Consuming a Linoleate-Rich Diet Increases Concentrations of Tetralinoleoyl Cardiolipin in Mouse Liver and Alters Hepatic Mitochondrial Respiration.

BACKGROUND: Hepatic mitochondrial dysfunction is a major cause of fat accumulation in the liver. Individuals with fatty liver conditions have hepatic mitochondrial structural abnormalities and a switch in the side chain composition of the mitochondrial phospholipid, cardiolipin, from poly- to monounsaturated fatty acids. Linoleic acid (LA), an essential dietary fatty acid, is required to remodel nascent cardiolipin (CL) to its tetralinoleoyl cardiolipin (L4CL, CL with 4 LA side chains) form, which is integral for mitochondrial membrane structure and function to promote fatty acid oxidation. It is unknown, however, whether increasing LA in the diet can increase hepatic L4CL concentrations and improve mitochondrial respiration in the liver compared with a diet rich in monounsaturated and saturated fatty acids. OBJECTIVES: The main aim of this study was to test the ability of a diet fortified with LA-rich safflower oil (SO), compared with the one fortified with lard (LD), to increase concentrations of L4CL and improve mitochondrial respiration in the livers of mice. METHODS: Twenty-four (9-wk-old) C57 BL/J6 male mice were fed either the SO or LD diets for ∼100 d, whereas food intake and body weight, fasting glucose, and glucose tolerance tests were performed to determine any changes in glycemic control. RESULTS: Livers from mice fed SO diet had higher relative concentrations of hepatic L4CL species compared with LD diet-fed mice (P value = 0.004). Uncoupled mitochondria of mice fed the SO diet, compared with LD diet, had an increased baseline oxygen consumption rate (OCR) and succinate-driven respiration (P values = 0.03 and 0.01). SO diet-fed mice had increased LA content in all phospholipid classes compared with LD-fed mice (P < 0.05). CONCLUSIONS: Our findings reveal that maintaining or increasing hepatic L4CL may result in increased OCR in uncoupled hepatic mitochondria in healthy mice whereas higher oleate content of CL reduced mitochondrial function shown by lower OCR in uncoupled mitochondria.

Frequent Interpersonal Stress and Inflammatory Reactivity Predict Depressive-Symptom Increases: Two Tests of the Social-Signal-Transduction Theory of Depression.

The social-signal-transduction theory of depression asserts that people who experience ongoing interpersonal stressors and mount a greater inflammatory response to social stress are at higher risk for depression. The current study tested this theory in two adult samples. In Study 1, physically healthy adults (N = 76) who reported more frequent interpersonal tension had heightened depressive symptoms at Visit 2, but only if they had greater inflammatory reactivity to a marital conflict at Visit 1. Similarly, in Study 2, depressive symptoms increased among lonelier and less socially supported breast-cancer survivors (N = 79). This effect was most pronounced among participants with higher inflammatory reactivity to a social-evaluative stressor at Visit 1. In both studies, noninterpersonal stress did not interact with inflammatory reactivity to predict later depressive symptoms.

Omega-3 supplementation and stress reactivity of cellular aging biomarkers: an ancillary substudy of a randomized, controlled trial in midlife adults.

