Intrauterine factors can impact fetal and child growth and may underlie the developmental origins of childhood obesity. Sex steroid hormone exposure during pregnancy is a plausible target because of the impact on placental vascularization, nutrient transportation, adipogenesis, and epigenetic modifications. In this study we assessed maternal sex steroid hormones in each trimester in relation to birthweight, neonatal adiposity, and infant growth trajectories, and evaluated sensitive windows of development.

Participants from a prospective pregnancy cohort who delivered at term were included in the analysis (n = 252). Estrone, estradiol, and estriol, as well as total and free testosterone throughout gestation were assessed using high-performance liquid chromatography and tandem mass spectrometry. Path analyses were used to assess the direct associations of sex steroid hormones in each trimester with birth outcomes and infant growth trajectories (birth to 12 months) adjusting for covariates and considering moderation by sex.

The associations between prenatal sex steroid hormones and fetal/infant growth varied by sex and timing of hormone exposure. First-trimester estrone was associated with higher birthweight z-scores (β = 0.37, 95% CI: 0.02, 0.73) and truncal skinfold thickness (TST) at birth (β = 0.94, 95% CI: 0.34, 1.54) in female infants. Third-trimester total testosterone was associated with higher TST at birth (β = 0.47, 95% CI: 0.03, 0.86) in both sexes. First-trimester estrone and estradiol and first- and third-trimester testosterone were associated with lower probabilities of high stable weight trajectory compared to low stable weight trajectory (Estrone: β = -3.87, 95% CI: -6.59, -1.16; Estradiol: β = -4.36, 95% CI: -7.62, -1.11; First-trimester testosterone: β = -3.53, 95% CI: -6.63, -0.43; Third-trimester testosterone: β = -3.67, 95% CI: -6.66, -0.69) during infancy in male infants.

We observed associations between prenatal sex steroid hormone exposure and birthweight, neonatal adiposity and infant growth that were sex and gestational timing dependent. Our findings suggest further investigation on additional mechanisms linking prenatal sex steroid exposure and fetal/postnatal growth is needed.

Polystyrene nanoplastics (PSNPs) have been recognized as emerging environmental pollutants with potential health impacts, particularly on metabolic disorders. However, the mechanism by which gestational exposure to PSNPs induces obesity in offspring remains unclear. This study, focused on the whitening of brown adipose tissue (BAT), aims to elucidate the fundamental mechanisms by which prenatal exposure to PSNPs promotes obesity development in mouse offspring.

Pregnant dams were subjected to various doses of PSNPs (0 µg/µL, 0.5 µg/µL, and 1 µg/µL), and their offspring were analyzed for alterations in body weight, adipose tissue morphology, thermogenesis, adipogenesis, and lipophagy. The findings revealed a notable reduction in birth weight and an increase in white adipocyte size in adult offspring mice. Notably, adult male mice exhibited BAT whitening, correlated with a negative dose-dependent downregulation of UCP1 expression, indicating thermogenesis dysfunction. Further investigation revealed augmented lipogenesis evidenced by the upregulation of FASN, SREBP-1c, CD36, and DGAT2 expression, coupled with the inhibition of lipophagy, indicated by elevated levels of mTOR, AKT, and p62 proteins and reduced levels of LC3II/LCI and Lamp2 proteins in male offspring.

These findings indicate that gestational PSNP exposure plays a role in the development of obesity in offspring through the whitening of brown adipose tissue, which is triggered by lipogenesis and lipophagy inhibition, providing a novel insight into the metabolic risks associated with gestational PSNPs exposure.

Although there is an interaction between sex, body fat distribution, and cardiac structure and function, these relationships have not been fully elucidated yet. This study aims to reveal the causal relationship between genetic determinants of fat distribution pattern and function of the left ventricular structure in different sexes.

Genetic variants for waist circumference, hip circumference, waist-to-hip ratio (WHR), and body mass index (BMI) were selected from genome-wide association studies conducted in European samples. The dataset for left ventricular (LV) parameters was obtained from over 35,000 European samples in the UK Biobank Cardiovascular Magnetic Resonance sub-study. Two-sample Mendelian randomization (MR) analysis was employed to explore causal relationships.

After adjusting for BMI, WHR shows a positive causal relationship with LV hypertrophy and a significant negative causal relationship with LV volume and diastolic function. In further subgroup analysis, we only found similar results in WHR among the female population (FWHR), while in the male population, there was no significant causal relationship between MWHR and LV hypertrophy and diastolic function. Additionally, in our MR analysis, no causal relationship was found between WHR and LVEF.

This study indicates that the fat distribution pattern has unique effects on the structure and function of the LV, and these effects vary by sex. This study provides evidence for a causal relationship between fat distribution and LV structure and function across both sexes.

Post-menopausal women experience more severe muscular fatty infiltration, though the mechanisms remain unclear. The decline in estrogen levels is considered as a critical physiological alteration during post-menopause. Fibro/adipogenic progenitors (FAPs) are identified as major contributors to muscular fatty infiltration. This study aimed to investigate the detailed mechanism underlying the excessive muscular fatty infiltration in postmenopausal females.

Supraspinatus muscle samples were collected from female patients with or without menopause, and from mice with or without ovariectomy (OVX), to evaluate muscular fatty infiltration and isolated FAPs. The expressions of (estrogen receptor 1) ESR1, methyltransferase-like 3 (METTL3), and adipogenesis ability in FAPs from post-menopausal women and OVX mice were investigated. RNA sequencing (RNA-Seq) was performed to explore the gene expression profiles and potential mechanisms in FAPs from Pdgfrα-CreERT2; Esr1 knockout (Esr1 KO) mice and Esr1 flox/flox (Esr1 f/f) mice. The interplay of the METTL3-ESR1 mediated loop and its role in regulating adipogenesis in FAPs were investigated using dual luciferase reporter assays, chromatin immunoprecipitation (ChIP), and protein and RNA stability assays. The effects of estrogen supplementation on muscular fatty infiltration and locomotor function in OVX mice were evaluated by immunofluorescent staining and functional analysis.

Decreased expression of ESR1/METTL3 and increased adipogenesis ability in FAPs was found in post-menopausal female. METTL3-mediated m6A methylation promoted ESR1 mRNA stability at the post-transcriptional level in FAPs. METTL3-mediated m6A modification promoted ESR1 expression by stabilizing ESR1 mRNA, while ESR1 acted as a transcription factor that enhanced METTL3 transcription in turn. ESR1 also suppressed the transcription of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), thereby inhibiting adipogenesis in FAPs. Reactivation of the METTL3-ESR1 mediated loop by estrogen alleviated excessive adipogenesis in FAPs from post-menopausal women, and it also reduced muscular fatty infiltration, and improved locomotor function in OVX mice.

Excessive muscular fatty infiltration in post-menopausal women arose from the disruption of the METTL3-ESR1 mediated loop of FAPs due to estrogen deficiency. Reactivation of the METTL3-ESR1 mediated loop by estrogen may serve as a novel intervention to inhibit excessive adipogenesis of post-menopausal female FAPs, thereby ameliorating muscular fatty infiltration and improving locomotor function in post-menopausal females.

