ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids.

Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals1,2. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic1,3. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum1. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases1,4-7. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80-90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.

Feasibility of omega-3 fatty acid fraction mapping using chemical shift encoding-based imaging at 3 T.

PURPOSE: The aim of this work is to develop an ω-3 fatty acid fraction mapping method at 3 T based on a chemical shift encoding model, to assess its performance in a phantom and in vitro study, and to further demonstrate its feasibility in vivo. METHODS: A signal model was heuristically derived based on spectral appearance and theoretical considerations of the corresponding molecular structures to differentiate between ω-3 and non-ω-3 fatty acid substituents in triacylglycerols in addition to the number of double bonds (ndb), the number of methylene-interrupted double bonds (nmidb), and the mean fatty acid chain length (CL). First, the signal model was validated using single-voxel spectroscopy and a time-interleaved multi-echo gradient-echo (TIMGRE) sequence in gas chromatography-mass spectrometry (GC-MS)-calibrated oil phantoms. Second, the TIMGRE-based method was validated in vitro in 21 adipose tissue samples with corresponding GC-MS measurements. Third, an in vivo feasibility study was performed for the TIMGRE-based method in the gluteal region of two healthy volunteers. Phantom and in vitro data was analyzed using a Bland-Altman analysis. RESULTS: Compared with GC-MS, MRS showed in the phantom study significant correlations in estimating the ω-3 fraction (p < 0.001), ndb (p < 0.001), nmidb (p < 0.001), and CL (p = 0.001); MRI showed in the phantom study significant correlations (all p < 0.001) for the ω-3 fraction, ndb, and nmidb, but no correlation for CL. Also in the in vitro study, significant correlations (all p < 0.001) between MRI and GC-MS were observed for the ω-3 fraction, ndb, and nmidb, but not for CL. An exemplary ROI measurement in vivo in the gluteal subcutaneous adipose tissue yielded (mean ± standard deviation) 0.8% ± 1.9% ω-3 fraction. CONCLUSION: The present study demonstrated strong correlations between gradient-echo imaging-based ω-3 fatty acid fraction mapping and GC-MS in the phantom and in vitro study. Furthermore, feasibility was demonstrated for characterizing adipose tissue in vivo.

Soft-tissue evidence for homeothermy and crypsis in a Jurassic ichthyosaur.

Ichthyosaurs are extinct marine reptiles that display a notable external similarity to modern toothed whales. Here we show that this resemblance is more than skin deep. We apply a multidisciplinary experimental approach to characterize the cellular and molecular composition of integumental tissues in an exceptionally preserved specimen of the Early Jurassic ichthyosaur Stenopterygius. Our analyses recovered still-flexible remnants of the original scaleless skin, which comprises morphologically distinct epidermal and dermal layers. These are underlain by insulating blubber that would have augmented streamlining, buoyancy and homeothermy. Additionally, we identify endogenous proteinaceous and lipid constituents, together with keratinocytes and branched melanophores that contain eumelanin pigment. Distributional variation of melanophores across the body suggests countershading, possibly enhanced by physiological adjustments of colour to enable photoprotection, concealment and/or thermoregulation. Convergence of ichthyosaurs with extant marine amniotes thus extends to the ultrastructural and molecular levels, reflecting the omnipresent constraints of their shared adaptation to pelagic life.

Comprehensive lipidomic analysis revealed the effects of fermented Morus alba L. intake on lipid profile in backfat and muscle tissue of Yuxi black pigs.

Mulberry leaf is a widely used protein feed and is often used as a strategy to reduce feed costs and improve meat quality in the livestock industry. However, to date, there is a lack of research on the improvement of meat quality using mulberry leaves, and the exact mechanisms are not yet known. The results showed that fermented mulberry leaves significantly reduced backfat content but had no significant effect on intramuscular fat (IMF). Lipidomic analysis showed that 98 and 303 differential lipid molecules (p < 0.05) were identified in adipose and muscle tissues, respectively, including triglycerides (TG), phosphatidylcholine, phosphatidylethanolamine, sphingolipids, and especially TG; therefore, we analysed the acyl carbon atom number of TG. The statistical results of acyl with different carbon atom numbers of TG in adipose tissue showed that the acyl group containing 13 carbon atoms (C13) in TG was significantly upregulated, whereas C15, C16, C17, and C23 were significantly downregulated, whereas in muscle tissue, the C12, C19, C23, C25, and C26 in TG were significantly downregulated. Acyl changes in TG were different for different numbers of carbon atoms in different tissues. We found that the correlations of C (14-18) in adipose tissue were higher, but in muscle tissue, the correlations of C (18-26) were higher. Through pathway enrichment analysis, we identified six and four metabolic pathways with the highest contributions of differential lipid metabolites in adipose and muscle tissues respectively. These findings suggest that fermented mulberry leaves improve meat quality mainly by inhibiting TG deposition by downregulating medium- and short-chain fatty acids in backfat tissue and long-chain fatty acids in muscle tissue.

