of Nrf2 and energy metabolism in cells, tissues and physiologic systems will provide novel insights for nutritional interventions for obesity and its comorbidities such as diabetes.
Lipid peroxidation yields multiple aldehyde species. Of these,
trans-4-hydroxy-2-nonenal (HNE), derived from
n-6 poly-unsaturated fatty acids (PUFA) is one of the most studied products of lipid ...peroxidation. On the other hand, oxidative damage to
n-3 PUFA, e.g. docosahexaenoic acid (DHA; 22:6,
n-3) and eicosapentaenoic acid, is now recognized as an important effector of oxidative stress and is of particular interest in
n-3 rich tissues such as brain and retina.
Trans-4-hydroxy-2-hexenal (HHE) is a major α,β-unsaturated aldehyde product of
n-3 PUFA oxidation and, like HNE, is an active biochemical mediator resulting from lipid peroxidation. HHE adducts are elevated in disease states, in some cases, at higher levels than the corresponding HNE adduct. HHE has properties in common with HNE, but there are important differences particularly with respect to adduction targets and detoxification pathways. In this review, the biochemistry and cell biology of HHE will be discussed. From this review, it is clear that further study is needed to determine the biochemical and physiological roles of HHE and its related aldehyde,
trans-4-oxo-2-hexenal.
Objective biomarkers are needed to assess adherence to vegetable and fruit intervention trials. Blood carotenoids are considered the best biomarker of vegetable and fruit intake, but collecting blood ...is invasive and the analyses are relatively expensive for population studies. Resonance Raman spectroscopy (RRS) is an innovative method for assessing carotenoids in skin noninvasively.
Our objective was to compare blood carotenoid concentrations with skin carotenoid assessments by RRS during a controlled feeding intervention.
Twenty-nine participants consumed low-carotenoid diets (6 wk, phases 1 and 3), a provided diet containing 6-cup equivalents (1046 g/d) of vegetables and fruit (8 wk, phase 2), and usual diet (final 8 wk, phase 4).
At baseline, skin and plasma total carotenoid values were correlated (r = 0.61, P < 0.001). Skin and plasma carotenoid values decreased (P < 0.001) 36% and 30%, respectively, from baseline to the end of phase 1 and then increased (P < 0.001) by >200% at the end of phase 2. Plasma carotenoids returned to baseline concentrations by the middle of phase 3 and skin carotenoid concentrations by the middle of phase 4. Skin carotenoid status predicted plasma values by using a mixed linear model including all time points (r = 0.72, P < 0.001), which indicates that changes in skin carotenoid status closely follow changes in plasma across a broad range of intakes. At the individual level, skin carotenoids predicted plasma values (r = 0.70, P < 0.001) over all time points.
Skin carotenoid status assessed by resonance Raman spectroscopy is a noninvasive, objective biomarker of changes in vegetable and fruit intake.
Obesity-induced changes in lipid metabolism are mechanistically associated with the development of insulin resistance and prediabetes. Recent studies have focused on the extent to which ...obesity-induced insulin resistance is mediated through oxylipins, derived from enzymatic and nonenzymatic lipid peroxidation. Vitamin E and vitamin C are widely used antioxidant supplements, but conflicting data exist as to whether supplementation with vitamins E and C reduces insulin resistance. The purpose of this work is (1) to test the hypothesis that supplementation with vitamin E and vitamin C prevents the development of insulin resistance and (2) to determine the extent to which antioxidant supplementation modifies obesity-induced changes in hepatic oxylipins. Using obesity-prone Sprague–Dawley rats fed a high-fat, hypercaloric diet, we found that vitamin E and C supplementation did not block the development of insulin resistance, despite increased plasma levels of these antioxidants and decreased hepatic F2-isoprostane (F2-IsoP) concentrations. The obese phenotype was associated with increased hepatic concentrations of cytochrome P450 (CYP450)-dependent linoleic acid and α-linolenic acid-derived epoxides. Antioxidant supplementation, but not obesity, decreased levels of the lipoxygenase (LOX)-dependent, arachidonic acid-derived products lipoxin A4 (LXA4), 8,15-dihydroxtetraenoate (8,15-DiHETE), and 5,15-DiHETE. Our data demonstrate that antioxidant supplementation and obesity impact hepatic LOX- and CYP450-dependent oxylipin metabolism.