Oestrogen insufficiency disrupted the METTL3ESR1 loop in post-menopausal FAPs, causing excessive muscular fatty infiltration. METTL3-mediated m6A modification stabilized ESR1 mRNA and enhanced ESR1 expression, while increased ESR1 further promoted METTL3 transcription. ESR1 inhibited the transcription of adipogenic factor PPARγ, ameliorating adipogenesis in FAPs. Reactivating the METTL3ESR1 loop via oestrogen in FAPs reduced muscular fatty infiltration and improved locomotor function.

Obesity, a major risk factor for cardiovascular disease (CVD), is associated with hypertension and vascular dysfunction. Perivascular adipose tissue (PVAT), a metabolically active tissue surrounding blood vessels, plays a key role in regulating vascular tone. In obesity, PVAT becomes dysregulated which may contribute to vascular dysfunction; how sex impacts the remodelling of PVAT and thus the altered vascular contractility during obesity is unclear.

To investigate sex-specific PVAT dysregulation in the setting of obesity as a potential driver of sex differences in vascular pathologies and CVD risk.

Adult male and female C57Bl/6J mice were fed an obesogenic high-fat diet (HFD) or regular chow for 16 weeks. Mesenteric PVAT (mPVAT) was isolated for RNA-sequencing and histological analysis, and mesenteric arteries were isolated for assessment of vascular function by wire myography. In a separate study, female mice were subjected to bilateral ovariectomy prior to dietary intervention to determine the contribution of ovarian hormones to PVAT dysregulation.

Transcriptomic analysis of mPVAT revealed sexually dimorphic responses to HFD, with upregulation of extracellular matrix (ECM) remodelling pathways in male but not female mice. Histological and RT-qPCR approaches demonstrated increased collagen deposition and ECM remodelling in mPVAT from obese male compared with obese female mice. Assessment of vascular function in mesenteric arteries -/+ PVAT revealed that in obesity, mPVAT impaired endothelium-mediated vasodilation in male but not female mice. Ovariectomy of female mice prior to HFD administration did not alter ECM transcript expression or collagen deposition in mPVAT compared to sham-operated female mice.

Obesity induces sex-specific molecular remodelling in mPVAT, with male mice exhibiting unique upregulation of ECM pathways and increased collagen deposition compared to females. Moreover, the relative protection of female mice from obesity-induced mPVAT dysregulation is not mediated by ovarian hormones. These data highlight a potential sex-specific mechanistic link between mPVAT and mesenteric artery dysfunction in obesity, and provides crucial insights for future development of treatment strategies that consider the unique cardiovascular risks in men and women.

Osteoporosis and obesity are prevalent diseases in menopause. The phytoestrogen genistein (Gen) is an antioxidant/anti-inflammatory agent proposed as natural therapy to counteract syndromes associated to menopause. In this work we evaluated the bone effect of Gen in a stress environment induced by hypoestrogenism and obesity. Bilaterally ovariectomized female Wistar rats were fed with high-fat diet (obese), or standard diet (non-obese). Osteoblasts (OB) primary cultures from femoral shafts, and retroperitoneal explants of white adipose tissue (WAT) in vitro exposed to Gen were employed as experimental systems. In obese rats, bone oxidative stress revealed by enhancement on H2O2 release, and significant reduction in OB nitric oxide (NO) production, cell growth, alkaline phosphatase activity (ALP), matrix mineralization and collagen deposition was detected. In OB-WAT co-cultures, Gen treatment inhibited H2O2 secretion, and prompted OB differentiation. A direct action of Gen on WAT was demonstrated. The phytoestrogen inhibited H2O2 and TBARS production, and diminished the secretion of the inflammatory adipokine leptin, through a mechanism of action mediated by estrogen receptor (ER) involvement, and MAPK and PI3K signal transduction pathways participation. A directional interaction from WAT to bone was evidenced by the incubation OB with conditioned medium obtained from WAT exposed to Gen (Gen-CM). The presence of Gen-CM improved OB growth, and reduced H2O2 production. The antioxidative effect of Gen on obese bone cells was partially dependent on its ability to reduce leptin secretion by WAT. Altogether, the results suggest that, under obesity, Gen may improve bone metabolism through a direct action on WAT.

Despite the recognized role of visceral adipose tissue in carcinogenesis, its independent association with cancer risk beyond traditional obesity measures remains unknown because of limited availability of imaging data.

We developed an estimation equation for visceral adipose tissue volume using elastic net regression based on demographic and anthropometric data in a subcohort of participants in the UK Biobank (UKB; n = 23 148) with abdominal magnetic resonance imaging scans. This equation was externally validated in 2713 participants from the 2017-2018 National Health and Nutrition Examination Survey according to sex, age, and race groups. We then applied the equation to the overall UKB cohort of 461 665 participants to evaluate the prospective association between estimated visceral adipose tissue and cancer risk using Cox proportional hazards models. We also calculated the population attributable risk of cancer associated with estimated visceral adipose tissue and body mass index (BMI).

Estimated visceral adipose tissue showed a high correlation with measured visceral adipose tissue in internal and external validations (r = 0.81-0.86). During a median 12-year follow-up in the UKB, we documented 37 397 incident cancer cases; estimated visceral adipose tissue was statistically significantly associated with elevated risk of obesity-related and individual cancers, independent of BMI and waist circumference. Population attributable risk for total cancer associated with high (quartiles 2-4 vs 1) estimated visceral adipose tissue (9.0% for men, 11.6% for women) was higher than high BMI (quartiles 2-4 vs 1 = 5.0% for men, 8.2% for women).

Estimated visceral adipose tissue showed robust performance in UKB and National Health and Nutrition Examination Survey and was associated with cancer risk independent of BMI and waist circumference. This study provides a potential clinical tool for visceral adipose tissue estimation and underscores that visceral adipose tissue can be an important target for cancer prevention.

Obesity, characterized by excessive fat accumulation in white adipose tissue (WAT), is linked to numerous health issues, including insulin resistance (IR), and type 2 diabetes mellitus (DM2). The distribution of adipose tissue differs by sex, with men typically exhibiting android adiposity and pre-menopausal women displaying gynecoid adiposity. After menopause, women have an increased risk of developing android-type obesity, IR, and DM2. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are important in treating obesity and DM2 by regulating insulin secretion, impacting glucose and lipid metabolism. GLP-1Rs are found in various tissues including the pancreas, brain, and adipose tissue. Studies suggest GLP-1RAs and estrogen replacement therapies have similar effects on tissues like the liver, central nervous system, and WAT, probably by converging pathways involving protein kinases. To investigate these interactions, female rats underwent ovariectomy (OVR) to promote a state of estrogen deficiency. After 20 days, the rats were euthanized and the tissues were incubated with 10 μM of liraglutide, a GLP-1RA. Results showed significant changes in metabolic parameters: OVR increased lipid catabolism in perirenal WAT and basal lipolysis in subcutaneous WAT, while liraglutide treatment enhanced stimulated lipolysis in subcutaneous WAT. Liver responses included increased stimulated lipolysis with liraglutide. Transcriptome analysis revealed distinct gene expression patterns in WAT of OVR rats and those treated with GLP-1RA, highlighting pathways related to lipid and glucose metabolism. Functional enrichment analysis showed estrogen's pivotal role in these pathways, influencing genes involved in lipid metabolism regulation. Overall, the study underscores GLP-1RA acting directly on adipose tissues and highlights the complex interactions between GLP-1 and estrogen in regulating metabolism, suggesting potential synergistic therapeutic effects in treating metabolic disorders like obesity and DM2.

