Objective: Adiposity induces the clustering of cardiometabolic risk factors, and pediatric adiposity is a better indicator for adulthood cardiometabolic diseases than pediatric metabolic syndrome. However, the observed prevalence of pediatric adiposity depends on the methods and cut-points used. Therefore, we aimed to define diagnostic criteria for adiposity which enable more valid identification of prepubertal children at increased cardiometabolic risk. Methods: The participants were 470 prepubertal children (249 boys) aged 6-8 years. The measures of adiposity included body mass index-standard deviation score (BMI-SDS), waist-to-height ratio (WHtR) and body fat percentage (BF%) assessed by bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA). Criteria for adiposity were determined by increased cardiometabolic risk. Cardiometabolic risk factors which correlated with BF% assessed by DXA in the upper but not lower half of BF% (serum insulin and plasma high-density lipoprotein cholesterol, triglycerides, gamma-glutamyl transferase, high-sensitivity C-reactive protein and uric acid) were included in the cardiometabolic risk score (CMS). We computed receiver operating characteristics curves for the measures of adiposity using the ≥90th percentile of CMS as a measure of increased cardiometabolic risk, and local regression curves were graphed to demonstrate the associations of the measures of adiposity with CMS. Results: In girls, WHtR of 0.445 (area under curve 0.778, its 95% confidence interval 0.65-0.91, sensitivity and specificity 0.73) and BF% of 19.5% assessed by BIA (0.801, 0.70-0.90, 0.73) were the best overall criteria for increased cardiometabolic risk. In boys, BMI-SDS of 0.48 (0.833, 0.75-0.92, 0.76) was the best overall criterion for increased cardiometabolic risk. While local regression curves in girls showed that WHtR of 0.445 corresponds well to a point where CMS began to increase, in boys local regression curves suggest that CMS began to increase even at a lower level of BMI-SDS than 0.48. Moreover, the diagnostic ability of the measures of adiposity to exclude increased cardiometabolic risk was poorer than the ability to detect it. Conclusions: In general, the measures of adiposity have sufficient diagnostic accuracy to be utilized as the screening tool for increased cardiometabolic risk. The observed cut-points for adiposity were lower than the traditional cut-points for adiposity.

Exercise, typically beneficial for skeletal health, has not yet been studied in lipodystrophy, a condition characterized by paucity of white adipose tissue, with eventual diabetes, and steatosis. We applied a mouse model of global deficiency of Bscl2 (SEIPIN), required for lipid droplet formation. Male twelve-week-old B6 knockouts (KO) and wild type (WT) littermates were assigned six-weeks of voluntary, running exercise (E) versus non-exercise (N=5-8). KO weighed 14% less than WT (p=0.01) and exhibited an absence of epididymal adipose tissue; KO liver Plin1 via qPCR was 9-fold that of WT (p=0.04), consistent with steatosis. Bone marrow adipose tissue (BMAT), unlike white adipose, was measurable, although 40.5% lower in KO vs WT (p=0.0003) via 9.4T MRI/advanced image analysis. SEIPIN ablation's most notable effect marrow adiposity was in the proximal femoral diaphysis (-56% KO vs WT, p=0.005), with relative preservation in KO-distal-femur. Bone via μCT was preserved in SEIPIN KO, though some quality parameters were attenuated. Running distance, speed, and time were comparable in KO and WT. Exercise reduced weight (-24% WT-E vs WT p<0.001) but not in KO. Notably, exercise increased trabecular BV/TV in both (+31%, KO-E vs KO, p=0.004; +14%, WT-E vs WT, p=0.006). The presence and distribution of BMAT in SEIPIN KO, though lower than WT, is unexpected and points to a uniqueness of this depot. That trabecular bone increases were achievable in both KO and WT, despite a difference in BMAT quantity/distribution, points to potential metabolic flexibility during exercise-induced skeletal anabolism.

Several non-synonymous single-nucleotide polymorphisms (nsSNPs) have been shown to be associated with obesity. Little is known about their associations and interactions with physical activity (PA) in relation to adiposity parameters among adolescents in Malaysia.

