Subcutaneous Adipocyte Size Research Articles

Exercise Reduces Glucose Intolerance, Cardiac Inflammation and Adipose Tissue Dysfunction in Psammomys obesus Exposed to Short Photoperiod and High Energy Diet.

Circadian disruption causes glucose intolerance, cardiac fibrosis, and adipocyte dysfunction in sand rats (Psammomys obesus). Exercise intervention can improve glucose metabolism, insulin sensitivity, adipose tissue function and protect against inflammation. We investigated the influence of exercise on male P. obesus exposed to a short photoperiod (5 h light:19 h dark) and high-energy diet. Exercise reduced glucose intolerance. Exercise reduced cardiac expression of inflammatory marker Ccl2 and Bax:Bcl2 apoptosis ratio. Exercise increased heart:body weight ratio and hypertrophy marker Myh7:Myh6, yet reduced Gata4 expression. No phenotypic changes were observed in perivascular fibrosis and myocyte area. Exercise reduced visceral adipose expression of inflammatory transcription factor Rela, adipogenesis marker Ppard and browning marker Ppargc1a, but visceral adipocyte size was unaffected. Conversely, exercise reduced subcutaneous adipocyte size but did not affect any molecular mediators. Exercise increased ZT7 Bmal1 and Per2 in the suprachiasmatic nucleus and subcutaneous Per2. Our study provides new molecular insights and histological assessments on the effect of exercise on cardiac inflammation, adipose tissue dysfunction and circadian gene expression in P. obesus exposed to short photoperiod and high-energy diet. These findings have implications for the protective benefits of exercise for shift workers in order to reduce the risk of diabetes and cardiovascular disease.

The Influence of Subcutaneous and Visceral Adipocyte Geometries on Metabolic Parameters and Metabolic Regulating Hormones in Obese and Non-Obese Subjects

Adipose tissue plays a pivotal role in endocrine and metabolic homeostasis. This study aimed to compare subcutaneous and visceral adipocyte measurements, including area, shortest diameter, longest diameter, and perimeter, between groups of different metabolic profiles; and to determine correlations of adipocyte geometries with metabolic parameters and hormones in obese (n=20) and non-obese subjects (n=14). We hypothesized that geometries of subcutaneous and visceral adipocytes differ between groups with distinct metabolic conditions, and that their measurements correlate with obesity parameters, metabolic profiles, and hormones differently within subcutaneous and visceral adipocyte parameters as well as between obese and non-obese subjects. A total of 34 subjects were classified based on insulin resistance, using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) >2.3, and the presence of hypertension (HT), defined as systolic blood pressure (SBP)/diastolic blood pressure (DBP) ≥130/80 mmHg. These subjects underwent open abdominal surgery, with blood sample collection in a fasting state before the operation, and abdominal subcutaneous and omental (visceral) adipose tissue collection during the operation. Subjects with insulin resistance (n=6) and those with HT (n=15) both had a greater size of visceral adipocytes compared to those without insulin resistance (n=28) or HT (n=19), respectively; however, there were no significant differences in subcutaneous adipocyte size between the groups. For correlation analyses in obese subjects, subcutaneous adipocyte measurements exhibited significant positive correlations with visceral adipocyte measurements (R=0.592-0.630); while they showed significant negative correlations with cholesterol (R=-0.573) and serum visfatin (R=-0.610), all with p<0.05. Furthermore, in obese subjects, visceral adipocytes geometries were positively correlated with body weight, waist circumference, and hip circumference (R=0.575-R=0.607), all with p<0.05. In non-obese subjects, geometries of subcutaneous adipocytes were significantly positively correlated with body weight, BMI, waist circumference, and visceral adipocyte size (R=0.555-0.642); while were negatively correlated with serum adiponectin (R=(-0.608)-(-0.676)), all with p<0.05. Furthermore, in non-obese subjects, the measurements of visceral adipocytes were significantly positively correlated with body weight, BMI, serum leptin levels, serum leptin/adiponectin ratio, waist circumference, and DBP (R=0.555-0.836); while were negatively correlated with serum adiponectin (R=(-0.608)-(-0.647), all with p<0.05. These results suggest that hypertrophy of visceral adipocytes, rather than subcutaneous adipocytes, could contribute to insulin resistance and hypertension. Subcutaneous adipocyte size in obese subjects was not correlated with obesity parameters but was negatively correlated with cholesterol and visfatin levels potentially reflecting a protective effect or a compensatory mechanism in which an increase in subcutaneous fat might be a response to store excess lipids more safely when visceral fat capacity is limited. In non-obese subjects, visceral adipocyte geometries were positively correlated with DBP but inversely related to serum levels of adiponectin, an anti-inflammatory adipokine, indicating that larger adipocytes in non-obese individuals are not benign but indicative of early metabolic derangement. In conclusion, subcutaneous fat in obese individuals may represent a potentially protective effect or compensatory response to metabolic disturbance induced by excess visceral fat. In non-obese individuals, a larger visceral adipocyte size could signal early metabolic alterations, even in the absence of obesity. The research was funded by the Faculty of Medicine Siriraj Hospital Research Fund ((IO) R015332009). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The size of human subcutaneous adipocytes, but not adiposity, is associated with inflammation, endoplasmic reticulum stress, and insulin resistance markers