Higher levels of omega-3 track with longer telomeres, lower inflammation, and blunted sympathetic and cardiovascular stress reactivity. Whether omega-3 supplementation alters the stress responsivity of telomerase, cortisol, and inflammation is unknown. This randomized, controlled trial examined the impact of omega-3 supplementation on cellular aging-related biomarkers following a laboratory speech stressor. In total, 138 sedentary, overweight, middle-aged participants (n = 93 women, n = 45 men) received either 2.5 g/d of omega-3, 1.25 g/d of omega-3, or a placebo for 4 months. Before and after the trial, participants underwent the Trier Social Stress Test. Saliva and blood samples were collected once before and repeatedly after the stressor to measure salivary cortisol, telomerase in peripheral blood lymphocytes, and serum anti-inflammatory (interleukin-10; IL-10) and pro-inflammatory (interleukin-6; IL-6, interleukin-12, tumor necrosis factor-alpha) cytokines. Adjusting for pre-supplementation reactivity, age, sagittal abdominal diameter, and sex, omega-3 supplementation altered telomerase (p = 0.05) and IL-10 (p = 0.05) stress reactivity; both supplementation groups were protected from the placebo group's 24% and 26% post-stress declines in the geometric means of telomerase and IL-10, respectively. Omega-3 also reduced overall cortisol (p = 0.03) and IL-6 (p = 0.03) throughout the stressor; the 2.5 g/d group had 19% and 33% lower overall cortisol levels and IL-6 geometric mean levels, respectively, compared to the placebo group. By lowering overall inflammation and cortisol levels during stress and boosting repair mechanisms during recovery, omega-3 may slow accelerated aging and reduce depression risk. ClinicalTrials.gov identifier: NCT00385723.

Perceived social support predicts self-reported and objective health and health behaviors among pregnant women.

Perinatal health and health behaviors play a crucial role in maternal and neonatal health. Data examining psychosocial factors which predict self-reported health and health behaviors as well as objective indicators downstream of health behaviors among pregnant women are lacking. In this longitudinal study design with 131 pregnant women, perceived social support was examined as a predictor of self-rated health and average levels of sleep quality, health-promoting and health-impairing behaviors, and red blood cell (RBC) polyunsaturated fatty acids across early, mid, and late pregnancy. Participants provided a blood sample and fatty acid methyl esters were analyzed by gas chromatography. Measures included the Multidimensional Scale of Perceived Social Support, Pittsburgh Sleep Quality Index, and Prenatal Health Behavior Scale. Regression models demonstrated that, after adjustment for income, race/ethnicity, age, relationship status, pre-pregnancy body mass index, greater social support was associated with better self-rated health (p = 0.001), greater sleep quality (p = 0.001), fewer health-impairing behaviors (p = 0.02), and higher RBC omega-3 fatty acids (p = 0.003). Associations among social support with health-promoting behaviors, RBC omega-6 fatty acids, or gestational weight gain were not significant. Findings underscore the benefits of perceived social support in the context of pregnancy. Examination of pathways that link social support with these outcomes will be meaningful in determining the ways in which perinatal psychosocial interventions may promote health.

Erythrocyte Long-Chain ω-3 Fatty Acids Are Positively Associated with Lean Mass and Grip Strength in Women with Recent Diagnoses of Breast Cancer.

BACKGROUND: Sarcopenia may hasten the risk of mortality in women with breast cancer. Long-chain omega-3 (n-3) polyunsaturated fatty acids (LCn-3PUFAs) may favor muscle mass which, in turn, could enhance resilience of cancer patients toward cancer treatment. OBJECTIVES: The objective of this study was to measure the relation of erythrocyte LCn-3PUFA concentrations with lean mass, grip strength, and postprandial energy metabolism in women with newly diagnosed breast cancer. METHODS: This cross-sectional analysis evaluated women (n = 150) ages 65 y and younger who were recently diagnosed with breast cancer (stages I-III). Erythrocyte LCn-3PUFA composition was measured using GC. Body composition was measured by DXA. Grip strength was assessed at the same visit. Postprandial energy metabolism was measured for 7.5 h after the consumption of a high-calorie, high-saturated-fat test meal using indirect calorimetry. Associations of fatty acids with outcomes were analyzed using multiple linear regression models and linear mixed-effects models. RESULTS: The ω-3 index, a measurement of LCn-3PUFA status, was positively associated with appendicular lean mass (ALM)/BMI (ß = 0.015, P = 0.01) and grip strength (ß = 0.757, P = 0.04) after adjusting data for age and cancer stage. However, when cardiorespiratory fitness was also included in the analyses, these relations were no longer significant (P > 0.08). After a test meal, a higher ω-3 index was associated with a less steep rise in fat oxidation (P = 0.02) and a steeper decline in glucose (P = 0.01) when adjusting for age, BMI, cancer stage, and cardiorespiratory fitness. CONCLUSIONS: The ω-3 index was positively associated with ALM/BMI and grip strength in women newly diagnosed with breast cancer and was associated with altered postprandial substrate metabolism. These findings warrant further studies to determine whether enriching the diet with LCn-3PUFAs during and after cancer treatments is causally linked with better muscle health and metabolic outcomes in breast cancer survivors.

Dietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates.

The consumption of a processed foods diet (PD) enriched with refined carbohydrates, saturated fats, and lack of fiber has increased in recent decades and likely contributed to increased incidence of chronic disease and weight gain in humans. These diets have also been shown to negatively impact brain health and cognitive function in rodents, non-human primates, and humans, potentially through neuroimmune-related mechanisms. However, mechanisms by which PD impacts the aged brain are unknown. This gap in knowledge is critical, considering the aged brain has a heightened state of baseline inflammation, making it more susceptible to secondary challenges. Here, we showed that consumption of a PD, enriched with refined carbohydrate sources, for 28 days impaired hippocampal- and amygdalar-dependent memory function in aged (24 months), but not young (3 months) F344 × BN rats. These memory deficits were accompanied by increased expression of inflammatory genes, such as IL-1ß, CD11b, MHC class II, CD86, NLRP3, and complement component 3, in the hippocampus and amygdala of aged rats. Importantly, we also showed that when the same PD is supplemented with the omega-3 polyunsaturated fatty acid DHA, these memory deficits and inflammatory gene expression changes were ameliorated in aged rats, thus providing the first evidence that DHA supplementation can protect against memory deficits and inflammatory gene expression in aged rats fed a processed foods diet. Lastly, we showed that while PD consumption increased weight gain in both young and aged rats, this effect was exaggerated in aged rats. Aging was also associated with significant alterations in hypothalamic gene expression, with no impact by DHA on weight gain or hypothalamic gene expression. Together, our data provide novel insights regarding diet-brain interactions by showing that PD consumption impairs cognitive function likely through a neuroimmune mechanism and that dietary DHA can ameliorate this phenomenon.

Fatty food, fatty acids, and microglial priming in the adult and aged hippocampus and amygdala.

Short-term (3-day) consumption of a high fat diet (HFD) rich in saturated fats is associated with a neuroinflammatory response and subsequent cognitive impairment in aged, but not young adult, male rats. This exaggerated effect in aged rats could be due to a "primed" microglial phenotype observed in the normal aging process in rodents in which aged microglia display a potentiated response to immune challenge. Here, we investigated the impact of HFD on microglial priming and lipid composition in the hippocampus and amygdala of young and aged rats. Furthermore, we investigated the microglial response to palmitate, the main saturated fatty acid (SFA) found in HFD that is proinflammatory. Our results indicate that HFD increased gene expression of microglial markers of activation indicative of microglial priming, including CD11b, MHCII, CX3CR1, and NLRP3, as well as the pro-inflammatory marker IL-1ß in both hippocampus and amygdala-derived microglia. Furthermore, HFD increased the concentration of SFAs and decreased the concentration of polyunsaturated fatty acids (PUFAs) in the hippocampus. We also observed a specific decrease in the anti-inflammatory PUFA docosahexaenoic acid (DHA) in the hippocampus and amygdala of aged rats. In a separate cohort of young and aged animals, isolated microglia from the hippocampus and amygdala exposed to palmitate in vitro induced an inflammatory gene expression profile mimicking the effects of HFD in vivo. These data suggest that palmitate may be a critical nutritional signal from the HFD that is directly involved in hippocampal and amygdalar inflammation. Interestingly, microglial activation markers were increased in response to HFD or palmitate in an age-independent manner, suggesting that HFD sensitivity of microglia, under these experimental conditions, is not the sole mediator of the exaggerated inflammatory response observed in whole tissue extracts from aged HFD-fed rats.