Determination of Anthropogenic Pollutants in Adipose Tissue of the Caspian Seal Pusa caspica Gmelin, 1788 by High-Resolution Accurate Mass Spectrometry.

Tissue contamination with persistent organic pollutants (POPs) in organisms proved possible to comprehensively characterize in a single test by combining gas chromatography and high-resolution accurate mass spectrometry. Adipose tissue samples were collected from two Caspian seals (Pusa caspica Gmelin, 1788) found dead on the Caspian Sea shore in 2020. Organochlorine pesticides, primarily DDT and HCH, and polychlorinated biphenyls (PCBs) were major pollutants found in the Caspian seals. The distribution of metabolites indicated the absence of recent pesticide use. The PCB content was relatively high, but still at the lower limit of the range of values determined previously, as was also the case with pesticides. Chlordanes, polychlorinated naphthalenes, and polybrominated diphenyl ethers were detected in minor quantities and were therefore not considered to be major pollutants of the Caspian seal. The pollutant levels were below a threshold at which a distinct effect on seal health can be expected. High-resolution accurate mass (HRAM) spectrometry was found to provide a convenient tool for both targeted and nontargeted analyses of a wide range of organic pollutants in a single experiment.

Imaging-based assessment of fatty acid composition in human bone marrow adipose tissue at 7 T: Method comparison and in vivo feasibility.

PURPOSE: To demonstrate the feasibility and accuracy of chemical shift-encoded imaging of the fatty acid composition (FAC) of human bone marrow adipose tissue at 7 T, and to determine suitable image-acquisition parameters using simulations. METHODS: The noise performance of FAC estimation was investigated using simulations with a range of inter-echo time, and accuracy was assessed using a phantom experiment. Furthermore, one knee of 8 knee-healthy subjects (ages 35-54 years) was imaged, and the fractions of saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA) were mapped. Values were compared between reconstruction methods, and between anatomical regions. RESULTS: Based on simulations, ΔTE = 0.6 ms was chosen. The phantom experiment demonstrated high accuracy of especially SFA using a constrained reconstruction model (slope = 1.1, average bias = -0.2%). The lowest accuracy was seen for PUFA using a free model (slope = 2.0, average bias = 9.0%). For in vivo images, the constrained model resulted in lower intersubject variation compared with the free model (e.g., in the femoral shaft, the SFA percent-point range was within 1.0% [vs. 3.0%]). Furthermore, significant regional FAC differences were detected. For example, using the constrained approach, the femoral SFA in the medial condyle was lower compared with the shaft (median [range]: 27.9% [27.1%, 28.4%] vs. 32.5% [31.8%, 32.8%]). CONCLUSION: Bone marrow adipose tissue FAC quantification using chemical-shift encoding is feasible at 7 T. Both the noise performance and accuracy of the technique are superior using a constrained signal model.

Positional and compositional analysis of saturated, monounsaturated, and polyunsaturated fatty acids in human adipose tissue triglyceride by 13 C nuclear magnetic resonance.

The synthesis and turnover of triglyceride in adipose tissue involves enzymes with preferences for specific fatty acid classes and/or regioselectivity regarding the fatty acid position within the glycerol moiety. The focus of the current study was to characterize both the composition of fatty acids and their positional distribution in triglycerides of biopsied human subcutaneous adipose tissue, from subjects with wide ranges of body mass index (BMI) and insulin sensitivity, using 13 C nuclear magnetic resonance (NMR) spectroscopy. The triglyceride sn2 position was significantly more enriched with monounsaturated fatty acids compared with that of sn1,3, while the abundance of saturated fatty acids was significantly lower in the sn2 position compared with that of sn1,3. Furthermore, the analysis revealed significant positive correlations between the total fraction of palmitoleic acid with both BMI and insulin sensitivity scores (homeostatic model assessment of insulin resistance index). Additionally, we established that 13 C NMR chemical shifts for ω-3 signals, centered at 31.9 ppm, provided superior resolution of the most abundant fatty acid species, including palmitoleate, compared with the ω-2 signals that were used previously. 13 C NMR spectroscopy reveals for the first time a highly nonhomogenous distribution of fatty acids in the glycerol sites of human adipose tissue triglyceride, and that these distributions are correlated with different phenotypes, such as BMI and insulin sensitivity.