BackgroundThe fat storage capacity of the adipose tissue prevents ectopic lipid deposition, which is one of the risk factors for metabolic abnormalities in obesity. This capacity depends upon the adipogenic gene expression and blood supply provision for tissue expansion through angiogenesis. Here, we studied hyperplasia/hypertrophy of subcutaneous white adipose tissue (scWAT) concerning adipogenic gene expression, angiogenic status, and metabolic parameters in non-obese and different classes of obese individuals.MethodsThe scWAT samples were collected from 80 individuals. The anthropometric parameters, adipose tissue cell size, serum biochemistry, ER stress-induced XBP1 splicing, PPARγ2, SFRP1, WNT10B, and VEGFA gene expression levels were studied. In addition, the CD31 level was investigated by Western blotting.ResultsThe obese individuals had greater waist circumferences and higher serum TG, TC, insulin, and HOMA-IR than the non-obese group. However, the largest adipocyte size, increased TNFα, insulin, and HOMA-IR, and the highest expression level of sXBP1, WNT10B, and VEGFA were observed in Class I obese individuals. It means that inflammation, insulin resistance, and ER stress accompany hypertrophic scWAT adipocytes with limited adipose tissue expansion ability. Furthermore, the Class II + III obese individuals showed high PPARγ2 expression and CD31 levels. There is adipogenesis through hyperplasia in this group. The SFRP1 expression was not significantly different in the studied groups.ConclusionThe results suggest that the capability of adipogenesis with inadequate angiogenesis is related to the metabolic status, inflammation, and ER function. Therefore, therapeutic strategies that support both angiogenesis and adipogenesis can effectively prevent the complications of obesity.

Elevated adipose differentiation-related protein level in ovariectomized mice correlates with tissue-specific regulation of estrogen.

Redistribution of adipose tissue in the abdomen during the menopausal transition is attributable mostly to estrogen drop with aging. Adipose differentiation-related protein (ADRP), a major component of lipid droplets, is closely related to the onset of lipid accumulation. We hypothesized that estrogen exerted its tissue-specific effect in reducing abdominal fat accumulation by regulation of ADRP. Twenty-four female C57/BL6 mice aged 8 weeks were randomly divided into 3 groups: sham operation (Sham), bilateral ovariectomy (OVX), and OVX plus 17β-estradiol (OVX + E2). After being fed 8 weeks of a high-fat diet, plasma lipid profiles including total cholesterol (TC), total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, body weight gain, visceral, and subcutaneous adipose tissue, adipocyte size, and ADRP expression were measured. In comparison to sham-operated mice, OVX mice presented a weight gain with higher plasma TC, TG, LDL-C levels, and lower HDL-C levels. E2 supplement ameliorated the increase in weight and lipid profiles. Elevated ADRP expression was observed in visceral adipose tissue of OVX mice, whereas treatment of estrogen suppressed the ADPR expression and reversed the fat accumulation in the abdomen. However, no significant difference of ADRP expression in subcutaneous adipose tissue was detected between sham, OVX, and OVX + E2 mice. Our findings suggested that enhanced ADRP expression in ovariectomized mice correlates with the tissue-specific regulation of estrogen, which may provide useful clues for further exploring the regulatory mechanism and corresponding anti-abdominal obesity treatment in postmenopausal women.

Machine learning-featured Secretogranin V is a circulating diagnostic biomarker for pancreatic adenocarcinomas associated with adipopenia.