The prevalence of obesity has continued to rise over the past three decades leading to significant increases in obesity-related medical care costs from metabolic and non-metabolic sequelae. It is now clear that expansion of body fat leads to an increase in inflammation with systemic effects on metabolism. In mouse models of diet-induced obesity, there is also an expansion of bone marrow adipocytes. However, the persistence of these changes after weight loss has not been well described. The objective of this study was to investigate the impact of high-fat diet (HFD) and subsequent weight loss on skeletal parameters in C57Bl6/J mice. Male mice were given a normal chow diet (ND) or 60% HFD at 6 weeks of age for 12, 16, or 20 weeks. A third group of mice was put on HFD for 12 weeks and then on ND for 8 weeks to mimic weight loss. After these dietary challenges, the tibia and femur were removed and analyzed by micro computed-tomography for bone morphology. Decalcification followed by osmium staining was used to assess bone marrow adiposity, and mechanical testing was performed to assess bone strength. After 12, 16, or 20 weeks of HFD, mice had significant weight gain relative to controls. Body mass returned to normal after weight loss. Marrow adipose tissue (MAT) volume in the tibia increased after 16 weeks of HFD and persisted in the 20-week HFD group. Weight loss prevented HFD-induced MAT expansion. Trabecular bone volume fraction, mineral content, and number were decreased after 12, 16, or 20 weeks of HFD, relative to ND controls, with only partial recovery after weight loss. Mechanical testing demonstrated decreased fracture resistance after 20 weeks of HFD. Loss of mechanical integrity did not recover after weight loss. Our study demonstrates that HFD causes long-term, persistent changes in bone quality, despite prevention of marrow adipose tissue accumulation, as demonstrated through changes in bone morphology and mechanical strength in a mouse model of diet-induced obesity and weight loss.

Previous Mendelian randomization (MR) of obesity and diabetic nephropathy (DN) risk used small sample sizes or focused on a single adiposity metric. We explored the independent causal connection between obesity-related factors and DN risk using the most extensive GWAS summary data available, considering the distribution of adiposity across childhood and adulthood.

Context: Sirtuins (SIRTs) are NAD+-dependent deacetylases, cellular sensors to detect energy availability, and modulate metabolic processes. SIRT1, the most studied family member, influences a number of tissues including adipose tissue. Expression and activity of SIRT1 reduce with weight gain and increase in conditions of starvation. Objective: To focus on SIRT1 plasma concentrations in different conditions of adiposity and to correlate SIRT1 with fat content and distribution, energy homeostasis and inflammation in under-weight, normal-weight, and obese individuals. Materials and Methods: 21 patients with anorexia nervosa, 26 normal-weight and 75 patients with obesity were evaluated. Body fat composition by dual-energy X-ray absorptiometry, ultrasound liver adiposity, echocardiographic epicardial fat thickness (EFT), inflammatory (ESR, CRP, and fibrinogen), and metabolic (FPG, insulin, LDL- and HDL-cholesterol, triglycerides) parameters, calculated basal metabolic rate (BMR) and plasma SIRT1 (ELISA) were measured. Results: SIRT1 was significantly higher in anorexic patients compared to normal-weight and obese patients (3.27 ± 2.98, 2.27 ± 1.13, and 1.36 ± 1.31 ng/ml, respectively). Linear regression models for each predictor variable adjusted for age and sex showed that SIRT1 concentration was inversely and significantly correlated with EFT, fat mass %, liver fat content, BMR, weight, BMI, WC, LDL-cholesterol, insulin, ESR. Stepwise multiple regression analysis revealed that age and EFT were the best independent correlates of SIRT1 (β = -0.026 ± 0.011, p = 0.025, and β = -0.516 ± 0.083, p < 0.001, respectively). Conclusions: Plasma SIRT1 shows a continuous pattern that inversely follows the whole spectrum of adiposity. SIRT1 significantly associates with EFT, a strong index of visceral fat phenotype, better than other indexes of adiposity studied here.

The genetic code does not fully explain individual variability and inheritance of susceptibility to endocrine conditions, suggesting the contribution of epigenetic factors acting across generations.

Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS)] and pharmacological (sitagliptin) preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1) Obese-Control (consumed control diet during intervention); (2) Obese-OFS (10% OFS diet); (3) Obese-S (sitagliptin drug); (4) Obese-OFS + S (combination treatment). Two reference groups were also included: (5) Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study); (6) Lean-Control (lean reference group that were never obese and consumed control diet throughout). Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p < 0.05). Gestational weight gain was lowest in Obese-OFS + S rats and highest in Obese-HFS rats (p < 0.05). Prepregnancy intervention did not affect reproductive parameters but did affect pregnancy outcomes including litter size. Male Obese-OFS offspring had significantly lower percent body fat than Obese-HFS at 17 weeks. Female Obese-S and Obese-OFS offspring had significantly lower fasting glucose at 17 weeks compared with Obese-Control and Obese-HFS. Clostridium cluster XI was higher in Obese-HFS and Obese-S dams at birth compared with all other groups. Dams with an adverse pregnancy outcome had significantly lower (p = 0.035) Lactobacillus spp. compared with dams with normal or small litters. At weaning, male offspring of Obese-HFS had higher levels of Methanobrevibacter than all other groups except Obese-S and female Obese-HFS offspring had higher Enterobacteriaceae compared with all other groups. At 11 and 17 weeks of age, Bacteroides/Prevotella spp. was significantly lower in male and female offspring of Obese-HFS dams compared with all other groups except Obese-OFS + S. Modest weight loss induced with a diet-drug combination did not affect maternal fecundity but did have sex-specific effects on offspring adiposity and glycemia that may be linked to changes in offspring microbiota.

Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here, we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically, they decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high-fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801, along with other compounds that regulate ghrelin secretion, may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin-based obesity treatments without altering the function of ghrelin receptors.

Low bone mass is often associated with elevated bone marrow adiposity. Since osteoblasts and adipocytes are derived from the same mesenchymal stem cell (MSC) progenitor, adipocyte formation may increase at the expense of osteoblast formation. Leptin is an adipocyte-derived hormone known to regulate energy and bone metabolism. Leptin deficiency and high-fat diet-induced obesity are associated with increased marrow adipose tissue (MAT) and reduced bone formation. Short-duration studies suggest that leptin treatment reduces MAT and increases bone formation in leptin-deficient ob/ob mice fed a regular diet. Here, we determined the long-duration impact of increased hypothalamic leptin on marrow adipocytes and osteoblasts in ob/ob mice following recombinant adeno-associated virus (rAAV) gene therapy. Eight- to 10-week-old male ob/ob mice were randomized into four groups: (1) untreated, (2) rAAV-Lep, (3) rAAV-green fluorescent protein (rAAV-GFP), or (4) pair-fed to rAAV-Lep. For vector administration, mice were injected intracerebroventricularly with either rAAV-leptin gene therapy (rAAV-Lep) or rAAV-GFP (9 × 10(7) particles) and maintained for 30 weeks. In a second study, the impact of increased hypothalamic leptin levels on MAT was determined in mice fed high-fat diets; ob/ob mice were randomized into two groups and treated with either rAAV-Lep or rAAV-GFP. At 7 weeks post-vector administration, half the mice in each group were switched to a high-fat diet for 8 weeks. Wild-type (WT) controls included age-matched mice fed regular or high-fat diet. High-fat diet resulted in a threefold increase in MAT in WT mice, whereas MAT was increased by leptin deficiency up to 50-fold. Hypothalamic leptin gene therapy increased osteoblast perimeter and osteoclast perimeter with minor change in cancellous bone architecture. The gene therapy decreased MAT levels in ob/ob mice fed regular or high-fat diet to values similar to WT mice fed regular diet. These findings suggest that leptin plays an important role in regulating the differentiation of MSCs to adipocytes and osteoblasts, a process that may be dysregulated by high-fat diet. However, the results also illustrate that reducing MAT by increasing leptin levels does not necessarily result in increased bone mass.

The risk of visceral obesity on erectile function has recently attracted much attention. The visceral adiposity index (VAI) is a brief and reliable indicator of visceral obesity measurement. Nevertheless, the association between VAI and erectile dysfunction (ED) is not completely clarified.

The Visceral Adiposity Index (VAI) is a straightforward and gender-specific marker that combines anthropometric measurements with lipid profiles. The objective of this study was to evaluate the relationship between VAI and coronary heart disease (CHD).

It is well known that adiposity is a risk factor for insulin resistance and type 2 diabetes mellitus. In the present study, we aimed to investigate the associations of measures of adiposity with indices of glycemia and of glycemic variability over a 72-h period in non-diabetic older adults.