•Antioxidant supplementation and obesity have independent effects on hepatic oxylipin profiles in obese rats.•Obesity increases epoxide derivatives of polyunsaturated fatty acids while lowering their soluble epoxide hydrolase products.•Supplementation with vitamin E and vitamin C lowers auto-oxidative and lipoxygenase-derived oxylipins.•Supplementation with vitamin E and vitamin C does not prevent obesity-induced insulin resistance despite reductions in oxidative damage.
Abstract Emerging evidence indicates that the fatty acid composition of obesogenic diets influences physiologic outcomes. There are scant data regarding how the content of non-essential fatty acids ...like monounsaturated fatty acids (MUFA) and saturated fatty acids (SFAs) impact the metabolism of polyunsaturated fatty acids (PUFAs). In this work, we tested the hypothesis that obesogenic diets enriched in oleic acid (OA; 18:1n-9) reduce polyunsaturated fatty acid (PUFA) levels vs an obesogenic diet enriched in SFAs. Adult male mice were fed for eight weeks either (1) a control 16% fat energy (en) diet with 5.7% en OA and 4.4% en SFA, (2) a 50% fat en diet with 33% en OA and 9.9% en SFA, or (3) a 50% en diet with a high SFA diet with 33% en SFA and 9.1% en OA. Dietary levels and intake of linoleic acid (LA; 18:2n-6) and α-linolenic acid (ALA;18:3n-3) were constant between the experimental groups. Several peripheral organs (liver, heart, kidney, and adipose) were analyzed for lipid composition and oxylipin analysis was performed for liver and adipose. Our data demonstrate that a high OA diet reduced tissue content of LA and ALA( ≥ 30%) in phospholipid and neutral lipid fractions, reduced the content of some LA-derived and ALA-derived oxylipins in liver and adipose, and conversely, elevated hepatic content of PGF2α . In all tissues examined, except for adipose, levels of arachidonic acid (ARA; 20:4n-6) and docosahexaenoic acid (DHA; 22:6n-3) were either elevated or unaffected by the obesogenic diets. Our data indicate that the non-essential fatty content of obesogenic diets impacts PUFA content in peripheral tissues and influences the levels of bioactive oxylipins.
4-Hydroxy-2-nonenal (4-HNE) is an abundant electrophilic lipid that mediates oxidative stress in endothelium by mechanisms that remain controversial. This study examines the effects of 4-HNE on ...nitric oxide (NO) and superoxide levels in bovine aorta endothelial cells (BAECs).
Exposure of BAECs to 4-HNE caused a dose-dependent inhibition of NO that correlated with losses of hsp90 and phosphorylated eNOS-serine1179 but not eNOS protein levels. 4-HNE failed to inhibit NO production in sepiapterin and ascorbate supplemented cells suggesting that tetrahydrobiopterin (BH4) is a limiting factor in non supplemented cells. This was verified by quantification of BH4 by high-performance liquid chromatography analysis with electrochemical detection and by examining GTP cyclohydrolase I (GTPCH) protein levels and activity all of which were diminished by 4-HNE treatment. Analysis of 2-hydroxyethidium indicated that 4-HNE increased superoxide release in BAECs. The effects of 4-HNE on GTPCH and hsp90 were efficiently counteracted by proteasomal inhibition, indicating that depletion of BH4 by 4-HNE is attributable to specific mechanisms involving protein degradation.
4-HNE by altering BH4 homeostasis mediates eNOS-uncoupling and superoxide generation in BAECs. By also decreasing phosphorylation of eNOS-serine 1179 4-HNE may specifically regulate NO/reactive oxygen species fluxes in the endothelium with important consequences to redox signaling.
Intake of total fat is linked to obesity and inversely associated with bone density in humans. Epidemiologic and animal studies show that long-chain n–3 (ω-3) PUFAs supplied as fish oil (FO) are ...beneficial to skeletal health.