BackgroundPancreatic cancer is one of the most fatal malignancies of the gastrointestinal cancer, with a challenging early diagnosis due to lack of distinctive symptoms and specific biomarkers. The exact etiology of pancreatic cancer is unknown, making the development of reliable biomarkers difficult. The accumulation of patient-derived omics data along with technological advances in artificial intelligence is giving way to a new era in the discovery of suitable biomarkers.MethodsWe performed machine learning (ML)-based modeling using four independent transcriptomic datasets, including GSE16515, GSE62165, GSE71729, and the pancreatic adenocarcinoma (PAC) dataset of the Cancer Genome Atlas. To find candidates for circulating biomarkers, we exported expression profiles of 1,703 genes encoding secretory proteins. Integrating three transcriptomic datasets into either a training or test set, ML-based modeling distinguishing PAC from normal was carried out. Another ML-model classifying long-lived and short-lived patients with PAC was also built to select prognosis-associated features. Finally, circulating level of SCG5 in the plasma was determined from the independent cohort (non-tumor = 25 and pancreatic cancer = 25). We also investigated the impact of SCG5 on adipocyte biology using recombinant protein.ResultsThree distinctive ML-classifiers selected 29-, 64- and 18-featured genes, recognizing the only common gene, SCG5. As per the prediction of ML-models, the SCG5 transcripts was significantly reduced in PAC and decreased further with the progression of the tumor, indicating its potential as a diagnostic as well as prognostic marker for PAC. External validation of SCG5 using plasma samples from patients with PAC confirmed that SCG5 was reduced significantly in patients with PAC when compared to controls. Interestingly, plasma SCG5 levels were correlated with the body mass index and age of donors, implying pancreas-originated SCG5 could regulate energy metabolism systemically. Additionally, analyses using publicly available Genotype-Tissue Expression datasets, including adipose tissue histology and pancreatic SCG5 expression, further validated the association between pancreatic SCG5 expression and the size of subcutaneous adipocytes in humans. However, we could not observe any definite effect of rSCG5 on the cultured adipocyte, in 2D in vitro culture.ConclusionCirculating SCG5, which may be associated with adipopenia, is a promising diagnostic biomarker for PAC.

Effect of tetra-hydroxylated bile acid on size and insulin sensitivity of subcutaneous adipocytes in healthy lean cats

Obesity leads to insulin resistance and is a major risk factor for the development of diabetes mellitus in cats. Prevention of obesity and obesity-induced insulin resistance is difficult, and reliable long-term strategies are currently lacking. Retinoid-related orphan receptor gamma (RORγ) was recently identified as an important transcription factor in the development of large insulin-resistant adipocytes in mice and humans. RORγ negatively affects adipocyte differentiation through expression of its target gene matrix metalloproteinase 3 (MMP3) and promotes the development of large insulin-resistant adipocytes. Preliminary studies in mice showed that RORγ can be inhibited by its ligand tetra-hydroxylated bile acid (THBA). In the present study, serum THBA levels were determined in healthy and diabetic cats. Moreover, potential side effects and the effects of THBA supplementation on adipocyte size, mRNA expression of RORγ, MMP3, interleukin 6, tumor necrosis factor α, adiponectin and leptin in feline subcutaneous adipocytes and insulin sensitivity were investigated in healthy normal weight cats. Thirteen healthy and 13 diabetic cats were used for determination of serum THBA level, and six healthy normal-weight cats were included in a feeding trial. Similar THBA levels were determined in serum of healthy and diabetic cats. Supplementation of 5 mg/kg THBA for 8 wk did not cause any negative effect on feeding behavior, general condition and blood parameters of tested cats. It significantly reduced adipocyte size and mRNA expression of MMP3, interleukin 6, and tumor necrosis factor α in adipocytes, while mRNA expression of adiponectin significantly increased and mRNA expression of RORγ and leptin remained unchanged. Administration of THBA did not influence fasting blood glucose levels or the response of cats to acute insulin administration. Based on these results, THBA is palatable and is considered safe for use in cats. It reduces expression of MMP3 and promotes the development of small adipocytes with increased expression of adiponectin and reduced expression of interleukin 6 and tumor necrosis factor α. Further studies are recommended to evaluate the effect of THBA on adipocyte size and insulin sensitivity in obese cats.

Identification of markers that distinguish adipose tissue and glucose and insulin metabolism using a multi-modal machine learning approach