Metaflammation is low-grade inflammation triggered by chronic metabolic imbalance and caused by dysregulated metabolites in metabolic inflammatory syndrome (MIS), which includes four diseases: obesity, type 2 diabetes mellitus (T2DM), atherosclerosis (AS), and nonalcoholic fatty liver diseases (NAFLD, recently proposed to be replaced by metabolic dysfunction-associated steatotic liver disease, MASLD). These diseases exhibit apparent sex dimorphism as regards MIS. Estrogen not only plays a crucial role in gender differences in adults but also possesses an anti-inflammatory effect on many metabolic diseases. In this study, we present a prediction of the differential proteins and signal transduction of estrogen in MIS through network pharmacology and review the validated studies on obesity, T2DM, AS, and NAFLD. Subsequently, we compared them to obtain valuable targets, identify current gaps, and provide perspectives for future research on the mechanisms of estrogen in metaflammation.

Visceral adipose tissue, a type of abdominal adipose tissue, is highly involved in lipolysis. Because increased visceral adiposity is strongly associated with the metabolic complications related with obesity, such as type 2 diabetes and cardiovascular disease, there is a need for precise, targeted, personalized and site-specific measures clinically. Existing studies showed that ectopic fat accumulation may be characterized differently among different populations due to complex genetic architecture and non-genetic or epigenetic components, ie, Asians have more and Africans have less visceral fat vs Europeans. In this review, we summarize the effects of multiple non-genetic and genetic factors on visceral fat distribution across races. Non-genetic factors include diet, socioeconomic status, sex hormones and psychological factors, etc. We examine genetic factors of racial differences in visceral fat content as well as possible regulatory pathways associated with interracial visceral fat distribution. A comprehensive understanding of both genetic and non-genetic factors that influence the distribution of visceral fat among races, leads us to predict risk of abdominal obesity and metabolic diseases in ethnic groups that enables targeted interventions through accurate diagnosis and treatment as well as reduced risk of obesity-associated complications.

Shaofu Zhuyu decoction has been widely used to treat gynecological diseases; however, its mechanism of action in endometriosis remains unclear. We analyzed Shaofu Zhuyu decoction's chemical composition using ultra-high performance liquid chromatography-mass spectrometry. In an endometriosis mouse model, ectopic lesions weight measurements and hematoxylin and eosin staining were used to assess the therapeutic efficacy of Shaofu Zhuyu decoction. Effects on intestinal microflora were analyzed using 16S ribosomal ribonucleic acid sequencing, and impacts on focal fibrosis were analyzed using Masson's trichrome staining. Moreover, fibrosis- and metabolism-related proteins were assessed using immunohistochemistry and enzyme-linked immunosorbent assay. The study identified 157 chemical constituents within Shaofu Zhuyu decoction. Shaofu Zhuyu decoction treatment in mice with endometriosis resulted in a reduction in ectopic lesions weight (P < 0.05) and delayed disease progression. Moreover, it improved the diversity and abundance of intestinal flora, and decreased the expression of Lachnospiraceae (P < 0.05), Rikenellaceae (P < 0.01), Ruminococcaceae (P < 0.01), Lachnoclostridium (P < 0.05), and unclassified_f__Ruminococcaceae (P < 0.05). Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment in carbohydrate, amino acid, and lipid metabolism pathways. Masson's trichrome staining revealed that compared to the untreated group, the Shaofu Zhuyu decoction group exhibited significantly reduced collagen deposition areas (P < 0.001), lower TGF-β1 (P < 0.001), COL1A1 (P < 0.05), and α-SMA (P < 0.01) expression in ectopic lesions, along with increased serum adiponectin (P < 0.05), decreased serum TGF-β1 (P < 0.001), and CTGF (P < 0.05). Shaofu Zhuyu decoction regulates the intestinal flora of mice with endometriosis while also reducing fibrosis at the lesion site. These findings highlight novel mechanisms for its efficacy in alleviating endometriosis.

Metabolic disorders and overweight or obesity are highly prevalent and intricately linked in patients with chronic heart failure (CHF). However, it remains unclear whether there is an interactive effect between these conditions and the prognosis of heart failure, and whether such an interaction is influenced by stratification based on age and sex.

A total of 4,955 patients with CHF were enrolled in this study. Metabolic status was assessed according to the presence or absence of metabolic syndrome (MetS). BMI categories included normal weight and overweight or obesity (BMI < 24, ≥ 24 kg/m2). Patients were divided into four phenotypes according to their metabolic status and BMI: metabolically healthy with normal weight (MHNW), metabolically unhealthy with normal weight (MUNW), metabolically healthy with overweight or obesity (MHO), and metabolically unhealthy with overweight or obesity (MUO). The incidence of primary outcomes, including all-cause and cardiovascular (CV) death, was recorded.

During a mean follow-up of 3.14 years, a total of 1,388 (28.0%) all-cause deaths and 815 (16.4%) CV deaths were documented. Compared to patients with the MHNW phenotype, those with the MUNW (adjusted hazard ratio [aHR], 1.66; 95% confidence interval [CI], 1.38-2.00) or MUO (aHR, 1.42 [95% CI, 1.24-1.63]) phenotypes had a greater risk of all-cause death, and those with the MHO phenotype (aHR, 0.61 [95% CI, 0.51-0.72]) had a lower risk of all-cause death. Moreover, the above phenomenon existed mainly among males and elderly females (aged ≥ 60 years). In nonelderly females (aged < 60 years), the detrimental effects of MetS were lower (aHR, 1.05 [95% CI, 0.63-1.75] among MUNW group and aHR, 0.52 [95% CI, 0.34-0.80] among MUO group), whereas the protective effects of having overweight or obesity persisted irrespective of metabolic status (aHR, 0.43 [95% CI, 0.26-0.69] among MHO group and aHR, 0.52 [95% CI, 0.34-0.80] among MUO group). Similar results were obtained in the Cox proportional risk analysis of the metabolic overweight/obesity phenotypes and CV death.

In male and elderly female patients with CHF, the detrimental effects of MetS outweighed the protective benefits of having overweight or obesity. Conversely, in nonelderly females, the protective effects of having overweight or obesity were significantly greater than the adverse impacts of MetS.

Metabolic syndrome (MetS) has complex effects on bone health, and dual-energy spectral computed tomography (CT) has become increasingly valuable for bone quantification. However, the relationship between bone base material pairs (BMPs) and abdominal fat volume in patients with MetS remains underexplored. This study thus aimed to analyze the relationship between abdominal fat volume and various bone BMPs using dual-energy spectral CT in young and middle-aged patients with MetS.