Persistent organochlorine pesticides in periprostatic adipose tissue from men with prostate cancer: Ethno-geographic variations, association with disease aggressiveness.

Although several studies have examined the relationship between organochlorine pesticides (OCPs) and prostate cancer (PCa) risk, no data are available concerning the association between OCPs concentrations in periprostatic adipose tissue (PPAT), which reflects cumulative exposure, and PCa aggressiveness. Moreover, no previous study has compared OCPs exposure in two distinct ethno-geographical populations. The objectives were to analyze OCPs in PPAT of PCa patients from either Mainland France or French West Indies in correlation with features of tumor aggressiveness, after adjusting for potential confounders such age, BMI, and polyunsaturated fatty acid (PUFA) content of PPAT. PPAT was analyzed in 160 patients (110 Caucasians and 50 African-Caribbeans), 80 with an indolent tumor (ISUP group 1 + pT2), and 80 with an aggressive tumor (ISUP group more than 3 + pT3). The concentrations of 29 OCPs were measured in PPAT concomitantly with the characterization of PUFA content. Exposure patterns of OCPs differed according to the ethno-geographical origin. Most OCPs were found at higher concentration in Caucasian patients, whereas pp'-DDE content was twice as high in African-Caribbeans. Chlordecone was only detected in PPAT from African-Caribbean patients. Most OCP concentrations were positively correlated with age, and some with BMI. After adjusting for age, BMI, and PUFA composition of PPAT, no significant association was found between OCPs content and risk of aggressive disease, except of mirex which appeared inversely associated with aggressive features of PCa in Caucasian patients. These results highlight a significant ethno-geographic variation in internal exposure to OCPs, which likely reflects differences in consumption patterns. The inverse relationship observed between mirex concentration and markers of PCa aggressiveness need to be further investigated.

Accumulation of organophosphorus pollutants in adipose tissue of obese women - metabolic alterations.

Organophosphorus pesticides (OPPs) and organophosphate esters (OPEs) are organophosphorus compounds created as substitutes for persistent environmental pollutants, namely organochlorines pesticides and brominated flame retardants, respectively. However, there is evidence that organophosphorus compounds are also widespread across the environment and have adverse effects on biota. In humans, OPPs and OPEs were reported to be carcinogenic, neurotoxic, hepatotoxic, nephrotoxic, amongst others. As lipophilic compounds, these accumulate in fat tissues as adipose tissue. Yet biomonitoring studies and analytical methodologies to assess these compounds in the human body are scarce, particularly in adipose tissue. In this study, the presence of six OPPs and seven OPEs was determined in samples of subcutaneous adipose tissue (scAT) and visceral adipose tissue (vAT) from 188 adult obese women. OPPs and OPEs were quantified by gas chromatography (GC) flame photometric detection and confirmed in GC tandem mass spectrometry. The detection frequencies ranged between 0.5-1.6% and 48-53%, respectively for OPPs and OPEs. Organophosphorus pollutants were present in both adipose tissues and median concentrations were 0.008 ± 0.020 µg/g scAT and 0.009 ± 0.020 µg/g vAT. A total of 32 Spearman's correlations were found between organophosphorus pollutants concentrations in adipose tissue and several biochemical parameters (18 positive and 14 negative). Our results show that anthropometric and hormonal parameters, cholesterol, glycaemia, macrominerals, urea and sedimentation velocity might be influenced by the presence of these compounds. The presence of organophosphorus pollutants in the environmental and their possible effect on female metabolic processes is concerning. Particularly because presently OPEs usage is not controlled or limited by any regulation. More studies are needed to fully understand these pollutants behaviour and hazard effects on human health, biota, and the environment so control regulations can be drawn to prevent and lessen their effects.

Cross-sectional associations of persistent organic pollutants measured in adipose tissue and metabolic syndrome in clinically diagnosed middle-aged adults.