A proinflammatory diet is associated with inflammatory gene expression among healthy, non-obese adults: Can social ties protect against the risks?

The Western diet, characterized by high intake of saturated fat, sugar, and salt, is associated with elevated inflammation and chronic disease risk. Few studies have investigated molecular mechanisms linking diet and inflammation; however, a small number of randomized controlled trials suggest that consuming an anti-inflammatory diet (i.e., a primarily plant-based diet rich in monounsaturated fat and lean protein) decreases proinflammatory gene expression. The current study investigated the association between everyday diet and proinflammatory gene expression, as well as the extent to which central adiposity and social involvement modulate risk. Participants were healthy middle-aged and older adults (N = 105) who completed a food frequency questionnaire and reported how many close social roles they have. Anthropometric measurements and blood samples also were collected; gene expression data were analyzed from LPS-stimulated peripheral blood mononuclear cells for interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. The inflammatory potential of each participant's diet was calculated using the Dietary Inflammatory Index (DII®). Participants with higher DII® scores, indicating a more proinflammatory diet, had greater IL-6 (b = -0.02, SE = 0.008, p = .01), IL-1ß (b = -0.01, SE = 0.006, p = .03), and TNF-α (b = -0.01, SE = 0.005, p = .04) gene expression if they had a smaller sagittal abdominal diameter (SAD); effects were not seen among those with higher SADs. Social involvement served a protective role, such that participants with smaller SADs had greater IL-6 (b = 0.01, SE = 0.004, p = .049) and IL-1ß (b = 0.01, SE = 0.003, p = .045) gene expression only if they had less social involvement; there was no effect of diet on gene expression among those who reported greater social participation. Results are the first to demonstrate a link between self-reported diet and proinflammatory gene expression. Importantly, the effect of diet on gene expression depended upon both body fat composition and social participation, both of which have previously been linked directly with proinflammatory gene expression and inflammation.

Associations of erythrocyte ω-3 fatty acids with biomarkers of ω-3 fatty acids and inflammation in breast tissue.

There is increasing evidence that chronic inflammation is associated with increased breast cancer risk. Long-chain omega-3 polyunsaturated fatty acids (LCω-3PUFA) may reduce circulating biomarkers of inflammation; however associations of blood LCω-3PUFA with breast tissue LCω-3PUFA and breast tissue biomarkers of inflammation are not well understood. We conducted a cross-sectional analysis of breast tissue and blood samples from n = 85 women with no history of breast cancer, who underwent breast reduction surgery. Fatty acids of erythrocytes and undissected breast tissues were analyzed by gas chromatography; C-reactive protein (CRP), interleukin (IL)-6 and IL-8 in plasma and tissue were measured by ELISA. Multivariable-adjusted regression models were used to estimate associations between erythrocyte LCω-3PUFA and breast tissue biomarkers. Women in the highest erythrocyte LCω-3PUFA tertile had LCω-3PUFA concentrations in the breast 73% (95% CI: 31-128%; p trend < 0.0001) higher than women in the lowest tertile. Associations for each individual LCω-3PUFA were similar in magnitude. No significant association was found for the shorter ω-3 PUFA, α-linolenic acid. Although compatible with no association, women in the highest tertile of erythrocyte eicosapentaenoic acid had a nonsignificant 32% (95% CI: -23 to 62%) reduced breast tissue CRP. No correlation was observed between erythrocyte ω-3 PUFA and tissue IL-6 or IL-8 concentrations. Our findings provide evidence that erythrocyte ω-3 fatty acids are valid measures of breast tissue concentrations, and limited evidence that inverse associations from prospective epidemiologic studies of blood LCω-3PUFA and breast cancer risk may be partly explained by reductions in breast tissue inflammation; however, these findings require replication.