Patients with MetS who underwent sleeve gastrectomy at the Center of Obesity and Metabolic Diseases, Beijing Shijitan Hospital, Capital Medical University, from June to November 2021 were retrospectively collected. The abdominal fat measurements and BMPs were acquired using dual-energy spectral CT imaging. These included the volumes of total abdominal fat (TAF), abdominal visceral fat (AVF), and abdominal subcutaneous fat (ASF), as well as bone densities based on hydroxyapatite (water), i.e., HAP (water), and calcium (water), i.e., Ca (water), BMPs. After grouping the patients by sex, we analyzed the differences in clinical and imaging features. The correlation between the clinical and imaging parameters of patients with MetS was evaluated with Pearson correlation coefficients. Age- and sex-adjusted partial correlation analysis between fat volume and bone BMPs was conducted for patients of different sexes. Additionally, multiple linear regression analyses were performed with age, sex, and TAF volume as the independent variables and with Ca (water) and HAP (water) as dependent variables.

A total of 112 young and middle-aged patients with MetS were included in this study, including 85 females and 27 males. Compared to male patients with MetS, the females with MetS exhibited higher lumbar Ca (water) and HAP (water) BMPs, with lower volumes of TAF and AVF and a smaller abdominal circumference (P<0.01). The volumes of TAF, AVF, and ASF were negatively correlated with the average Ca (water) and HAP (water) BMPs in the first to third lumbar vertebrae (L1-L3) (P<0.05). Ca (water) and HAP (water) BMPs decreased with age and increasing TAF volume (P<0.001). The fitted equations for the relationship between bone BMPs with age, sex, and TAF volume were as follows: (I) bone Ca (water) BMP = 76.469 - 0.500 age + 6.762 sex - 0.002 TAF volume; (II) bone HAP (water) BMP =171.704 - 1.138 age + 11.825 sex - 0.004 TAF volume.

In young and middle-aged patients with MetS, the abdominal fat volume was negatively correlated with lumbar bone Ca (water) and HAP (water) BMPs, implying that increased abdominal fat volume may play a crucial role in the pathogenesis of osteopenia among those with MetS. The reduction of bone Ca (water) and HAP (water) with high abdominal fat volume may hold clinical significance for fracture risk in individuals with MetS.

The pharmacological effects of pomegranates have been described considering metabolic aspects such as hypoglycemic and hypolipidemic activities. The pomegranate extract has activity on the central nervous system (CNS) as a natural antidepressant and anxiolytic. The chemical composition of pomegranates is complex since the bioactive compounds are multiple secondary metabolites that have been identified in the extracts derived from the peel, seed, flowers, leaves, or in their combination; so, it has not been easy to identify an individual compound as responsible for its observed pharmacological properties. From this point of view, the present review analyzes the effects of crude extracts or fractions of pomegranates and their possible mechanisms of action concerning antidepressant- and anxiolytic-like effects in animal models. Serotonin receptors, estrogen receptors, the peroxisome proliferator-activated receptor gamma (PPARγ), or monoamine oxidase enzymes, as well as potent antioxidant and neuroplasticity properties, have been described as possible mediators involved in the antidepressant- and anxiolytic-like behaviors after pomegranate treatment. The pharmacological effects observed on the CNS in experimental models associated with a specific stress level suggest that pomegranates could simultaneously modulate the stress response by activating several targets. For the present review, scientific evidence was gathered to integrate it and suggest a possible pathway for mediators to be involved in the mechanisms of action of the pomegranate's antidepressant- and anxiolytic-like effects. Furthermore, the potential benefits are discussed on comorbid conditions with anxiety and depression, such as perimenopause transition and pain.

The decline in estrogen during menopause contributes to a variety of menopausal symptoms, for which hormone replacement therapy (HRT) has been extensively applied. Regarding side effects and limited effectiveness of HRT for specific individuals, there is a growing interest in safe alternatives such as phytoestrogens which are structurally analogous to estrogens. This study aims to investigate the efficacy of yam and gromwell extracts, rich in bioactive compounds, and the synergistic effect of extracts on symptoms induced by estrogen deficiency in ovariectomized (OVX) mice.

OVX mice receive dietary intervention of either yam, gromwell extract, or their mixture for 14 weeks. Sham-operated mice and E2-injected OVX mice serve as positive controls. Following 14 weeks of oral administration, blood, adipose tissue, vagina, uterus, femurs, and tibias are harvested for further investigation. Consequently, yam and gromwell extracts ameliorate menopausal conditions such as weight gain, glucose intolerance, dyslipidemia, and osteoporosis in estrogen-deficient OVX mice. In addition, the mixture of yam and gromwell extracts synergistically aids in the relief of the indications.

These results indicate the potential use of yam and gromwell extracts, as well as their mixture, for the development of healthy functional foods to modulate menopausal symptoms.

Visceral fat accumulation and obesity-induced chronic inflammation have been proposed as early markers for multiple disease states, especially in women. Nevertheless, the potential impact of fat distribution on α1-acid glycoprotein(AGP), a marker of inflammation, remains unclear. This research was conducted to investigate the relationships among obesity, fat distribution, and AGP levels.

A cross-sectional observational study was performed using blood samples from adult females recruited through the National Health and Nutrition Examination Survey from 2015 to 2018. Serum levels of AGP were measured using the Tina-quant α-1-Acid Glycoprotein Gen.2 assay. Based on the fat distribution data obtained from dual-energy X-ray absorptiometry assessments, body mass index (BMI), total percent fat (TPF), android percent fat (APF), gynoid percent fat (GPF), android fat/gynoid fat ratio (AGR), visceral percent fat (VPF), subcutaneous percent fat (SPF), visceral fat/subcutaneous fat ratio (VSR) were used as dependent variables. To investigate the link between fat distribution and AGP, multivariate linear regression analysis was utilized. Furthermore, a sensitivity analysis was also performed.

The present study included 2,295 participants. After adjusting for covariates, BMI, TPF, APF, GPF, VPF, and SPF were found to be positively correlated with AGP levels (BMI: β = 23.65 95%CI:20.90-26.40; TPF: β = 25.91 95%CI:23.02-28.80; APF: β = 25.21 95%CI:22.49-27.93; GPF: β = 19.65 95%CI:16.96-22.34; VPF: β = 12.49 95%CI:9.08-15.90; SPF: β = 5.69, 95%CI:2.89-8.49; AGR: β = 21.14 95%CI:18.16-24.12; VSR: β = 9.35 95%CI:6.11-12.59, all P < 0.0001). All the above indicators exhibited a positive dose-response relationship with AGP. In terms of fat distribution, both AGR and VSR showed positive associations with AGP (P for trend < 0.0001). In particular, when compared to individuals in tertile 1 of AGR, participants in tertiles 2 and 3 had 13.42 mg/dL (95% CI 10.66-16.18) and 21.14 mg/dL (95% CI 18.16-24.12) higher AGP levels, respectively. Participants in the highest tertile of VSR were more likely to exhibit a 9.35 mg/dL increase in AGP compared to those in the lowest tertile (95% CI 6.11-12.59).