The study of metabolomics has improved our knowledge of the biology behind type 2 diabetes and its related metabolic physiology. We aimed to investigate markers of adipose tissue morphology, as well as insulin and glucose metabolism in 53 non-obese male individuals. The participants underwent extensive clinical, biochemical and magnetic resonance imaging phenotyping, and we also investigated non-targeted serum metabolites. We used a multi-modal machine learning approach to evaluate which serum metabolomic compounds predicted markers of glucose and insulin metabolism, adipose tissue morphology and distribution. Fasting glucose was associated with metabolites of intracellular insulin action and beta-cell dysfunction, namely cysteine-s-sulphate and n-acetylgarginine, whereas fasting insulin was predicted by myristoleoylcarnitine, propionylcarnitine and other metabolites of beta-oxidation of fatty acids. OGTT-glucose levels at 30 min were predicted by 7-Hoca, a microbiota derived metabolite, as well as eugenol, a fatty acid. Both insulin clamp and HOMA-IR were predicted by metabolites involved in beta-oxidation of fatty acids and biodegradation of triacylglycerol, namely tartrate and 3-phosphoglycerate, as well as pyruvate, xanthine and liver fat. OGTT glucose area under curve (AUC) and OGTT insulin AUC, was associated with bile acid metabolites, subcutaneous adipocyte cell size, liver fat and fatty chain acids and derivates, such as isovalerylcarnitine. Finally, subcutaneous adipocyte size was associated with long chain fatty acids, markers of sphingolipid metabolism, increasing liver fat and dopamine-sulfate 1. Ectopic liver fat was predicted by methylmalonate, adipocyte cell size, glutathione derived metabolites and fatty chain acids. Ectopic heart fat was predicted visceral fat, gamma-glutamyl tyrosine and 2-acetamidophenol sulfate. Adipocyte cell size, age, alpha-tocopherol and blood pressure were associated with visceral fat. We identified several biomarkers associated with adipose tissue pathophysiology and insulin and glucose metabolism using a multi-modal machine learning approach. Our approach demonstrated the relative importance of serum metabolites and they outperformed traditional clinical and biochemical variables for most endpoints.

Garcinia cambogia attenuates adipogenesis by affecting CEBPB and SQSTM1/p62-mediated selective autophagic degradation of KLF3 through RPS6KA1 and STAT3 suppression

ABSTRACT The overexpansion of adipose tissues leads to obesity and eventually results in metabolic disorders. Garcinia cambogia (G. cambogia) has been used as an antiobesity supplement. However, the molecular mechanisms underlying the effects of G. cambogia on cellular processes have yet to be fully understood. Here, we discovered that G. cambogia attenuated the expression of CEBPB (CCAAT/enhancer binding protein (C/EBP), beta), an important adipogenic factor, suppressing its transcription in differentiated cells. In addition, G. cambogia inhibited macroautophagic/autophagic flux by decreasing autophagy-related gene expression and autophagosome formation. Notably, G. cambogia markedly elevated the expression of KLF3 (Kruppel-like factor 3 (basic)), a negative regulator of adipogenesis, by reducing SQSTM1/p62-mediated selective autophagic degradation. Furthermore, increased KLF3 induced by G. cambogia interacted with CTBP2 (C-terminal binding protein 2) to form a transcriptional repressor complex and inhibited Cebpa and Pparg transcription. Importantly, we found that RPS6KA1 and STAT3 were involved in the G. cambogia-mediated regulation of CEBPB and autophagic flux. In an obese animal model, G. cambogia reduced high-fat diet (HFD)-induced obesity by suppressing epididymal and inguinal subcutaneous white adipose tissue mass and adipocyte size, which were attributed to the regulation of targets that had been consistently identified in vitro. These findings provide new insight into the mechanism of G. cambogia-mediated regulation of adipogenesis and suggest molecular links to therapeutic targets for the treatment of obesity. Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; ATG: autophagy-related; Baf: bafilomycin A1; BECN1: beclin 1; CEBP: CCAAT/enhancer binding protein (C/EBP); CHX: cycloheximide; CREB: cAMP response element binding protein; CTBP: C-terminal binding protein; EGCG: (-)-epigallocatechin gallate; eWAT: epididymal white; G. cambogia: Garcinia cambogia; GFP: green fluorescent protein; H&E: hematoxylin and eosin; HFD: high-fat diet; iWAT: inguinal subcutaneous white; KLF: Kruppel-like factor; LAP: liver-enriched transcriptional activating proteins; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; ND: normal diet; PPARG: peroxisome proliferator activated receptor gamma; qPCR: quantitative real-time PCR; RFP: red fluorescent protein; RPS6KA1: ribosomal protein S6 kinase A1; siRNA: small-interfering RNA; SQSTM1/p62: sequestosome 1; STAT: signal transducer and activator of transcription; TEM: transmission electron microscopy

PTIP Deficiency in B Lymphocytes Reduces Subcutaneous Fat Deposition in Mice.