Per- or polyfluoroalkyl substances (PFAS), a family of synthetic polyfluorinated compounds, are widely used in consumer products. Ubiquitous exposures to PFAS, in consideration of their persistence, bioaccumulation potential, and toxicities have led to concerns regarding possible harmful effects during critical periods of development in early-life and long-term consequences on health. The potential effects of PFAS depend on various factors including the type of PFAS and the timing and level of exposure. We performed a systematic review of the epidemiologic literature to assess the effects of early-life PFAS exposure on prenatal and postnatal growth, adiposity, and puberty in children and adolescents. For birth size, most studies indicated that prenatal PFAS exposure, in particular long-chain PFAS, may impair fetal growth, albeit some reports of null associations with maternal PFAS. For growth within 2 years of age, prenatal PFAS exposure showed no associations with height and either null or negative associations with weight. However, postnatal PFAS exposures were inversely related to height and weight at 2 years in a cross-sectional study. For postnatal adiposity, prenatal PFAS may mostly have negative associations with body mass index in the first 2 years of life, but positive relationships with adiposity in childhood and adolescence, although some studies showed null associations. For puberty, the evidence for associations between early-life PFAS exposure and pubertal development or sex hormone levels were limited and inconclusive. From experimental studies, plausible mechanisms through which PFAS may affect early-life growth and puberty include PFAS-induced activation of peroxisome proliferator-activated receptor, alterations of thyroid or steroid hormone synthesis and metabolism, and their weak estrogenic or anti-androgenic properties. Although the published literature suggests possible effects of PFAS exposures on early-life growth, adiposity, and puberty, current human evidence is limited in establishing PFAS-induced effects on early-life physical development. Further investigation is warranted to clarify PFAS-induced effects on growth and physical development in consideration of the critical time-window of exposure, concomitant exposure to chemical mixtures including various PFAS types, and possible non-monotonic dose-response relationship for growth and adiposity trajectories.

The methylation levels of ZNF577 in breast tumors has been previously identified as a possible epigenetic mark of breast cancer associated with obesity. The aim of the current study was to investigate differences in methylation levels of ZNF577 depending on obesity, menopausal state and dietary pattern in blood leukocytes, a non-invasive sample. The methylation levels of ZNF577 of two CpG sites (CpGs) located in promoter and island previously identified as differentially methylated according to adiposity and menopausal state by 450 k array (cg10635122, cg03562414) were evaluated by pyrosequencing in DNA from the blood leukocytes of breast cancer patients [n = 90; n = 64 (71.1%) overweight/obesity and n = 26 (28.9%) normal-weight] and paired tumor tissue biopsies (n = 8 breast cancer patients with obesity; n = 3/5 premenopausal/postmenopausal women). Differences in methylation levels were evaluated at each CpGs individually and at the mean of the two evaluated CpGs. Adherence to the Mediterranean diet was evaluated using the MEDAS-validated questionnaire, and the consumption of food groups of interest was also evaluated using the recommended intakes of the Sociedad Española de Nutricion Comunitaria. The methylation levels of ZNF577 were correlated between paired leukocytes and breast tumor biopsies (r = 0.62; p = 0.001). Moreover, higher methylation was found in leukocytes from patients with obesity (p = 0.002) and postmenopausal patients (p = 0.022) than patients with normal-weight or premenopausal, respectively. After adjusting for the body mass index and age, higher levels of ZNF577 methylation were also found in women with greater adherence to the Mediterranean diet (p = 0.017) or specific foods. Relevantly, the methylation levels of ZNF577 showed a good ability for fish consumption detection [area under the ROC curve (AUC) = 0.72; p = 0.016]. In conclusion, the association between methylation of ZNF577 and adiposity, menopausal state, and adherence to the Mediterranean diet can be detected in the blood leukocytes. The results guarantee the need of performing further studies in longer longitudinal cohorts in order to elucidate the role of ZNF577 methylation in the association between breast cancer, adiposity and dietary patterns.

Objective: Women with polycystic ovary syndrome (PCOS) are characterized by insulin resistance and higher prevalence of obesity. Serum ferritin is increased in obesity and is associated with insulin resistance. The aim of the present study was to evaluate the relationships between serum ferritin concentration with insulin resistance and body composition estimated by dual-energy X-ray absorptiometry (DXA) in PCOS women in comparison to the control group. Patients and Methods: One hundred four women were enrolled to the study-65 women with PCOS and 39 women matched for age and BMI as a control group. Serum ferritin concentration and oral glucose tolerance test (OGTT) were performed. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. DXA was performed to estimate fat, fat-free mass, and visceral adipose tissue (VAT). Results: Women with PCOS have higher serum concentration of ferritin (p = 0.002), insulin at baseline (p = 0.03), at 60 min of OGTT (p = 0.01), at 120 min of OGTT (p = 0.004), HOMA-IR (p = 0.03), and VAT (p = 0.0001) in comparison to the control group. We observed a relationship of serum ferritin with insulin concentration at baseline (r = 0.25, p = 0.04) and at 120 min of OGTT (r = 0.31, p = 0.01) and with HOMA-IR (r = 0.30, p = 0.01) in the PCOS group. We noticed an association between serum ferritin concentration and VAT (r = 0.42, p = 0.001), trunk fat mass (r = 0.25, p = 0.04), and android fat mass (r = 0.25, p = 0.04) in the PCOS group. Multiple regression analysis revealed that ferritin (p = 0.02, β = 0.17), insulin at baseline (p = 0.001, β = 0.30), glucose at the 120 min of OGTT (p = 0.007, β = 0.26), and triglycerides (p = 0.001, β = 0.33) were independent predictors of VAT amount in PCOS women. Conclusions: Elevated serum ferritin concentration is connected with insulin resistance as well as with DXA-estimated VAT, android, and trunk fat mass in PCOS women, and could be a marker of metabolic dysfunction.

To investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D).

STATs (Signal Transducers and Activators of Transcription) 5A and 5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH) and prolactin in fat cells. Previous studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. Male and female mice harboring adipocyte-specific deletion of both STAT5 genes (STAT5AKO) exhibit increased subcutaneous or inguinal adipose tissue mass, but no changes in visceral or gonadal fat mass. Both depots display substantial increases in adipocyte size with no changes in lipolysis in adipose tissue explants. RNA sequencing analysis of subcutaneous adipose tissue and indirect calorimetry experiments reveal sex-dependent differences in adipose gene expression and whole-body energy expenditure, respectively, resulting from the loss of adipocyte STAT5.

Subcutaneous (sc) and visceral (vis) adipose tissue (AT) contribute to the variability in pathophysiological consequences of obesity and adverse fat distribution. To gain insights into the molecular mechanisms distinguishing vis and sc fat, we compared the transcriptome during differentiation of immortalized adipocytes from murine epididymal (epi) and inguinal (ing) AT. RNA was extracted on different days of adipogenesis (-2, 0, 2, 4, 6, 8) and analyzed using Clariom™ D mouse assays (Affymetrix) covering >214,900 transcripts in >66,100 genes. Transcript Time Course Analysis revealed 137 differentially expressed genes. The top genes with most divergent expression dynamics included developmental genes like Alx1, Lhx8, Irx1/2, Hoxc10, Hoxa5/10, and Tbx5/15. According to pathway analysis the majority of the genes were enriched in pathways related to AT development. Finally, in paired samples of human vis and sc AT (N = 63), several of these genes exhibited depot-specific variability in expression which correlated closely with body mass index and/or waist-to-hip ratio. In conclusion, intrinsically programmed differences in gene expression patterns during adipogenesis suggest that fat depot specific regulation of adipogenesis contributes to individual risk of obesity.

Bone marrow adipocytes (BMAds) constitute the most abundant stromal component of adult human bone marrow. Two subtypes of BMAds have been described, the more labile regulated adipocytes (rBMAds) and the more stable constitutive adipocytes (cBMAds), which develop earlier in life and are more resilient to environmental and metabolic disruptions. In vivo, rBMAds are enriched in saturated fatty acids, contain smaller lipid droplets (LDs) and more readily provide hematopoietic support than their cBMAd counterparts. Mouse models have been used for BMAds research, but isolation of primary BMAds presents many challenges, and thus in vitro models remain the current standard to study nuances of adipocyte differentiation. No in vitro model has yet been described for the study of rBMAds/cBMAds. Here, we present an in vitro model of BM adipogenesis with differential rBMAd and cBMAd-like characteristics. We used OP9 BM stromal cells derived from a (C57BL/6xC3H)F2-op/op mouse, which have been extensively characterized as feeder layer for hematopoiesis research. We observed similar canonical adipogenesis transcriptional signatures for spontaneously-differentiated (sOP9) and induced (iOP9) cultures, while fatty acid composition and desaturase expression of Scd1 and Fads2 differed at the population level. To resolve differences at the single adipocyte level we tested Raman microspectroscopy and show it constitutes a high-resolution method for studying adipogenesis in vitro in a label-free manner, with resolution to individual LDs. We found sOP9 adipocytes have lower unsaturation ratios, smaller LDs and higher hematopoietic support than iOP9 adipocytes, thus functionally resembling rBMAds, while iOP9 more closely resembled cBMAds. Validation in human primary samples confirmed a higher unsaturation ratio for lipids extracted from stable cBMAd-rich sites (femoral head upon hip-replacement surgery) versus labile rBMAds (iliac crest after chemotherapy). As a result, the 16:1/16:0 fatty acid unsaturation ratio, which was already shown to discriminate BMAd subtypes in rabbit and rat marrow, was validated to discriminate cBMAds from rBMAd in both the OP9 model in vitro system and in human samples. We expect our model will be useful for cBMAd and rBMAd studies, particularly where isolation of primary BMAds is a limiting step.