Overall, this study revealed a positive dose-dependent relationship between fat proportion/distribution and AGP levels in women. These findings suggest that physicians can associate abnormal serum AGP and obesity with allow timely interventions.

Perivascular adipose tissue (PVAT) regulates vascular function due to its capacity to synthesize vasoactive products and its mechanical properties. PVATs most abundant cells are adipocytes, and their populations are maintained by the maturation of adipocyte progenitor cells (APC), which may play a pivotal role in the pathogenesis of cardiovascular diseases. However, the distribution of APC within PVAT depots, their potential variation in spatial location, and the influence of sex and age on their abundance remain unknown. We hypothesize that APC abundance in PVAT is affected by location, age, sex and that APC subtypes have specific spatial distributions. PVAT from thoracic and abdominal aorta, and mesenteric arteries, and AT from interscapular, gonadal, and subcutaneous depots from 13-week and 30-week-old females and males Pdgfrα-CreERT2 x LSL-tdTomato mice (n = 28) were analyzed. Abdominal aorta PVAT had fewer progenitors than mesenteric PVAT and gonadal AT. Aging reduced the abundance of APC in the thoracic aorta but increased their numbers in mesenteric PVAT. Females had more APC than males in mesenteric PVAT and gonadal AT depots. APC exhibited unique spatial distribution in the aorta and mesenteric PVAT where they localized neighboring vasa vasorum and arteries. APC subtypes (APC1, APC2, APC3, diff APC) were identified in all PVAT depots. Thoracic aorta PVAT APC3 were located in the adventitia while diff APC were in the parenchyma. This study identified variability in APC populations based on depot, age, and sex. The distinctive spatial distribution and the presence of diverse APC subtypes suggest that they may contribute differently to cardiovascular diseases-induced PVAT remodeling.

Oestradiol withdrawal at menopause predisposes women to metabolic syndrome, a cluster of interrelated conditions including obesity, insulin resistance, dyslipidaemia and hypertension that together confer an increased risk of developing type 2 diabetes mellitus and cardiovascular disease. Hormone replacement therapies are commonly used to treat acute symptoms of the perimenopausal period, and whilst they have been associated with metabolic improvements in many studies, long-term use is considered unviable. Novel approaches are required to mitigate the risk of postmenopausal metabolic syndrome. In 2012, the exercise-inducible myokine irisin was isolated from the skeletal muscle of mice and identified to have anti-obesity and antidiabetic effects in vivo. Irisin is now recognised to exert pleiotropic action on cognitive, bone and metabolic health. There is accumulating evidence from in vitro and in vivo rodent studies that irisin can mitigate each component condition of metabolic syndrome. In postmenopausal women, independent associations have been observed between (a) exercise and plasma irisin concentration and (b) plasma irisin concentration and reduced incidence of metabolic syndrome. To date, however, no study has considered the mechanistic basis by which irisin, whether exercise-induced or exogenously administered, could reduce the incidence or severity of metabolic syndrome in postmenopausal women. This review aims to analyse the literature concerning the metabolic actions of irisin, with a focus on its therapeutic potential for metabolic syndrome driven by a state of oestradiol depletion. It evaluates the practicality of exercise as a therapy and discusses other irisin-based therapeutic strategies that may alleviate postmenopausal metabolic syndrome. Finally, it highlights areas where future research is required to advance knowledge of irisin's biological action such that it could be considered a viable candidate for clinical application.

Osteoporosis is a common bone metabolic disease that causes a heavy social burden and seriously threatens life. Improving osteogenic capacity is necessary to correct bone mass loss in the treatment of osteoporosis. Osteoblasts are derived from the differentiation of bone marrow mesenchymal stem cells, a process that opposes adipogenic differentiation. The peroxisome proliferator‑activated receptor γ and Wnt/β‑catenin signaling pathways mediate the mutual regulation of osteogenesis and adipogenesis. Lipid substances play an important role in the occurrence and development of osteoporosis. The content and proportion of lipids modulate the activity of immunocytes, mainly macrophages, and the secretion of inflammatory factors, such as IL‑1, IL‑6 and TNF‑α. These inflammatory effectors increase the activity and promote the differentiation of osteoclasts, which leads to bone imbalance and stronger bone resorption. Obesity also decreases the activity of antioxidases and leads to oxidative stress, thereby inhibiting osteogenesis. The present review starts by examining the bidirectional differentiation of BM‑MSCs, describes in detail the mechanism by which lipids affect bone metabolism, and discusses the regulatory role of inflammation and oxidative stress in this process. The review concludes that a reasonable adjustment of the content and proportion of lipids, and the alleviation of inflammatory storms and oxidative damage induced by lipid imbalances, will improve bone mass and treat osteoporosis.

This study investigated whether epigenetic age acceleration (AA) is associated with the change in cognitive function and the risk of incident dementia over 9 years, separately in males and females.

Six epigenetic AA measures, including GrimAge, were estimated in baseline blood samples from 560 Australians aged ≥70 years (50.7% female). Cognitive assessments included global function, episodic memory, executive function, and psychomotor speed. Composite cognitive scores were also generated. Dementia (Diagnostic and Statistical Manual for Mental Disorders - IV [DSM-IV] criteria) was adjudicated by international experts.

Associations between epigenetic AA and cognitive performance over-time varied by sex. In females only, GrimAA/Grim2AA was associated with worse delayed recall, composite cognition, and composite memory (adjusted-beta ranged from -0.1372 to -0.2034). In males only, GrimAA/Grim2AA was associated with slower processing speed (adjusted-beta, -0.3049) and increased dementia risk (adjusted hazard ratios [HRs], 1.78 and 2.00, respectively).

Epigenetic AA is associated with cognitive deterioration in later life but with evidence of sex-specific associations.

Epigenetic age acceleration was associated with cognitive deterioration over time.However, these associations differed by sex.In females, accelerated GrimAge appeared to be a better marker of decline in memory.In males, accelerated GrimAge was associated with slower processing speed over time.Association between accelerated GrimAge and dementia risk was found only in males.

Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes. Estrogen [17β-estradiol (E2)] is known to offer protection against obesity via diverse me-chanisms, while its specific effects on visceral adipose tissue (VAT) remain to be fully elucidated.

To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes.

Metabolic parameters were collected, encompassing body weight, weights of visceral and subcutaneous adipose tissues (VAT and SAT), random blood glucose levels, glucose tolerance, insulin tolerance, and overall body composition. The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software. Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively.

Feeding a high-fat diet (HFD) moderately increased the weights of both VAT and SAT, but this increase was mitigated by the protective effect of endogenous E2. Conversely, ovariectomy (OVX) led to a significant increase in VAT weight and the VAT/SAT weight ratio, and this increase was also reversed with E2 treatment. Notably, OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone, signaling a widespread reduction in lipid metabolic activity, which was completely counteracted by E2 administration. This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level.