Recent studies have predominantly focused on the role of B cells in metabolic diseases, yet the function of B cells in adipose homeostasis remains unclear. Pax transactivation domain-interacting protein (PTIP), a licensing factor for humoral immunity, is necessary for B cell development and activation. Here, using mice that lack PTIP in B cells (PTIP-/- mice), we explored the role of B cells in adipose homeostasis under physiological conditions. Fat deposition in 8-week-old mice was measured by micro-CT, and PTIP-/- mice presented a marked decrease in the deposition of subcutaneous adipose tissue (SAT). Untargeted lipidomics revealed that the triglyceride composition in SAT was altered in PTIP-/- mice. In addition, there was no difference in the number of adipocyte progenitor cells in the SAT of wild-type (WT) and PTIP-/- mice as measured by flow cytometry. To study the effects of steady-state IgM and IgG antibody levels on fat deposition, PTIP-/- mice were injected intraperitoneally with serum from WT mice once every 3-4 days for 4 weeks. The iSAT mass of the recipient mice showed no significant increase in comparison to the controls after 4 weeks of injections. Our findings reveal that PTIP plays an essential role in regulating subcutaneous adipocyte size, triglyceride composition, and fat deposition under physiological conditions by controlling B cells. The decreased subcutaneous fat deposition in PTIP-/- mice does not appear to be related to the number of adipocyte progenitor cells. The steady-state levels of IgM and IgG antibodies in vivo are not associated with the subcutaneous fat deposition.

Assessment of Periprostatic and Subcutaneous Adipose Tissue Lipolysis and Adipocyte Size from Men with Localized Prostate Cancer.

The prostate is surrounded by periprostatic adipose tissue (PPAT), the thickness of which has been associated with more aggressive prostate cancer (PCa). There are limited data regarding the functional characteristics of PPAT, how it compares to subcutaneous adipose tissue (SAT), and whether in a setting of localized PCa, these traits are altered by obesity or disease aggressiveness. PPAT and SAT were collected from 60 men (age: 42–78 years, BMI: 21.3–35.6 kg/m2) undergoing total prostatectomy for PCa. Compared to SAT, adipocytes in PPAT were smaller, had the same basal rates of fatty acid release (lipolysis) yet released less polyunsaturated fatty acid species, and were more sensitive to isoproterenol-stimulated lipolysis. Basal lipolysis of PPAT was increased in men diagnosed with less aggressive PCa (Gleason score (GS) ≤ 3 + 4) compared to men with more aggressive PCa (GS ≥ 4 + 3) but no other measured adipocyte parameters related to PCa aggressiveness. Likewise, there was no difference in PPAT lipid biology between lean and obese men. In conclusion, lipid biological features of PPAT do differ from SAT; however, we did not observe any meaningful difference in ex vivo PPAT biology that is associated with PCa aggressiveness or obesity. As such, our findings do not support a relationship between altered PCa behavior in obese men and the metabolic reprogramming of PPAT.

Adipose TBX1 regulates β-adrenergic sensitivity in subcutaneous adipose tissue and thermogenic capacity in vivo

ObjectiveT-box 1 (TBX1) has been identified as a genetic marker of beige adipose tissue. TBX1 is a mesodermal development transcription factor essential for tissue patterning and cell fate determination. However, whether it plays a role in the process of adipose beiging or how it functions in adipose tissue has not been reported. Here, we examined the function of TBX1 in adipose tissue as well as adipose-derived stem cells from mice and humans. MethodsAdipose-specific TBX1 transgenic (TBX1 AdipoTG) and adipose-specific TBX1 knockout (TBX1 AdipoKO) mice were generated to explore the function of TBX1 in the process of adipose beiging, metabolism and energy homeostasis in vivo. In vitro, we utilized a siRNA mediated approach to determine the function of TBX1 during adipogenesis in mouse and human stem cells. ResultsAdipose-specific overexpression of TBX1 was not sufficient to fully induce beiging and prevent diet-induced obesity. However, adipose TBX1 expression was necessary to defend body temperature during cold through regulation of UCP1 and for maintaining β3-adrenergic sensitivity and glucose homeostasis in vivo. Loss of adipose TBX1 expression enhanced basal lipolysis and reduced the size of subcutaneous iWAT adipocytes. Reduction of TBX1 expression via siRNA significantly impaired adipogenesis of mouse stromal vascular cells but significantly enhanced adipogenesis in human adipose derived stem cells. ConclusionsAdipose expression of TBX1 is necessary, but not sufficient, to defend body temperature during cold via proper UCP1 expression. Adipose TBX1 expression was also required for proper insulin signaling in subcutaneous adipose as well as for maintaining β-adrenergic sensitivity, but overexpression of TBX1 was not sufficient to induce adipocyte beiging or to prevent diet-induced obesity. TBX1 expression is enriched in adipose stem cells in which it has contrasting effects on adipogenesis in mouse versus human cells. Collectively, these data demonstrate the importance of adipose TBX1 in the regulation of beige adipocyte function, energy homeostasis, and adipocyte development.

Aqueous Extract of Humulus japonicus Attenuates Hyperlipidemia and Fatty Liver in Obese Mice.