INTRODUCTION: Although often overlooked in clinical settings, accumulation of persistent organic pollutants (POPs) in visceral adipose tissue (VAT) is thought to be a relevant risk factor for metabolic syndrome (MetS). METHODS: One hundred and seventeen patients undergoing non-oncological surgery were randomly recruited and classified as MetS + if presented 3 out of the 5 MetS components: waist circumference (WC), systolic and diastolic blood pressure (SBP and DBP, respectively), serum glucose, insulin, triglycerides (TG) and high-density lipoprotein (HDL) cholesterol levels, according International Diabetes Federation (IDF) criteria. Seventeen organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in adipose tissue samples. Linear, logistic and weighted quantile sum (WQS) regression models, adjusted for age and sex, were performed. RESULTS: One third of the participants were males (36.8%) with a median age of 44 years, showing clinical evidences of MetS (35.0%). Adjusted linear regression models showed that WC correlated positively with all OCP concentrations. Higher fasting serum glucose levels were related to higher HCB and γ-HCH concentrations. The remaining OCPs and PCBs were not associated with this MetS component. HCB was inversely associated with HDL cholesterol levels, while PCB-180 was positively associated. HCB and γ-HCH concentrations were also positively correlated with DBP and SBP levels. PCB-138 was also positively associated with SBP. Adjusted logistic models revealed that exposure to HCB and γ-HCH were associated with increased odds of MetS [ORs (95%CI) 1.53 (1.22-1.92) and 1.39 (1.10-1.76) respectively; p < 0.01]. No associations were observed for the remaining POPs. WQS models showed a positive and significant mixture effect of POPs on the odds of MetS (exp [beta] = 2.34; p < 0.001), with γ-HCH (52.9%), o,p'-DDT (26.9%) and HCB (19.7%) driving the association. CONCLUSIONS: Our findings support that POPs accumulated in VAT, specifically HCB and (gamma)-HCH, are associated with both isolated components and clinically diagnosed SMT.

Adipose tissue levels of polybrominated diphenyl ethers in relation to prognostic biomarkers and progression-free survival time of breast cancer patients in eastern area of southern China: A hospital-based study.

Evidence indicates that individual or groups of polybrominated diphenyl ethers (PBDEs) are associated with risk of breast cancer (BC). Epidemiological studies of PBDEs and BC progression are scarce. This study aimed to investigate the relationships between PBDE burdens in adipose tissues and prognostic biomarkers of BC as well as progression-free survival (PFS) of patients for the first time. The concentrations of 14 PBDE congeners in breast adipose tissues of 183 cases from the eastern area of southern China were analyzed by gas chromatography-mass spectrometry (GC-MS). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression models for the associations between PBDE levels and prognostic biomarkers. Kaplan-Meier and Cox regression analyses were conducted to identify the correlations between PBDEs and PFS. The results showed that BDE-99 and 190 levels were positively associated with clinical stage and N stage respectively (OR = 2.61 [1.26-5.40], OR = 2.78 [1.04-7.46]). Concentrations of BDE-28 and BDE-183 were negatively associated with the expression of estrogen receptor (ER) (OR = 0.30 [0.11-0.81]; 0.39 [0.15-0.99]) and progesterone receptor (PR) (OR = 0.36 [0.14-0.92]; 0.37 [0.15-0.91]), and increased BDE-47 was associated with lower human epidermal growth factor receptor 2 (HER2) expression (OR = 0.44 [0.23-0.86]). Adipose levels of BDE-71, 99, 138, 153, 154 and total PBDEs were positively associated with p53 expression (all P < 0.05). Finally, BDE-47, 99 and 183 were considered as independent prognostic factors for shorter PFS in the Cox models (adjusted hazard ratios = 3.14 [1.26-7.82]; 2.25 [1.03-4.94]; 2.60 [1.08-6.25], respectively). The recurrence risk and prognosis of BC may be closely bound to the body burdens of certain PBDE congeners. Further epidemiological and experimental studies are needed for confirmation.

Novel ECL Method for the Determination of Skatole in Porcine Adipose Tissue.