In conclusion, the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat, leading to a universally decreased lipid metabolic status in E2 deficient mice. E2 treatment effectively reversed this condition, shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

White adipose tissue (WAT) requires extracellular Ca2+ influx for lipolysis, differentiation, and expansion. This partly occurs via plasma membrane Ca2+ voltage-dependent channels (CaVs). However, WFA exists in different depots whose function varies with age, sex, and location. To explore whether their CaV expression profiles also differ we used RNAseq and qPCR on gonadal, mesenteric, retroperitoneal, and inguinal subcutaneous fat depots from rats of different ages and sex. CaV expression was found dependent on age, sex, and WFA location. In the gonadal depots of both sexes a significantly lower expression of CaV1.2 and CaV1.3 was seen for adults compared to pre-pubescent juveniles. A lower level of expression was also seen for CaV3.1 in adult male but not female gonadal WFA, the latter of whose expression remained unchanged with age. Relatively little expression of CaV3.2 and 3.2 was observed. In post-pubescent inguinal subcutaneous fat, where the third and fourth mammary glands are located, CaV3.1 was decreased in males but increased in females - thus suggesting that this channel is associated with mammogenesis; however, no difference in intracellular Ca2+ levels or adipocyte size were noted. For all adult depots, CaV3.1 expression was larger in females than males - a difference not seen in pre-pubescent rats. These observations are consistent with the changes of CaV3.1 expression seen in 3T3-L1 cell differentiation and the ability of selective CaV3.1 antagonists to inhibit adipogensis. Our results show that changes in CaV expression patterns occur in fat depots related to sexual dimorphism: reproductive tracts and mammogenesis.

In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors.

Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways.

1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation.

Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages.

In this review, we delve into the intricate relationship between white adipose tissue (WAT) remodeling and metabolic aspects in obesity, with a specific focus on individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). WAT is a highly heterogeneous, plastic, and dynamically secreting endocrine and immune organ. WAT remodeling plays a crucial role in metabolic health, involving expansion mode, microenvironment, phenotype, and distribution. In individuals with MHO, WAT remodeling is beneficial, reducing ectopic fat deposition and insulin resistance (IR) through mechanisms like increased adipocyte hyperplasia, anti-inflammatory microenvironment, appropriate extracellular matrix (ECM) remodeling, appropriate vascularization, enhanced WAT browning, and subcutaneous adipose tissue (SWAT) deposition. Conversely, for those with MUO, WAT remodeling leads to ectopic fat deposition and IR, causing metabolic dysregulation. This process involves adipocyte hypertrophy, disrupted vascularization, heightened pro-inflammatory microenvironment, enhanced brown adipose tissue (BAT) whitening, and accumulation of visceral adipose tissue (VWAT) deposition. The review underscores the pivotal importance of intervening in WAT remodeling to hinder the transition from MHO to MUO. This insight is valuable for tailoring personalized and effective management strategies for patients with obesity in clinical practice.

For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45-50 years of age) and it is mainly in the past several hundred years that the lifespan has been extended to >75 years, primarily due to public health advances, medical interventions, antibiotics, and nutrition. Therefore, the underlying biological mechanisms responsible for disease risk following menopause must have evolved during the complex processes leading to Homo sapiens to serve functions in the pre-menopausal state. Furthermore, as a primary function for the survival of the species is effective reproduction, it is likely that most of the advantages of having such post-menopausal risks relate to reproduction and the ability to address environmental stresses. This opinion/perspective will be discussed in the context of how such post-menopausal risks could enhance reproduction, with improved survival of offspring, and perhaps why such risks are preserved. Not all post-menopausal females exhibit risk for this set of diseases, and those who do develop such diseases do not have all of the conditions. The diseases of the post-menopausal state do not operate as a unified complex, but as independent variables, with the potential for some overlap. The how and why there would be such heterogeneity if the risk factors serve essential functions during the reproductive years is also discussed and the concept of sets of reversible epigenetic changes associated with puberty, pregnancy, and lactation is offered to explain the observations regarding the distribution of post-menopausal conditions and their potential roles in reproduction. While the involvement of an epigenetic system with a dynamic "modification-demodification-remodification" paradigm contributing to disease risk is a hypothesis at this point, validation of it could lead to a better understanding of post-menopausal disease risk in the context of reproduction with commonalities may also lead to future improved interventions to control such risk after menopause.

The human gut microbiota regulates estrogen metabolism through the "estrobolome," the collection of bacterial genes that encode enzymes like β-glucuronidases and β-glucosidases. These enzymes deconjugate and reactivate estrogen, influencing circulating levels. The estrobolome mediates the enterohepatic circulation and bioavailability of estrogen. Alterations in gut microbiota composition and estrobolome function have been associated with estrogen-related diseases like breast cancer, enometrial cancer, and polycystic ovarian syndrome (PCOS). This is likely due to dysregulated estrogen signaling partly contributed by the microbial impacts on estrogen metabolism. Dietary phytoestrogens also undergo bacterial metabolism into active metabolites like equol, which binds estrogen receptors and exhibits higher estrogenic potency than its precursor daidzein. However, the ability to produce equol varies across populations, depending on the presence of specific gut microbes. Characterizing the estrobolome and equol-producing genes across populations can provide microbiome-based biomarkers. Further research is needed to investigate specific components of the estrobolome, phytoestrogen-microbiota interactions, and mechanisms linking dysbiosis to estrogen-related pathology. However, current evidence suggests that the gut microbiota is an integral regulator of estrogen status with clinical relevance to women's health and hormonal disorders.

The weight-adjusted-waist index (WWI) is a novel obesity index, and gallstones are associated with obesity. This study aimed to investigate the possible relationship between WWI and gallstones.

The datasets from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were used in a cross-sectional investigation. Multivariate linear regression models were used to examine the linear connection between WWI and gallstones incidence. Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationship.

The study comprised 8004 participants over the age of 20, including 833 reported with gallstones. Participants in the higher WWI tertile tended to have a higher gallstones prevalence. In the final adjusted model, a positive association between WWI and gallstones prevalence was observed (OR = 1.34, 95% CI: 1.20‒1.49). Participants in the highest WWI tertile had a significantly 71% higher risk of gallstones than those in the lowest WWI tertile (OR = 1.71, 95% CI: 1.35‒2.17). A nonlinear correlation was found between the WWI and gallstones prevalence, with an inflection point of 12.7.

Our study found that higher WWI levels connected with increased prevalence of gallstones. However, more prospective studies are needed to validate our findings.

Thermogenic activation via trans-and de novo browning of white adipocytes is a promising strategy to accelerate lipid metabolism for regulating obesity-related disorders. In this study, we investigated the intricate interplay between angiogenic regulation and browning in white adipocytes using the bioactive compound, resveratrol (Rsv). Rsv has previously been documented for its regulatory influence on the trans and de novo browning of white adipocytes. Our findings revealed that concurrent activation of angiogenesis is prerequisite for inducing browning within the microenvironment of white adipocytes when exposed to browning activators. Additionally, we observed a significant browning effect on white adipocytes when the local adipose tissue environment was prompted to undergo angiogenesis, notably facilitated by a proangiogenic molecule known as Vascular endothelial growth factor (VEGF). Intriguingly, this effect was reversed when angiogenesis was inhibited by treatment with the antiangiogenic agent thalidomide. Furthermore, the study revealed the role of VEGF in paracrine activation of white adipocytes resulting in the induction of browning in both 3T3-L1 cell lines and primary mouse white adipocytes. The cross-talk between angiogenesis and browning was found to be initiated via the transcriptional activation of Estrogen receptor α (ERα) triggering the VEGF/VEGFR2 signaling pathway leading to browning and a reconfiguration of lipid metabolism within adipocytes. In conclusion, this study sheds light on the intricate cross-talk between angiogenesis and browning of white adipocytes. Notably, the findings underscore the reciprocal relationship between these processes, wherein inhibition of one process exerts discernible effects on the other.