In this study, the effects of Humulus japonicus (HJ) aqueous extract on 3T3-L1 preadipocytes and HepG2 cells (in vitro model) as well as on C57BL/6 mice fed on high-fat diet (HFD) (in vivo model) were evaluated. Mice fed on HFD for 12-weeks were taken the HJ water extract (HJW) at various doses, 50, 150, and 250 mg/kg, orally for 8 weeks. We have noticed the accumulation of fat globules in preadipocytes and HepG2 cells using Oil Red O staining. In addition, supplementation with HJW considerably inhibited the weight gain, lipid accumulation, and adipogenesis and decreased the size of subcutaneous adipocytes in 3T3-L1 adipocytes. Furthermore, treatment with HJW improved hyperlipidemia via decreasing the levels of serum triglyceride (TG) and low-density lipoproteins as well as the atherogenic index. Supplementation with HJW could attenuate HFD-induced lipid accumulation, increase the mRNA expressions of fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD1), and would elevate the levels of serum aspartate aminotransferase and alanine aminotransferase in mice liver. The levels of TG and FAS mRNA in HepG2 cells treated with palmitate were reduced in a dose-dependent manner. In sum, HJW could alleviate the HFD-induced obesity and decrease the dyslipidemia profiles; the keys that could contribute to cardiovascular and nonalcoholic liver diseases.

PCBs–high-fat diet interactions as mediators of gut microbiota dysbiosis and abdominal fat accumulation in female mice

Polychlorinated biphenyls (PCBs), one type of lipophilic pollutant, are ubiquitous in daily life. PCBs exposure has been implicated in the alterations of gut microbial community which is profoundly associated with diverse metabolic disorders, including obesity. High-fat diet (H) is a dietary pattern characterized by a high percentage of fat. According to the theory that similarities can be easily solvable in each other, PCBs and H exposures are inevitably and objectively coexistent in a real living environment, prompting great concerns about their individual and combined effects on hosts. However, the effects of PCBs-H interactions on gut microbiota and obesity are still incompletely understood. In the present study, the effects of PCBs and/or H on the gut microbiota alteration and obesity risk in mice were examined and the interactions between PCBs and H were investigated. Obtained results showed that PCBs and/or H exposure induced prominent variations in the gut microbiota composition and diversity. Exposure to PCBs also resulted in higher body fat percentage, greater size of abdominal subcutaneous adipocytes and increased expression of proinflammatory cytokines including TNF-α, iNOS and IL-6. Such PCBs-induced changes could be further enhanced upon the co-exposure of H, implying that obese individuals may be vulnerable to PCBs exposure. Taken together, the present study is helpful for a better understanding of the gut microbiota variation influenced by PCBs and/or H exposure, and furthermore, provides a novel insight into the mechanism of PCBs-H interactions on host adiposity.

Abstract MP38: Effect of Dietary Carbohydrate Type on Serum Lipid Profile, Adipose Tissue Macrophage Infiltration and Inflammatory Status, and Peripheral Macrophage Cholesterol Efflux

Introduction: While much has been published on the effect of different amounts of dietary carbohydrate (carb) on cardiovascular disease (CVD) risk, data on effects of different types of carb (simple, refined and unrefined) are limited. Objective: To determine the relative comparability for an isocaloric replacement of unrefined-carb (UC; e.g., brown rice and bread/pasta made from whole wheat flour), refined-carb (RC; e.g., white rice and bread/pasta made from white flour) and simple-carb (SC; e.g., sucrose and high fructose corn syrup) on serum lipid and lipoprotein profile, adipose tissue gene expression of macrophage and inflammation markers, cytokine secretion and adipocyte size, and cholesterol efflux in peripheral blood mononuclear cells (PBMC). Methods: Study subjects (men and postmenopausal women [N=11], 65±8 y, BMI 29.8±3.2 kg/m 2 , LDL-C ≥2.6 mmol/L) were provided with isocaloric diets (60% E total carb, 15% E protein, 25% E fat) enriched in SC, RC or UC for 4.5 weeks, with a 2-week washout period between diet phases, using a randomized, cross-over design. Body weight was maintained within +/- 2 kg. At the end of each diet phase serum lipid and lipoprotein profile was determined using standard methods. Abdominal subcutaneous adipose tissue biopsies were collected and used to assess gene expression of macrophage and inflammation markers, cytokine secretion, and cell size. PBMCs were isolated and cultured to assess cholesterol efflux. Results: Fasting serum TC (p=0.004) and LDL-C (p=0.002) concentrations were higher after subjects consumed the RC diet than after the SC and UC diet phases. No significant differences were observed among diets in serum HDL-C (p=0.32), VLDL-C (p=0.17), TG (p=0.19), and NEFA (p=0.99) concentrations. Adipocyte size was largest after subjects consumed the RC diet and smallest after the SC diet (p<0.0001). There were no significant differences among diets in gene expression of the macrophage markers CD14 (p=0.62) and CD68 (p=0.62), and the inflammatory markers adiponectin (p=0.66), leptin (p=0.42), and IL-6 (p=0.92), except for a trend towards higher serum amyloid-1 expression after the RC diet (p=0.059). Inflammatory cytokine secretion of adiponectin (p=0.52), leptin (p=0.89), and IL-6 (p=0.07) were not significantly different among diet phases. No significant differences were observed in macrophage cholesterol efflux among diets (p=0.18). Conclusions: Consuming the RC diet resulted in higher serum TC and LDL-C concentrations, and concurrently increased abdominal subcutaneous adipocyte size. Dietary carb type had no significant effect on markers of macrophage infiltration, inflammation or cytokine secretion in adipose tissue, or macrophage cholesterol efflux. Results from this study provide mechanistic support for the epidemiologic findings that increasing consumption of RC diet is positively associated with CVD risk.