This study tested the hypothesis that increasing dietary FO would decrease adiposity and improve bone-related outcomes in growing obese mice.
Male C57BL/6 mice at 6 wk old were assigned to 6 treatment groups and fed either a normal-fat diet (3.85 kcal/g and 10% energy as fat) or a high-fat diet (HF; 4.73 kcal/g and 45% energy as fat) containing either 0%, 3%, or 9% energy as FO (0FO, 3FO, and 9FO, respectively) ad libitum for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured.
The HF diet increased the expression of the adipose tissue tumor necrosis factor α (Tnfa) and serum concentrations of leptin and tartrate-resistant acid phosphatase (TRAP), and decreased serum concentrations of osteocalcin and bone-specific alkaline phosphatase (P < 0.05). FO decreased fat mass (P < 0.05), serum TRAP (P < 0.05), and adipose tissue Tnfa expression (P < 0.01). Bone content of long-chain n–3 PUFAs was increased and n–6 PUFAs were decreased with the elevation in dietary FO content (P < 0.01). Compared with mice fed 9FO, animals fed 3FO had higher femoral bone volume/total volume (25%), trabecular number (23%), connectivity density (82%), and bone mass of second lumbar vertebrae (12%) and lower femoral trabecular separation (-19%). Mice fed the 3FO HF diet had 42% higher bone mass than those fed the 0FO HF diet.
These data indicate increasing dietary FO ≤3% energy can decrease adiposity and mitigate HF diet–induced bone deterioration in growing C57BL/6 mice possibly by reducing inflammation and bone resorption. FO at 9% diet energy had no further beneficial effects on bone of obese mice.
Metallothioneins (MTs) perform important regulatory and cytoprotective functions in tissues including the brain. While it is known that energy restriction (ER) and dietary
-3 polyunsaturated fatty ...acid (PUFA) deficiency impact postnatal brain growth and development, little data exist regarding the impact of undernutrition upon MT expression in growing animals. We tested the hypothesis that ER with and without dietary
-3 PUFA deficiency reduces MT expression in juvenile rats. ER rats were individually pair-fed at 75% of the ad libitum (AL) intake of control rats provided diets consisting of either soybean oil (SO) that is α-linolenic acid (ALA; 18:3
-3) sufficient or corn oil (CO; ALA-deficient). Fatty acids (FA) and metal concentrations of liver and brain regions were analyzed. Tissue expression of MTs (
) and modulators of MT expression including glucocorticoid receptors (
and
) and several mediators of thyroid hormone regulation (
,
,
,
, and
) were measured. Plasma corticosterone and triiodothyronine levels were also evaluated. ER, but not metal deficiency, reduced
expression in the cerebellum (50%) and cerebral cortex (23%). In liver, a reduction in dietary
-3 PUFA reduced
,
,
,
, and
. ER elevated
,
, and
and reduced
in the liver. Given MT's role in cellular protection, further studies are needed to evaluate whether ER or
-3 PUFA deficiency may leave the juvenile brain and/or liver more susceptible to endogenous or environmental stressors.
Obesity is a risk factor for cancer. Disruption of the daily feeding and fasting rhythm can contribute to obesity. This study tested the hypothesis that time-restricted feeding (TRF) attenuates ...obesity-enhanced metastasis.
In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were fed the standard AIN93G diet or a high-fat diet (HFD) with or without dark-phase restricted feeding (12 h per day) for 10 weeks. Pulmonary metastases from a subcutaneous tumor were quantified.
The number and size of lung metastases were greater in the HFD group than in the AIN93G group, but did not differ between the TRF and AIN93G groups. TRF prevented HFD-induced increases in plasma concentrations of glucose, insulin, proinflammatory cytokines (leptin, monocyte chemotactic protein-1, plasminogen activator inhibitor-1), and angiogenic factors (angiopoietin-2, hepatic growth factor, vascular endothelial growth factor).
TRF attenuates the HFD-enhanced spontaneous metastasis of LLC in mice.
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