Loneliness predicts postprandial ghrelin and hunger in women.

Loneliness is strongly linked to poor health. Recent research suggests that appetite dysregulation provides one potential pathway through which loneliness and other forms of social disconnection influence health. Obesity may alter the link between loneliness and appetite-relevant hormones, one unexplored possibility. We examined the relationships between loneliness and both postmeal ghrelin and hunger, and tested whether these links differed for people with a higher versus lower body mass index (BMI; kg/m(2)). During this double-blind randomized crossover study, women (N=42) ate a high saturated fat meal at the beginning of one full-day visit and a high oleic sunflower oil meal at the beginning of the other. Loneliness was assessed once with a commonly used loneliness questionnaire. Ghrelin was sampled before the meal and postmeal at 2 and 7h. Self-reported hunger was measured before the meal, immediately postmeal, and then 2, 4, and 7h later. Lonelier women had larger postprandial ghrelin and hunger increases compared with less lonely women, but only among participants with a lower BMI. Loneliness and postprandial ghrelin and hunger were unrelated among participants with a higher BMI. These effects were consistent across both meals. These data suggest that ghrelin, an important appetite-regulation hormone, and hunger may link loneliness to weight gain and its corresponding negative health effects among non-obese people.

Omega-3 supplementation and loneliness-related memory problems: secondary analyses of a randomized controlled trial.

OBJECTIVE: Loneliness enhances risk for episodic memory declines over time. Omega-3 supplementation can improve cognitive function for people experiencing mild cognitive difficulties. Accordingly, we explored whether omega-3 supplementation would attenuate loneliness-related episodic memory problems. METHODS: Participants (n = 138) from a parent randomized controlled trial were randomized to the placebo, 1.25 grams/d of omega-3, or 2.50 grams/d of omega-3 conditions for a 4-month period. They completed a baseline loneliness questionnaire and a battery of cognitive tests both at baseline and at the end of the randomized controlled trial. RESULTS: After adjustment for baseline verbal episodic memory scores, lonelier people within the placebo condition had poorer verbal episodic memory postsupplementation, as measured by immediate (b = -0.28, t (117) = -2.62, p = .010) and long-delay (b = -0.06, t (116) = -2.07, p = .040) free recall, than their less lonely counterparts. This effect was not observed in the 1.25- and 2.50-grams/d supplementation groups (all p values > .10). The plasma omega-6:omega-3 ratio data mirrored these results. There were no loneliness-related effects of omega-3 supplementation on short-delay recall or the other cognitive tests (all p values > .32). CONCLUSION: These results suggest that omega-3 supplementation attenuates loneliness-related verbal episodic memory declines over time and support the use of exploring novel interventions for treating episodic memory problems among lonely people. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00385723.

Restricted carbohydrate diets below 45% energy are not associated with risk of mortality in the National Health and Nutrition Examination Survey, 1999-2018.