Abdominal subcutaneous and visceral adipocyte size, lipolysis and inflammation relate to insulin resistance in male obese humans

Obesity is associated with a disturbed adipose tissue (AT) function characterized by adipocyte hypertrophy, an impaired lipolysis and pro-inflammatory phenotype, which contributes to insulin resistance (IR). We investigated whether AT phenotype in different AT depots of obese individuals with and without type 2 diabetes mellitus (T2DM) is associated with whole-body IR. Subcutaneous (SC) and visceral (V) AT biopsies from 18 lean, 17 obese and 8 obese T2DM men were collected. AT phenotype was characterized by ex vivo measurement of basal and stimulated lipolysis (mature adipocytes), adipocyte size distribution (AT tissue sections) and AT immune cells (flow cytometry). In VAT, mean adipocyte size, CD45+ leukocytes and M1 macrophages were significantly increased in both obese groups compared to lean individuals. In SCAT, despite adipocyte hypertrophy, no significant differences in immune cell populations between groups were found. In SCAT, multiple linear regression analysis showed that none of the AT phenotype markers independently contributed to HOMA-IR while in VAT, mean adipocyte size was significantly related to HOMA-IR. In conclusion, beside adipocyte hypertrophy in VAT, M1 macrophage- or B-cell-mediated inflammation, may contribute to IR, while inflammation in hypertrophic SCAT does not seem to play a major role in IR.

Fat depot-specific differences of macrophage infiltration and cellular senescence in obese bovine adipose tissues.

Obesity is associated with the chronic inflammation and senescence of adipose tissues. Macrophage is a key mediator of chronic inflammation that infiltrates obese adipose tissue and stimulates metabolic disorders. However, the fat depot-specific differences of macrophage infiltration and senescence, especially the influence on intramuscular adipose tissue, have remained unclear. We investigated the fat depot-specific differences of macrophage infiltration and senescence in obese bovine adipose tissue from three different anatomical sites (subcutaneous, intramuscular and visceral). Macrophage infiltrations and crown-like structures were observed in visceral adipose tissue, although there were few macrophages in subcutaneous and intramuscular adipose tissues. The positive reaction of senescence marker SA-βgal activity was observed in visceral adipose tissue. In contrast, the activity of SA-βgal in subcutaneous and intramuscular adipose tissues were low. The expression of p53 gene, the master regulator of cellular senescence, in visceral adipose tissue was higher than that of subcutaneous and intramuscular adipose tissue. At the cellular level, p53 gene expression was negatively correlated with the size of subcutaneous adipocytes. In contrast, p53 gene expressions were positively correlated with the size of intramuscular and visceral adipocytes. These results indicate that anatomical sites of obese adipose tissue affect macrophage infiltration and the senescent state in a fat depot-specific manner.

Oral administration of Rehmannia glutinosa extract for obesity treatment via adiposity and fatty acid binding protein expression in obese rats

We investigated the anti-obesity effect of Rehmannia glutinosa aqueous extract (RGE) in high fat diet (HFD) induced obese rats on the blood lipid concentration and expression of adipocyte fatty acid binding protein (FABP). In additional experiments, C57BL6 mice were used to determine lipolysis and the oral lipid emulsion tolerance test. RGE administration significantly reduced the size of subcutaneous adipocytes and. Most importantly, RGE administration markedly attenuated the up-regulation of FABP mRNA and protein expression in subcutaneous adipose tissue induced by an HFD. Oral RGE administration prevented weight gain and hyperlipidemia induced by long-term HFD feeding, presumably via a mechanism that inhibits the intestinal absorption of dietary fat by RGE. Taken together, RGE can act as an anti-obesity agent by lowering FABP gene and protein expression in adipose tissue as well as blood lipid levels.