Male breast cancer (MBC) represents a rare subtype of breast cancer, with limited prognostic factor studies available. The purpose of this research was to develop a unique nomogram for predicting MBC patient overall survival (OS) and breast cancer-specific survival (BCSS).

From 2010 to 2020, clinical characteristics of male breast cancer patients were obtained from the Surveillance, Epidemiology and End Results (SEER) database. Following univariate and multivariate analyses, nomograms for OS and BCSS were created. Kaplan-Meier plots were further generated to illustrate the relationship between independent risk variables and survival. The nomogram's ability to discriminate was measured by employing the area under a time-dependent receiver operating characteristic curve (AUC) and calibration curves. Additionally, when the nomogram was used to direct clinical practice, we also used decision curve analysis (DCA) to evaluate the clinical usefulness and net clinical benefits.

A total of 2143 patients were included in this research. Univariate and multivariate analysis showed that age, grade, surgery, chemotherapy status, brain metastasis status, subtype, marital status, race, and AJCC-T, AJCC-N, and AJCC-M stages were significantly correlated with OS. Lung metastasis, age, marital status, grade, surgery, and AJCC-T, AJCC-N, and AJCC-M stages were significantly correlated with BCSS. By comprising these variables, a predictive nomogram was constructed in the SEER cohort. Then, it could be validated well in the validation cohort by receiver operating characteristics (ROCs) curve and calibration plot. Furthermore, the nomogram demonstrated better decision curve analysis (DCA) results, indicating the ability to forecast survival probability with greater accuracy.

We created and validated a unique nomogram that can assist clinicians in identifying MBC patients at high risk and forecasting their OS/BCSS.

Estrogens are classically considered essential hormonal signals, but they exert profound effects in a number of physiological and pathological states, including glucose homeostasis and insulin resistance. Estrogen deficiency after menopause in most women leads to increased androgenicity and changes in body composition, and it is recommended to manipulate the β-cell function of the pancreas, insulin-induced glucose transport, and hepatic glucose output, hence, the increasing incidence of type 2 diabetes mellitus. Recently, studies have reported that gut biota alteration due to estrogen deficiency contributes to altered energy metabolism and, hence, accentuates the pathology of diabetes mellitus. Emerging research suggests estrogen deficiency via genetic disposition or failure of ovaries to function in old age modulates the insulin resistance and glucose secretion workload on pancreatic beta cells by decreasing the levels of good bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Lactobacillus spp., Faecalibacterium prausnitzii, Roseburia spp., and Prevotella spp., and increasing the levels of bad bacteria's such as Bacteroides spp., Clostridium difficile, Escherichia coli, and Enterococcus spp. Alteration in these bacteria's concentrations in the gut further leads to the development of impaired glucose uptake by the muscles, increased gluconeogenesis in the liver, and increased lipolysis and inflammation in the adipose tissues. Thus, the present review paper aims to clarify the intricate interactions between estrogen deficiency, gut microbiota regulation, and the development of diabetes mellitus.

Endogenous sex hormones and DNA methylation both play important roles in various diseases. However, their interplay is largely unknown. A deeper understanding of their interrelationships could provide new insights into the pathology of disease development. We, therefore, investigated associations between circulating sex hormones, sex hormone binding globulin (SHBG), and DNA methylation in blood, using samples from 77 men (65 with repeated samples), from the population-based Northern Sweden Health and Disease Study (NSHDS). DNA methylation was measured in buffy coat using the Infinium Methylation EPIC BeadChip (Illumina). Sex hormone (oestradiol, oestrone, testosterone, androstenedione, dehydroepiandrosterone, and progesterone) and SHBG concentrations were measured in plasma using a high-performance liquid chromatography tandem mass spectrometry (LC/MS-MS) method and an enzyme-linked immunoassay, respectively. Associations between sex hormones, SHBG, and DNA methylation were estimated using both linear regression and mixed-effects models. Additionally, we used the comb-p method to identify differentially methylated regions based on nearby P values. We identified one novel CpG site (cg14319657), at which DNA methylation was associated with dehydroepiandrosterone, surpassing a genome-wide significance level. In addition, more than 40 differentially methylated regions were associated with levels of sex hormones and SHBG and several of these mapped to genes involved in hormone-related diseases. Our findings support a relationship between circulating sex hormones and DNA methylation and suggest that further investigation is warranted, both for validation, further exploration and to gain a deeper understanding of the mechanisms and potential consequences for health and disease.

Metabolism in males and females is distinct. Differences are usually linked to sexual reproduction, with circulating signals (e.g. hormones) playing major roles. In contrast, sex differences prior to sexual maturity and intrinsic to individual metabolic tissues are less understood. We analyzed Drosophila melanogaster larvae and find that males store more fat than females, the opposite of the sexual dimorphism in adults. We show that metabolic differences are intrinsic to the major fat storage tissue, including many differences in the expression of metabolic genes. Our previous work identified fat storage roles for Spenito (Nito), a conserved RNA-binding protein and regulator of sex determination. Nito knockdown specifically in the fat storage tissue abolished fat differences between males and females. We further show that Nito is required for sex-specific expression of the master regulator of sex determination, Sex-lethal (Sxl). "Feminization" of fat storage cells via tissue-specific overexpression of a Sxl target gene made larvae lean, reduced the fat differences between males and females, and induced female-like metabolic gene expression. Altogether, this study supports a model in which Nito autonomously controls sexual dimorphisms and differential expression of metabolic genes in fat cells in part through its regulation of the sex determination pathway.

The Mediterranean diet (MedD) has been shown to have beneficial effects on health, well-being, and mental status. It potentially modulates gene expressions linked to oxidative stress, contributing to its beneficial effects on overall health. The aim of this study was to assess the effects of MedD treatment in healthy human volunteers on the expression of ten genes related to oxidative stress and inflammation in women and men. Of 30 enrolled subjects, 17 were eligible, 10 women and 7 men. All of them received the same MedD treatment. Before and after 8 weeks of MedD treatment, an evaluation of body composition, blood tests, and anthropometric and clinical parameters was performed. Furthermore, 10 genes were amplified and analyzed. The study showed significant differences between females and males in body composition and biochemical parameters before and after MedD treatment. Significant differences between females and males in Resistance Force (p < 0.009) and Diastolic Blood Pressure (p < 0.04) before MedD treatment, and in High-Density Lipoprotein (p < 0.02) after MedD treatment, were observed. Moreover, a significant upregulation of Apolipoprotein E and Angiotensin I-Converting Enzyme in females has been shown. Sex differences impact MedD treatment response, and influence the genetic expression of genes related to oxidative stress; our findings may help to personalize diet therapy and contribute to overall health and well-being.