Introduction: Cardiometabolic diseases (CMD) are the leading causes of death for people living in the United States. Dietary strategies, such as restricting carbohydrate intake, are becoming popular strategies for improving health status. However, there is limited and often contradictory evidence on whether restricting carbohydrate intake is related to all-cause, CMD, or cardiovascular disease (CVD) mortality. Methods: The objective of the present study was to evaluate the association between restricted carbohydrate diets (<45%en) and mortality from all-causes, CMD, and CVD, stratified by fat amount and class. Data were acquired using the National Health and Nutrition Examination Survey (1999-2018) linked with mortality follow-up until December 31, 2019 from the Public-use Linked Mortality Files. Multivariable survey-weighted Cox proportional hazards models estimated hazard ratios for 7,958 adults (≥20 y) that consumed <45%en from carbohydrates and 27,930 adults that consumed 45-65%en from carbohydrates. Results: During the study period a total of 3,780 deaths occurred, including 1,048 from CMD and 1,007 from CVD, during a mean follow-up of 10.2 y. Compared to individuals that met carbohydrate recommendations (45-65%en), those that consumed carbohydrate restricted diets (<45%en) did not have significantly altered risk of mortality from all-causes (HR: 0.98; 95% CI: 0.87, 1.11), CMD (1.18; 0.95, 1.46), or CVD (1.20; 0.96, 1.49). These findings were maintained when the restricted carbohydrate diet group was stratified by intake of total fat, saturated fat (SFA), monounsaturated fat (MUFA), and polyunsaturated fat (PUFA). Discussion: Carbohydrate restriction (<45%en) was not associated with mortality from all-causes, CVD, or CMD. Greater efforts are needed to characterize the risk of mortality associated with varied degrees of carbohydrate restriction, e.g., low (<26%en) and high (>65%en) carbohydrate diets separately.

Gut Microbiota Richness and Diversity Track With T Cell Aging in Healthy Adults.

BACKGROUND: This study examined how gut microbiota diversity and richness relate to T cell aging among 96 healthy adults of all ages. It also explored whether these links differed throughout the lifespan. METHODS: Peripheral blood was obtained from 96 study participants (N = 96, aged 21-72) to assess mRNA markers of T cell aging (p16ink4a, p14ARF, B3gat1, Klrg1) and DNA methylation. T cell aging mRNA markers were combined into an aging index, and the Horvath epigenetic clock algorithm was used to calculate epigenetic age based on DNA methylation status of over 500 loci. Participants also collected a stool sample from which the V4 region of the 16S rRNA gene was sequenced to derive the Shannon and Simpson diversity indices, and the total count of observed operational taxonomic units (richness). Models controlled for BMI, comorbidities, sex, dietary quality, smoking status, physical activity, and sleep quality. RESULTS: Lower microbiota richness was associated with higher T cell age based on mRNA markers, but when probing the region of significance, this relationship was only significant among adults 45 years and older (p = .03). Lower Shannon diversity (p = .05) and richness (p = .07) marginally correlated with higher epigenetic age (ie, greater T cell DNA methylation). CONCLUSIONS: Gut microbiota complexity may correspond with the rate of T cell aging, especially in mid-to-late life. These results suggest an interplay between the gut microbiome and immunological aging that warrants further experimental work.

Differences in Plasma Fatty Acid Composition Related to Chronic Pancreatitis: A Pilot Study.

OBJECTIVES: Chronic pancreatitis (CP) is an inflammatory disease affecting the absorption of fat-soluble nutrients. Signaling in pancreatic cells that lead to inflammation may be influenced by fatty acids (FAs) through diet and de novo lipogenesis. Here, we investigated the relationship between plasma FA composition in CP with heterogeneity of etiology and complications of CP. MATERIALS AND METHODS: Blood and clinical parameters were collected from subjects with CP (n = 47) and controls (n = 22). Plasma was analyzed for FA composition using gas chromatography and compared between controls and CP and within CP. RESULTS: Palmitic acid increased, and linoleic acid decreased in CP compared with controls. Correlations between age or body mass index and FAs are altered in CP compared with controls. Diabetes, pancreatic calcifications, and substance usage, but not exocrine pancreatic dysfunction, were associated with differences in oleic acid and linoleic acid relative abundance in CP. De novo lipogenesis index was increased in the plasma of subjects with CP compared with controls and in calcific CP compared with noncalcific CP. CONCLUSIONS: Fatty acids that are markers of de novo lipogenesis and linoleic acid are dysregulated in CP depending on the etiology or complication. These results enhance our understanding of CP and highlight potential pathways targeting FAs for treating CP.

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study.

INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

Zinc deficiency augments leptin production and exacerbates macrophage infiltration into adipose tissue in mice fed a high-fat diet.

