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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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14 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Reexamining Fat: Exploring Diversity, Plasticity, Development, Functional Implication, and Therapeutic Options

Obesity has become so prevalent in many developed countries that it is increasingly perceived as a new norm, despite decades of interventions and drug development. Although research continues to explore novel strategies, no single approach to date has demonstrated sustained success in reducing its population-level dominance. This underscores the need to better evaluate and integrate the growing body of knowledge surrounding obesity’s multifaceted nature. Stamped under one ‘fat’ name, adipose tissue varies by color, location, morphology, composition, and function. This variability suggests a level of complexity that demands deeper investigation. Although the relevance and roles of different adipose types have been extensively discussed throughout the literature, their interdependence, synergy, and collective impact on the body remain to be fully expounded. This review aims to further consolidate and elucidate the available information on the different adipose tissue types and their association with obesity and metabolic health. We also discuss existing and emerging therapeutic strategies, highlighting their respective strengths and limitations.

BAT↗
DOE OSTI2025

Investigating the role of adipose tissue in mobility and aging: design and methods of the Adipose Tissue ancillary to the Study of Muscle, Mobility, and Aging (SOMMA-AT)

Background Age-related changes in adipose tissue affect chronic medical diseases and mobility disability but mechanism remains poorly understood. The goal of this study is to define methods for phenotyping unique characteristics of adipose tissue from older adults. Methods Older adults enrolled in study of muscle, mobility, and aging selected for the adipose tissue ancillary (SOMMA-AT; N = 210, 52.38% women, 76.12 ± 4.37 years) were assessed for regional adiposity by whole-body magnetic resonance (AMRA) and underwent a needle-aspiration biopsy of abdominal subcutaneous adipose tissue (ASAT). ASAT biopsies were flash frozen, fixed, or processed for downstream applications and deposited at the biorepository. Biopsy yields, qualitative features, adipocyte sizes, and concentration of adipokines secreted in ASAT explant conditioned media were measured. Inter-measure Spearman correlations were determined. Results Regional, but not total, adiposity differed by sex: women had greater ASAT mass (8.20 ± 2.73 kg, p < .001) and biopsy yield (3.44 ± 1.81 g, p < .001) than men (ASAT = 5.95 ± 2.30 kg, biopsy = 2.30 ± 1.40 g). ASAT mass correlated with leptin (r = 0.54, p < .001) and not resistin (p = .248) and adiponectin (p = .353). Adipocyte area correlated with ASAT mass (r = 0.34, p < .001), BMI (r = 0.33, p < .001), adiponectin (r = −0.22, p = .005) and leptin (r = 0.18, p = .024) but not with resistin (p = .490). Conclusion In addition to the detailed ASAT biopsy processing in this report, we found that adipocyte area correlated with ASAT mass, and both measures related to some key adipokines in the explant conditioned media. In conclusion, these results, methods, and biological repositories underscore the potential of this unique cohort to impact the understanding of aging adipose biology on disease, disability, and other aging tissues.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Implementation of dietary methionine restriction using casein after selective, oxidative deletion of methionine

Dietary methionine restriction (MR) is normally implemented using diets formulated from elemental amino acids (AA) that reduce methionine content to 0.17%. However, translational implementation of MR with elemental AA-based diets is intractable due to poor palatability. To solve this problem and restrict methionine using intact proteins, casein was subjected to mild oxidation to selectively reduce methionine. Diets were then formulated using oxidized casein, adding back methionine to produce a final concentration of 0.17%. The biological efficacy of dietary MR using the oxidized casein (Ox Cas) diet was compared with the standard elemental MR diet in terms of the behavioral, metabolic, endocrine, and transcriptional responses to the four diets. The Ox Cas MR diet faithfully reproduced the expected physiological, biochemical, and transcriptional responses in liver and inguinal white adipose tissue. Collectively, these findings demonstrate that dietary MR can be effectively implemented using casein after selective oxidative reduction of methionine.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Elucidating nanoscale mechanical properties of diabetic human adipose tissue using atomic force microscopy

Abstract Obesity-related type 2 diabetes (DM) is a major public health concern. Adipose tissue metabolic dysfunction, including fibrosis, plays a central role in DM pathogenesis. Obesity is associated with changes in adipose tissue extracellular matrix (ECM), but the impact of these changes on adipose tissue mechanics and their role in metabolic disease is poorly defined. This study utilized atomic force microscopy (AFM) to quantify difference in elasticity between human DM and non-diabetic (NDM) visceral adipose tissue. The mean elastic modulus of DM adipose tissue was twice that of NDM adipose tissue (11.50 kPa vs. 4.48 kPa) to a 95% confidence level, with significant variability in elasticity of DM compared to NDM adipose tissue. Histologic and chemical measures of fibrosis revealed increased hydroxyproline content in DM adipose tissue, but no difference in Sirius Red staining between DM and NDM tissues. These findings support the hypothesis that fibrosis, evidenced by increased elastic modulus, is enhanced in DM adipose tissue, and suggest that measures of tissue mechanics may better resolve disease-specific differences in adipose tissue fibrosis compared with histologic measures. These data demonstrate the power of AFM nanoindentation to probe tissue mechanics, and delineate the impact of metabolic disease on the mechanical properties of adipose tissue.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations

"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., triglycerides) is high or low relative to its distribution in the population. Quantile-specific offspring-parent regression slopes (β OP ) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h 2 ), estimated by 2β OP /(1 + $\Gamma$ spouse ), decreased 0.0047 ± 0.0007 (P = 2.9 × 10 -14 ) for each one-percent decrement in fasting triglyceride concentrations, i.e., h 2 ± SE were: 0.428 ± 0.059, 0.230 ± 0.030, 0.111 ± 0.015, 0.050 ± 0.016, and 0.033 ± 0.010 at the 90th, 75th, 50th, 25th, and 10th percentiles of the triglyceride distribution, respectively. Consistent with quantile-dependent expressivity, 11 drug studies report smaller genotype differences at lower (post-treatment) than higher (pre-treatment) triglyceride concentrations. This meant genotype-specific triglyceride changes could not move in parallel when triglycerides were decreased pharmacologically, so that subtracting pre-treatment from post-treatment triglyceride levels necessarily created a greater triglyceride decrease for the genotype with a higher pre-treatment value (purported precision-medicine genetic markers). In addition, sixty-five purported gene-environment interactions were found to be potentially attributable to triglyceride's quantile-dependent expressivity, including gene-adiposity (APOA5, APOB, APOE, GCKR, IRS-1, LPL, MTHFR, PCSK9, PNPLA3, PPARγ2), gene-exercise (APOA1, APOA2, LPL), gene-diet (APOA5, APOE, INSIG2, LPL, MYB, NXPH1, PER2, TNFA), gene-alcohol (ALDH2, APOA5, APOC3, CETP, LPL), gene-smoking (APOC3, CYBA, LPL, USF1), gene-pregnancy (LPL), and gene-insulin resistance interactions (APOE, LPL).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Quantile-dependent expressivity of plasma adiponectin concentrations may explain its sex-specific heritability, gene-environment interactions, and genotype-specific response to postprandial lipemia

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. adiponectin) is high or low relative to its distribution. We have previously shown that the heritability ( h 2 ) of adiposity, lipoproteins, postprandial lipemia, pulmonary function, and coffee and alcohol consumption are quantile-specific. Whether adiponectin heritability is quantile specific remains to be determined. Plasma adiponectin concentrations from 4,182 offspring-parent pairs and 1,662 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (β OP , h 2 = 2 β OP /(1 + r spouse )) and full-sib regression slopes ( β FS , h 2 = {(1 + 8r spouse β FS ) 0.05 -1}/(2r spouse )) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples. Quantile-specific h 2 (± SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted adiponectin distribution when estimated from β OP ( P trend = 2.2 × 10 -6 ): 0.30 ± 0.03 at the 10th, 0.33 ± 0.04 at the 25th, 0.43 ± 0.04 at the 50th, 0.55 ± 0.05 at the 75th, and 0.57 ± 0.08 at the 90th percentile, and when estimated from β FS (P trend = 7.6 × 10 -7 ): 0.42 ± 0.03 at the 10th, 0.44 ± 0.04 at the 25th, 0.56 ± 0.05 at the 50th, 0.73 ± 0.08 at the 75th, and 0.79 ± 0.11 at the 90th percentile. Consistent with quantile-dependent expressivity, adiponectin’s: (1) heritability was greater in women in accordance with their higher adiponection concentrations; (2) relationships to ADIPOQ polymorphisms were modified by adiposity in accordance with its adiponectin-lowering effect; (3) response to rosiglitazone was predicted by the 45T> G ADIPOQ polymorphism; (4) difference by ADIPOQ haplotypes increased linearly with increasing postprandial adiponectin concentrations. Adiponectin heritability is quantile dependent, which may explain sex-specific heritability, gene-environment and gene-drug interactions, and postprandial response by haplotypes.