Children born to parents who are overweight or obese have a high risk of adult obesity, but it is unclear if transgenerational associations relating to unfavorable body composition differ by parent.

To examine differential mother-offspring and father-offspring associations in body composition in early childhood.

A total of 240 mother-father-offspring trios from a prospective UK population-based pre-birth cohort (Southampton Women's Survey) were included for anthropometry and dual-energy x-ray absorptiometry assessment of whole-body-less-head body composition in the offspring at 3 different ages (4, 6-7, and 8-9 years) and in the mother and father at the 8- to 9-year offspring visit. Associations were assessed using linear regression adjusting for the other parent.

Positive associations between mother-daughter body mass index (BMI) and fat mass were observed at ages 6 to 7 (BMI: β = .29 SD/SD, 95% CI = .10, .48; fat mass β = .27 SD/SD, 95% CI = .05, .48) and 8 to 9 years (BMI: β = .33 SD/SD, 95% CI = .13, .54; fat mass β = .31 SD/SD, 95% CI = .12, .49), with similar associations at age 4 years but bounding the 95% CI. The mother-son, father-son, and father-daughter associations for BMI and fat mass were weaker at each of the ages studied.

A strong association between the fat mass of mothers and their daughters but not their sons was observed. In contrast, father-offspring body composition associations were not evident. The dimorphic parent-offspring effects suggest particular attention should be given to early prevention of unfavorable body composition in girls born to mothers with excess adiposity.

We investigated whether excessive retroperitoneal adipose tissue (AT) expansion programmed by maternal obesity (MO) affects adipocyte size distribution and gene expression in relation to adipocyte proliferation and differentiation in male and female offspring (F1) from control (F1C) and obese (F1MO) mothers. Female Wistar rats (F0) ate a control or high-fat diet from weaning through pregnancy and lactation. F1 were weaned onto a control diet and euthanized at 110 postnatal days. Fat depots were weighed to estimate the total AT. Serum glucose, triglyceride, leptin, insulin, and the insulin resistance index (HOMA-IR) were determined. Adipocyte size and adipogenic gene expression were examined in retroperitoneal fat. Body weight, retroperitoneal AT and adipogenesis differed between male and female F1Cs. Retroperitoneal AT, glucose, triglyceride, insulin, HOMA-IR and leptin were higher in male and female F1MO vs. F1C. Small adipocytes were reduced in F1MO females and absent in F1MO males; large adipocytes were increased in F1MO males and females vs. F1C. Wnt, PI3K-Akt, and insulin signaling pathways in F1MO males and Egr2 in F1MO females were downregulated vs. F1C. MO induced metabolic dysfunction in F1 through different sex dimorphism mechanisms, including the decreased expression of pro-adipogenic genes and reduced insulin signaling in males and lipid mobilization-related genes in females.

Oxidative stress, a key mediator of cardiovascular disease, metabolic alterations, and cancer, is independently associated with menopause and obesity. Yet, among postmenopausal women, the correlation between obesity and oxidative stress is poorly examined. Thus, in this study, we compared oxidative stress states in postmenopausal women with or without obesity. Body composition was assessed via DXA, while lipid peroxidation and total hydroperoxides were measured in patient's serum samples via thiobarbituric-acid-reactive substances (TBARS) and derivate-reactive oxygen metabolites (d-ROMs) assays, respectively. Accordingly, 31 postmenopausal women were enrolled: 12 with obesity and 19 of normal weight (mean (SD) age 71.0 (5.7) years). Doubled levels of serum markers of oxidative stress were observed in women with obesity in women with obesity compared to those of normal weight (H₂O₂: 32.35 (7.3) vs. 18.80 (3.4) mg H₂O₂/dL; malondialdehyde (MDA): 429.6 (138.1) vs. 155.9 (82.4) mM in women with or without obesity, respectively; p < 0.0001 for both). Correlation analysis showed that both markers of oxidative stress increased with an increasing body mass index (BMI), visceral fat mass, and trunk fat percentage, but not with fasting glucose levels. In conclusion, obesity and visceral fat are associated with a greater increase in oxidative stress in postmenopausal women, possibly increasing cardiometabolic and cancer risks.

Menopause-related decline in estrogen levels is accompanied by a change in adipose tissue distribution from a gynoid to an android and an increased prevalence of obesity in women. These unfavorable phenomena can be partially restored by hormone replacement therapy, suggesting a significant role for estrogen in the regulation of adipocytes' function. Indeed, preclinical studies proved the involvement of these hormones in adipose tissue development, metabolism, and inflammatory activity. However, the relationship between estrogen and obesity is bidirectional. On the one hand-their deficiency leads to excessive fat accumulation and impairs adipocyte function, on the other-adipose tissue of obese individuals is characterized by altered expression of estrogen receptors and key enzymes involved in their synthesis. This narrative review aims to summarize the role of estrogen in adipose tissue development, physiology, and in obesity-related dysfunction. Firstly, the estrogen classification, synthesis, and modes of action are presented. Next, their role in regulating adipogenesis and adipose tissue activity in health and the course of obesity is described. Finally, the potential therapeutic applications of estrogen and its derivates in obesity treatment are discussed.

Metabolism in males and females is distinct. Differences are usually linked to sexual reproduction, with circulating signals (e.g. hormones) playing major roles. By contrast, sex differences prior to sexual maturity and intrinsic to individual metabolic tissues are less understood. We analyzed Drosophila melanogaster larvae and find that males store more fat than females, the opposite of the sexual dimorphism in adults. We show that metabolic differences are intrinsic to the major fat storage tissue, including many differences in the expression of metabolic genes. Our previous work identified fat storage roles for Spenito (Nito), a conserved RNA-binding protein and regulator of sex determination. Nito knockdown specifically in the fat storage tissue abolished fat differences between males and females. We further show that Nito is required for sex-specific expression of the master regulator of sex determination, Sex-lethal (Sxl). "Feminization" of fat storage cells via tissue-specific overexpression of a Sxl target gene made larvae lean, reduced the fat differences between males and females, and induced female-like metabolic gene expression. Altogether, this study supports a model in which Nito autonomously controls sexual dimorphisms and differential expression of metabolic genes in fat cells in part through its regulation of the sex determination pathway.

Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased ('adipose neuropathy'). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose-resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the incidence of peripheral neuropathy and adipose tissue dysregulation across several ages in both male and female mice. We also investigated the anti-aging treatment rapamycin, an mTOR inhibitor, as a means to prevent or reduce adipose neuropathy. We found that HET3 mice displayed a reduced neuropathy phenotype compared to inbred C56BL/6 J mice, indicating genetic contributions to this aging phenotype. Compared to female HET3 mice, male HET3 mice had worse neuropathic phenotypes by 62 weeks of age. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126 weeks), after reproductive senescence. We found that rapamycin overall had little impact on neuropathy measures, and actually worsened adipose tissue inflammation and fibrosis. Despite its success as a longevity treatment in mice, higher doses and longer delivery paradigms for rapamycin may lead to a disconnect between life span and beneficial health outcomes.