Zinc (Zn) deficiency and obesity are global public health problems. Zn deficiency is associated with obesity and comorbid conditions that include insulin resistance and type 2 diabetes. However, the function of Zn in obesity remains unclear. Using a mouse model of combined high-fat and low-Zn intake (0.5-1.5 mg/kg), we investigated whether Zn deficiency exacerbates the extent of adiposity as well as perturbations in metabolic and immune function. C57BL/6 mice were randomly assigned to receive either a high-fat diet (HFD) or a control (C) diet for 6 wk, followed by further subdivision into 2 additional groups fed Zn-deficient diets (C-Zn, HFD-Zn), along with a C diet and an HFD, for 3 wk (n = 8-9 mice/group). The extent of visceral fat, insulin resistance, or systemic inflammation was unaffected by Zn deficiency. Strikingly, Zn deficiency significantly augmented circulating leptin concentrations (HFD-Zn vs. HFD: 3.15 ± 0.16 vs. 2.59 ± 0.12 µg/L, respectively) and leptin signaling in the liver of obese mice. Furthermore, gene expression of macrophage-specific markers ADAM8 (A disintegrin and metalloproteinase domain-containing protein 8) and CD68 (cluster of differentiation 68) was significantly greater in adipose tissue in the HFD-Zn group than in the HFD group, as confirmed by CD68 protein analysis, indicative of increased macrophage infiltration. Inspection of Zn content and mRNA profiles of all Zn transporters in the adipose tissue revealed alterations of Zn metabolism to obesity and Zn deficiency. Our results demonstrate that Zn deficiency increases leptin production and exacerbates macrophage infiltration into adipose tissue in obese mice, indicating the importance of Zn in metabolic and immune dysregulation in obesity.

Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial.

Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind four-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5g/day n-3 PUFAs, (2) l.25g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention's impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. ClinicalTrials.gov identifier: NCT00385723.

Fat Intake Modifies the Association between Restricted Carbohydrate Diets and Prevalent Cardiometabolic Diseases among Adults in the United States: National Health and Nutrition Examination Survey, 1999-2018.

Background: Cardiometabolic diseases (CMDs), which include heart disease, stroke, and diabetes, account for over one-third of the mortality burden in the United States annually. Nearly one-half of all deaths from CMD are attributable to suboptimal diet quality, and many Americans are turning to special diets for general health improvement. Among the most popular of these diets restrict daily carbohydrate intake to <45% of energy, yet their association with CMD is not well understood. Objectives: This study evaluated the association between restricted carbohydrate diets and prevalent CMD, stratified by fat intake. Methods: Dietary and CMD data were retrieved from 19,078 participants aged ≥20 y in the National Health and Nutrition Examination Survey, 1999-2018. The National Cancer Institute methodology was used to assess usual dietary intake. Results: Compared to participants that met recommendations for all macronutrients, those that consumed restricted carbohydrate diets were 1.15 (95% CI: 1.14, 1.16) times as likely to have CMD; and those that met recommendations for carbohydrates, but not all macronutrients, were 1.02 (95% CI: 1.02, 1.03) times as likely to have CMD. Higher intakes of saturated and polyunsaturated fat were associated with greater prevalence of CMD in restricted and recommended carbohydrate intake groups. Higher intake of monounsaturated fat was associated with lower prevalence of CMD among participants that met carbohydrate, but not all macronutrient, recommendations. Conclusions: To our knowledge, this is the first nationally representative study to evaluate the relationship between carbohydrate restriction and CMD, stratifying by fat intake. Greater efforts are needed to understand longitudinal relationships between carbohydrate restriction and CMD.

Greenhouse gas emissions, cost, and diet quality of specific diet patterns in the United States.