A new method for the determination of skatole present in porcine adipose tissue samples utilizing the electrochemiluminescence of skatole is presented. It has been observed that oxygen radicals produced at a high cathodic voltage can react with oxidized skatole to create an excited intermediate molecule that then relaxes, generating peak photon emission at around 480 nm. A strong electrochemiluminescence or electrogenerated chemiluminescence (ECL) signal using boron-doped diamond (BDD) electrodes was observed optimally when a reduction potential of -1.8 V was applied, held for 40 s, before holding an oxidation potential of 0.8 V for 10 s. Using this principle, a calibration curve using known concentrations of skatole showed good linearity (range 0.025-2 µM) and a very low detection limit (LOD, 0.7 nM). A method that demonstrates for the first time an approach that utilizes this ECL reaction, and has the potential to be developed into an analytical device for use in the slaughterhouse, has been developed. This was achieved by extracting skatole out of the porcine adipose tissues into acetonitrile - giving an extraction efficiency of 67.6%. This method was then validated by analyzing the skatole content of 33 pig fat samples that had been previously tested using a standard technique, high-performance liquid chromatography (HPLC), containing a range of concentrations (0.02-2.58 µg/g). This ECL method exhibited excellent reliability and correlation with HPLC, giving a R2 coefficient of 0.911, thus demonstrating the potential for this method to be developed for an on-line skatole detector.

Omega-3 fatty acids in adipose tissue and risk of atrial fibrillation.

BACKGROUND: The aim of the present study was to examine the relation between adipose tissue content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the risk of incident atrial fibrillation (AF). METHODS: In this case-cohort study based on data from the Danish Diet, Cancer and Health cohort, a total of 5255 incident cases of AF was identified during 16.9 years of follow-up. Adipose tissue biopsies collected at baseline from all cases and from a randomly drawn subcohort of 3440 participants were determined by gas chromatography. Data were analysed using weighted Cox regression. RESULTS: Data were available for 4741 incident cases of AF (2920 men and 1821 women). Participants in the highest vs. the lowest quintile of EPA experienced a 45% lower risk of AF (men HR 0.55 (95% CI 0.41-0.69); women HR 0.55 (0.41-0.72)). For DHA, no clear association was found in men, whereas in women, participants in the highest quintile of DHA in adipose tissue had a 30% lower risk of incident AF (HR 0.70 (0.54-0.91)) compared to participants in the lowest quintile. CONCLUSIONS: A monotonous inverse association was found for the content of EPA in adipose tissue and risk of AF in both men and women. The content of DHA was inversely associated with the risk of AF in women, whereas no clear association was found for men.

Influence of Life-History Parameters on Persistent Organic Pollutant Concentrations in Blubber of Eastern North Pacific Gray Whales (Eschrichtius robustus).

Exposure to persistent organic pollutants (POPs) can significantly impact marine mammal health, reproduction, and fitness. This study addresses a significant 20-year gap in gray whale contaminant monitoring through analysis of POPs in 120 blubber biopsies. The scope of this substantial sample set is noteworthy in its range and diversity with collection between 2003 and 2017 along North America's west coast and across diverse sex, age, and reproductive parameters, including paired mothers and calves. Mean blubber concentrations of polychlorinated biphenyls (∑PCBs), dichlorodiphenyltrichloroethanes (∑DDTs), and chlordanes (∑CHLs) generally decreased since previous reports (1968-1999). This is the first report of polybrominated diphenyl ethers (PBDEs) and select hexachlorocyclohexanes (HCHs) in this species. Statistical modeling of the 19 most frequently detected compounds in this dataset revealed sex-, age-, and reproductive status-related patterns, predominantly attributed to maternal offloading. Mean POP concentrations differed significantly by sex in adults (17 compounds, up to 3-fold higher in males) but not in immatures (all 19 compounds). Mean POP concentrations were significantly greater in adults versus immatures in both males (17 compounds, up to 12-fold) and females (13 compounds, up to 3-fold). POP concentrations were detected with compound-specific patterns in nursing calves, confirming maternal offloading for the first time in this species.

Associations between polybrominated diphenyl ethers (PBDEs) levels in adipose tissues and blood lipids in women of Shantou, China.