Postprandial↗
DOE OSTI2020

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (β FS ) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed β FS increased significantly with increasing percentiles of the offspring’s age- and sex-adjusted leptin distribution (P linear = 0.0001), which was accelerated at the higher concentrations (P quadratic = 0.0003). β FS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, P difference = 3.6 × 10 –6 ). Consistent with quantile-dependent expressivity, the β FS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP , LEPR , MnSOD , PPARγ , PPARγ2 , and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. β FS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (P linear = 0.04 and P linear = 8.5 × 10 –6 , respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male–female differences in heritability and some gene-environment interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Timing based clustering in the Northern Finland Birth Cohorts 1966 and 1986 suggests two new patterns for childhood BMI curve [Poster]

Childhood body mass index (BMI) is a widely used measure of adiposity in children (<18 years of age). Children grow with individual tempo and individuals of the same age, or of the same BMI, might be in different phases in their individual growth curves. Variability between different childhood BMI curves can be separated in two components: phase variability (x-axis; time) and amplitude variability (y-axis; BMI). Phase variability can be thought of arising from differences in maturational age between individuals. This is related to the timing of peaks and valleys in a child’s BMI curve.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease

In the United States non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. It occurs in every age group, but predominantly in people with risk factors such as obesity and type 2 diabetes. NAFLD is marked by fat accumulation in the liver leading to liver inflammation, which may lead to scarring and irreversible damage progressing to cirrhosis and liver failure. In animal models, genetic ablation of the protein G0S2 leads to alleviation of liver damage and insulin resistance in high fat diets. The research presented in this paper aims to aid in rational based drug design for the treatment of NAFLD by providing a pathway for a solution state NMR structure of G0S2. Here we describe the expression of G0S2 in an E. coli system from two different constructs, both of which are confirmed to be functionally active based on the ability to inhibit the activity of Adipose Triglyceride Lipase. In one of the constructs, preliminary NMR spectroscopy measurements show dominant alpha-helical characteristics as well as resonance assignments on the N-terminus of G0S2, allowing for further NMR work with this protein. Additionally, the characterization of G0S2 oligomers are outlined for both constructs, suggesting that G0S2 may defensively exist in a multimeric state to protect and potentially stabilize the small 104 amino acid protein within the cell. This information presented on the structure of G0S2 will further guide future development in the therapy for NAFLD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A chloroplast diacylglycerol lipase modulates glycerolipid pathway balance in Arabidopsis

SUMMARY Two parallel pathways compartmentalized in the chloroplast and the endoplasmic reticulum contribute to thylakoid lipid synthesis in plants, but how these two pathways are coordinated during thylakoid biogenesis and remodeling remains unknown. We report here the molecular characterization of a homologous ADIPOSE TRIGLYCERIDE LIPASE‐LIKE gene, previously referred to as ATGLL . The ATGLL gene is ubiquitously expressed throughout development and rapidly upregulated in response to a wide range of environmental cues. We show that ATGLL is a chloroplast non‐regioselective lipase with a hydrolytic activity preferentially towards 16:0 of diacylglycerol (DAG). Comprehensive lipid profiling and radiotracer labeling studies revealed a negative correlation of ATGLL expression and the relative contribution of the chloroplast lipid pathway to thylakoid lipid biosynthesis. Additionally, we show that genetic manipulation of ATGLL expression resulted in changes in triacylglycerol levels in leaves. We propose that ATGLL, through affecting the level of prokaryotic DAG in the chloroplast, plays important roles in balancing the two glycerolipid pathways and in maintaining lipid homeostasis in plants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice

Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp -/- ) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP– PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP– PPARδ interaction that suppresses PPAR activity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue

Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Quantile-dependent expressivity of serum C-reactive protein concentrations in family sets

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., C-reactive protein, CRP) is high or low relative to its distribution. We have previously shown that the heritabilities ( h 2 ) of coffee and alcohol consumption, postprandial lipemia, lipoproteins, leptin, adiponectin, adiposity, and pulmonary function are quantile-specific. Whether CRP heritability is quantile-specific is currently unknown. Methods Serum CRP concentrations from 2,036 sibships and 6,144 offspring-parent pairs were analyzed from the Framingham Heart Study. Quantile-specific heritability from full-sib (β FS , h 2 ={(1 + 8r spouse β FS ) 0.5 - 1}/(2r spouse )) and offspring-parent regression slopes (β OP , h 2 = 2β OP /(1 + r spouse )) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples. Results Quantile-specific h 2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted CRP distribution when estimated from β OP ( P trend = 0.0004): 0.02 ± 0.01 at the 10th, 0.04 ± 0.01 at the 25th, 0.10 ± 0.02 at the 50th, 0.20 ± 0.05 at the 75th, and 0.33 ± 0.10 at the 90th percentile, and when estimated from β FS ( P trend = 0.0008): 0.03±0.01 at the 10th, 0.06 ± 0.02 at the 25th, 0.14 ± 0.03 at the 50th, 0.24 ± 0.05 at the 75th, and 0.53 ± 0.21 at the 90th percentile. Conclusion Heritability of serum CRP concentration is quantile-specific, which may explain or contribute to the inflated CRP differences between CRP (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), FGB (rs1800787), IL-6 (rs1800795, rs1800796), IL6R (rs8192284), TNF- α (rs1800629) and APOE genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or Staphylococcus aureus bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.

59 BASIC BIOLOGICAL SCIENCES↗