BACKGROUND: Major policy agendas are calling for accelerated investment in research that addresses the impact of diet patterns on multiple domains of sustainability. OBJECTIVES: To evaluate the comparative greenhouse gas emissions, diet cost, and diet quality of plant-based, low-grain, restricted carbohydrate, low-fat, and time-restricted diet patterns on a daily per capita basis. METHODS: Dietary data from the National Health and Nutrition Examination Survey (2013-2016, n = 4025) were merged with data on greenhouse gas emissions (GHGEs) and food prices from multiple databases. The Healthy Eating Index-2015 was used to measure diet quality. RESULTS: The plant-based diet pattern had the lowest GHGEs [3.5 kg carbon dioxide equivalent (CO2eq); 95% confidence interval (CI): 3.3, 3.8 kg CO2eq] and among the lowest diet cost ($11.51; 95% CI: $10.67, $12.41), but diet quality (45.8; 95% CI: 43.3, 48.5) was similar (P > 0.005) to most other diet patterns. All of the sustainability impacts of the low-grain diet pattern were intermediate. The restricted carbohydrate diet pattern had the highest diet cost ($18.46; 95% CI: $17.80, $19.13) but intermediate diet quality (46.8; 95% CI: 45.7, 47.9) and moderate-to-high GHGEs (5.7 kg CO2eq; 95% CI: 5.4, 5.9 kg CO2eq). The low-fat diet pattern had the highest diet quality (52.0; 95% CI: 50.8, 53.1) and intermediate GHGEs (4.4 kg CO2eq; 95% CI: 4.1, 4.6 kg CO2eq) and diet cost ($14.53; 95% CI: $13.73, $15.38). The time-restricted diet pattern had among the lowest diet quality score (42.6; 95% CI: 40.8, 44.6), had GHGEs similar to most other diet patterns (4.6 kg CO2eq; 95% CI: 4.2, 5.0 kg CO2eq), and low-to-moderate diet cost ($12.34; 95% CI: $11.38, $13.40). CONCLUSIONS: Most diet patterns are associated with sustainability trade-offs. The nature of these trade-offs can help inform discussions on food and nutrition policy in the United States, including the National Strategy on Hunger, Nutrition, and Health, and future Dietary Guidelines for Americans.

Omega-3 fatty acids reduce depressive symptoms only among the socially stressed: A corollary of the social signal transduction theory of depression.

OBJECTIVE: There is mixed evidence about whether omega-3 fatty acids reduce depressive symptoms. We previously reported that 4 months of omega-3 supplementation reduced inflammatory responsivity to a lab-based social stressor. In another study, we showed that those with exaggerated inflammatory responsivity to a social stressor had the greatest depressive symptom increases over time, especially if they experienced frequent social stress. Here we tested whether omega-3 supplementation reduced subthreshold depressive symptoms among those who experienced frequent social stress. METHOD: Healthy, sedentary, generally overweight middle-aged and older adults (N = 138) were randomly assigned to 4 months of pill placebo (n = 46), 1.25 grams per day (g/d) omega-3 (n = 46), or 2.5 g/d omega-3 (n = 46). At a baseline visit and monthly follow-up visits, they reported depressive symptoms and had their blood drawn to assess plasma levels of omega-3 fatty acids. Participants completed the Trier Inventory of Chronic Stress at Visit 2 and the Test of Negative Social Exchange at Visit 3. RESULTS: Among those who were overweight or obese, both doses of omega-3 reduced depressive symptoms only in the context of frequent hostile interactions and social tension, and 2.5 g/d of omega-3 lowered depressive symptoms among those with less social recognition or more performance pressure (ps < .05). Findings were largely corroborated with plasma omega-3 fatty acids. No other social stress or work stress measure moderated omega-3 fatty acids' relationship with depressive symptoms (ps > .05). CONCLUSIONS: Omega-3 fatty acids' antidepressant effect may be most evident among those who experience frequent social stress, perhaps because omega-3 fatty acids reduce inflammatory reactivity to social stressors. (PsycInfo Database Record (c) 2023 APA, all rights reserved).