Animal studies have indicated that exposure to polybrominated diphenyl ethers (PBDEs) during development can permanently affect blood/liver lipid balance. However, no epidemiological study has assessed the relationship between PBDEs in adipose tissues and blood lipid metabolism. In this study, we explored the associations between PBDEs levels in female adipose tissues and lipid profiles. We recruited 150 female patients undergoing plastic surgery from hospital in Shantou, China, collected their characteristics, clinical information, and adipose tissue samples. Fourteen PBDE congeners in adipose tissues were analyzed by gas chromatography-mass spectrometry (GC-MS). Multiple linear and logistic regression models were used to explore the relationships between PBDEs and lipid profiles, while restricted cubic spline (RCS) regression and Bayesian kernel machine regression (BKMR) models were used to evaluate the nonlinearity of mixtures. Median levels of ΣPBDEs and dominant congeners BDE-153, -209, and -183 in adipose tissues were 73.91, 26.12, 14.10 and 9.01 ng/g lipid, respectively. In the multiple linear model, BDE-153 and BDE-209 were negatively associated with triglycerides (TG), similarly for BDE-190 and total cholesterol (TC). While in the adjusted logistic models, BDE-138 was negatively associated with TC (OR = 0.76, 95%CI: 0.58, 0.99) and total lipids (TL) (OR = 0.76, 95%CI: 0.58, 0.99). Diastolic blood pressure was positively correlated with BDE-28 and BDE-71 (P < 0.05). Furthermore, a non-linear relationship was observed in BDE-138 and blood lipid levels using a RCS model (Pnonlinearity<0.05). BKMR analysis indicated that with the cumulative levels across PBDEs increased, the health risks of hypertriglyceridemia gradually rebounded, and the health risks of hypercholesterolemia and high total lipid gradually rebounded and then declined, but without statistical significance. PBDEs pollution was still prevalent in Shantou city, and several PBDE congeners were significant risk factors for dyslipidemia and blood pressure alteration. There exist deleterious effects of PBDEs and blood lipids.

Sex differences in adipose development in a hunter-gatherer population.

OBJECTIVE: Humans are unusually sexually dimorphic in body composition, with adult females having on average nearly twice the fat mass as males. The development of adipose sex differences has been well characterized for children growing up in food-abundant environments, with less known about cross-cultural variation, particularly in populations without exposure to market foods, mechanized technologies, schooling, vaccination, or other medical interventions. METHODS: To add to the existing cross-cultural data, we fit multiple growth curves to body composition and anthropometric data to describe adipose development for the Savanna Pumé, South American hunter-gatherers. RESULTS: (1) Little evidence is found for an adiposity 'rebound' at the end of early childhood among either Savanna Pumé girls or boys. (2) Rather, fat deposition fluctuates during childhood, from age ~4 to ~9 years, with no appreciable accumulation until the onset of puberty, a pattern also observed among Congo Baka hunter-gatherers. (3) Body fat fluctuations are more pronounced for girls than boys. (4) The age of peak skeletal, weight, and adipose gains are staggered to a much greater extent among the Savanna Pumé compared to the National Health and Nutrition Examination Survey (NHANES III) reference, suggesting this is an important developmental strategy in lean populations. CONCLUSION: Documenting growth patterns under diverse preindustrial energetic conditions provides an important baseline for understanding sex differences in body fat emerging today under food abundance.

Adipose Tissue-Derived CCL5 Enhances Local Pro-Inflammatory Monocytic MDSCs Accumulation and Inflammation via CCR5 Receptor in High-Fat Diet-Fed Mice.

The C-C chemokine motif ligand 5 (CCL5) and its receptors have recently been thought to be substantially involved in the development of obesity-associated adipose tissue inflammation and insulin resistance. However, the respective contributions of tissue-derived and myeloid-derived CCL5 to the etiology of obesity-induced adipose tissue inflammation and insulin resistance, and the involvement of monocytic myeloid-derived suppressor cells (MDSCs), remain unclear. This study used CCL5-knockout mice combined with bone marrow transplantation (BMT) and mice with local injections of shCCL5/shCCR5 or CCL5/CCR5 lentivirus into bilateral epididymal white adipose tissue (eWAT). CCL5 gene deletion significantly ameliorated HFD-induced inflammatory reactions in eWAT and protected against the development of obesity and insulin resistance. In addition, tissue (non-hematopoietic) deletion of CCL5 using the BMT method not only ameliorated adipose tissue inflammation by suppressing pro-inflammatory M-MDSC (CD11b+Ly6G-Ly6Chi) accumulation and skewing local M1 macrophage polarization, but also recruited reparative M-MDSCs (CD11b+Ly6G-Ly6Clow) and M2 macrophages to the eWAT of HFD-induced obese mice, as shown by flow cytometry. Furthermore, modulation of tissue-derived CCL5/CCR5 expression by local injection of shCCL5/shCCR5 or CCL5/CCR5 lentivirus substantially impacted the distribution of pro-inflammatory and reparative M-MDSCs as well as macrophage polarization in bilateral eWAT. These findings suggest that an obesity-induced increase in adipose tissue CCL5-mediated signaling is crucial in the recruitment of tissue M-MDSCs and their trans-differentiation to tissue pro-inflammatory macrophages, resulting in adipose tissue inflammation and insulin resistance.