Fatty Acid Metabolic Remodeling During Type 2 Diabetes Remission After Bariatric Surgery.

Hypertrophic remodeling of white adipose tissues is associated with overexposure of lean organs to circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs), ultimately leading to insulin resistance. Bariatric surgery promotes type 2 diabetes (T2D) remission through a succession of weight loss-dependent and -independent mechanisms. However, the longitudinal contribution of adipocyte size reduction and fatty acid metabolic handling remain unknown. Here we show that severely obese participants with T2D display hypertriglyceridemia and excessive systemic lipolysis during intravenous lipid overload. Three days after biliopancreatic diversion with duodenal switch (DS), whole-body glycerol turnover was normalized and associated with lower HOMA-insulin resistance index. A mean excess weight loss of 84% was achieved 12 months after DS. The smaller subcutaneous adipocyte size predicted better glycemic control in T2D. TG disposal and acylcarnitine production during lipid overload, along with muscle insulin sensitivity, improved with weight loss. Nevertheless, systemic NEFA fluxes and NEFA spillover remained similar, suggesting that increased NEFA storage capacity per volume of adipose tissue exactly compensated for the decrease in fat mass during weight loss. In conclusion, T2D remission after DS is mainly associated with greater circulating TG disposal, lower systemic lipolysis, and better fatty acid handling by lean tissues.

Cardiovascular risk score is linked to subcutaneous adipocyte size and lipid metabolism.

Although white adipose tissue mass and distribution correlates with cardiovascular disease, the fat cell-specific perturbations underlying this association are not known. We determined the relationship between adipocyte size and lipid metabolism with cardiovascular risk. Adipocyte size as well as spontaneous (basal) and hormone-stimulated effects on adipocyte lipid metabolism (lipolysis and lipogenesis) were investigated in abdominal subcutaneous adipose tissue of 304 men and 775 women. Subjects were classified into five categories according to Adult Treatment PanelIII (ATPIII) metabolic syndrome criteria. Adipocyte size increased with increasing ATPIII score (P<0.0001). For lipolysis, there was a gradual increase in basal and catecholamine-stimulated lipolysis and a decrease in insulin-mediated inhibition of stimulated lipolysis with ATPIII (P<0.0001). In contrast, the lipolytic action of atrial natriuretic peptide was similar between ATPIII classes. Basal and insulin-stimulated lipogenesis decreased with increasing score (P<0.0001). Circulating free fatty acid levels were 50% higher in the top risk category (4-5) compared with the lowest score (P<0.0001). Fat cell size correlated positively with increasing ATPIII score and lipolysis but negatively with lipogenesis. All these differences were independent of age, sex and body weight status (P<0.0001 to 0.02 after correction). When all functional measures were put together, maximum insulin-stimulated lipogenesis, insulin-antilipolytic sensitivity and basal lipolysis together explained about 20% in the variation of ATPIII in score. Independently of sex, age and body weight status, a high cardiovascular risk score associates with increased circulating free fatty acid levels and hormone-specific alterations of lipolysis/lipogenesis in enlarged subcutaneous fat cells.

GH administration decreases subcutaneous abdominal adipocyte size in men with abdominal obesity

ObjectiveTo investigate the effects of short-term GH administration on abdominal subcutaneous adipocyte size and CT attenuation in men with abdominal obesity. Design6-week, randomized, double-blind, placebo-controlled study of GH (starting dose 2μg/kg/d) vs placebo of 15 abdominally obese men (mean age: 34±6years; mean BMI: 37.7±6.1kg/m2, mean IGF-1 SDS: −1.9±0.5) who underwent abdominal subcutaneous adipose tissue (SAT) aspirations to determine adipocyte size, CTs for body composition and measures of glucose tolerance at baseline and 6weeks. GH dosing was titrated to target IGF-1 levels in the upper normal age-appropriate range. ResultsGH administration decreased subcutaneous abdominal adipocyte size compared to placebo. Adipocyte size was positively associated with 120-min glucose and HOMA-IR and inversely associated with peak-stimulated GH and CT attenuation. CT attenuation of SAT was inversely associated with 120-min glucose and HOMA-IR and increased following GH administration. ConclusionIn men with abdominal obesity, subcutaneous abdominal adipocyte size is positively associated with measures of impaired glucose tolerance and administration of GH at doses that raise IGF-1 levels within the normal range, decreases abdominal subcutaneous adipocyte size, suggesting that GH administration improves the health of adipose tissue.Clinical trials number: NCT00131378