Noninvasive, longitudinal imaging-based analysis of body adipose tissue and water composition in a melanoma mouse model and in immune checkpoint inhibitor-treated metastatic melanoma patients.

BACKGROUND: As cancer cachexia (CC) is associated with cancer progression, early identification would be beneficial. The aim of this study was to establish a workflow for automated MRI-based segmentation of visceral (VAT) and subcutaneous adipose tissue (SCAT) and lean tissue water (LTW) in a B16 melanoma animal model, monitor diseases progression and transfer the protocol to human melanoma patients for therapy assessment. METHODS: For in vivo monitoring of CC B16 melanoma-bearing and healthy mice underwent longitudinal three-point DIXON MRI (days 3, 12, 17 after subcutaneous tumor inoculation). In a prospective clinical study, 18 metastatic melanoma patients underwent MRI before, 2 and 12 weeks after onset of checkpoint inhibitor therapy (CIT; n = 16). We employed an in-house MATLAB script for automated whole-body segmentation for detection of VAT, SCAT and LTW. RESULTS: B16 mice exhibited a CC phenotype and developed a reduced VAT volume compared to baseline (B16 - 249.8 µl, - 25%; controls + 85.3 µl, + 10%, p = 0.003) and to healthy controls. LTW was increased in controls compared to melanoma mice. Five melanoma patients responded to CIT, 7 progressed, and 6 displayed a mixed response. Responding patients exhibited a very limited variability in VAT and SCAT in contrast to others. Interestingly, the LTW was decreased in CIT responding patients (- 3.02% ± 2.67%; p = 0.0034) but increased in patients with progressive disease (+ 1.97% ± 2.19%) and mixed response (+ 4.59% ± 3.71%). CONCLUSION: MRI-based segmentation of fat and water contents adds essential additional information for monitoring the development of CC in mice and metastatic melanoma patients during CIT or other treatment approaches.

Dose-response effects of aerobic exercise on adiposity markers in postmenopausal women: pooled analyses from two randomized controlled trials.

BACKGROUND/OBJECTIVE: Exercise may reduce the risk of breast cancer through adiposity changes, but the dose-response effects of exercise volume on adiposity markers are unknown in postmenopausal women. We aimed to compare the dose-response effects of prescribed aerobic exercise volume on adiposity outcomes. PARTICIPANTS/METHODS: Data from the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) and Breast Cancer and Exercise Trial in Alberta (BETA) were pooled for this analysis (N = 720). These were 12-month randomized controlled trials, where participants were randomized to 225 min/week (mid-volume) of aerobic exercise versus usual inactive lifestyle (ALPHA), or 150 min/week (low-volume) versus 300 min/week (high-volume) (BETA). Fat mass and fat-free mass were measured using DXA and intra-abdominal and subcutaneous fat area were assessed with computed tomography. RESULTS: After 12 months of aerobic exercise, increasing exercise volumes from no exercise/control to 300 min/week resulted in statistically significant reductions in BMI, weight, fat mass, fat percentage, intra-abdominal and subcutaneous fat area (P < 0.001). Compared with controls, fat mass loss was -1.13, -1.98 and -2.09 kg in the low-, mid- and high-volume groups, respectively. Similarly, weight loss was -1.47, -1.83, -2.21 kg in the low-, mid- and high-volume groups, respectively, compared to controls, and intra-abdominal fat area loss was -7.44, -15.56 and -8.76 cm2 in the low-, mid- and high-volume groups, respectively, compared to controls. No evidence for a dose-response effect on fat-free mass was noted. CONCLUSION: A dose-response effect of exercise volume on adiposity markers was noted, however, the differences in adiposity markers were smaller when comparing 225 min/week to 300 min/week of exercise. Given the strong positive associations between obesity and postmenopausal breast cancer risk, this study provides evidence on the importance of exercise volume as part of the exercise prescription to reduce adiposity and, ultimately, postmenopausal breast cancer risk.

F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes.

OBJECTIVE: F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. METHODS: We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. RESULTS: F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. CONCLUSIONS: F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.