Obesity-related Metabolic Diseases Research Articles

Retinoic acid receptor-related orphan receptor α stimulates adipose tissue inflammation by modulating endoplasmic reticulum stress

Adipose tissue inflammation has been linked to metabolic diseases such as obesity and type 2 diabetes. However, the molecules that mediate inflammation in adipose tissue have not been addressed. Although retinoic acid receptor-related orphan receptor α (RORα) is known to be involved in the regulation of inflammatory response in some tissues, its role is largely unknown in adipose tissue. Conversely, it is known that endoplasmic reticulum (ER) stress and unfolding protein response (UPR) signaling affect the inflammatory response in obese adipose tissue, but whether RORα regulates these processes remains unknown. In this study, we investigate the link between RORα and adipose tissue inflammation. We showed that the inflammatory response in macrophages or 3T3-L1 adipocytes stimulated by lipopolysaccharide, as well as adipose tissue in obese mice, markedly increased the expression of RORα. Adenovirus-mediated overexpression of RORα or treatment with the RORα-specific agonist SR1078 enhanced the expression of inflammatory cytokines and increased the number of infiltrated macrophages into adipose tissue. Furthermore, SR1078 up-regulated the mRNA expression of ER stress response genes and enhanced phosphorylations of two of the three mediators of major UPR signaling pathways, PERK and IRE1α. Finally, we found that alleviation of ER stress using a chemical chaperone followed by the suppression of RORα induced inflammation in adipose tissue. Our data suggest that RORα-induced ER stress response potentially contributes to the adipose tissue inflammation that can be mitigated by treatment with chemical chaperones. The relationships established here between RORα expression, inflammation, and UPR signaling may have implications for therapeutic targeting of obesity-related metabolic diseases.

Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease.

Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand-independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested 2 novel synthetic compounds GHSR-IA1 and GHSR-IA2. In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids. Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR-IA1 increased metabolic rate in chow-fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR-IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice. Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity-related metabolic disorders including diabetes mellitus.

Effects of Epigallocatechin-3-Gallate on Autophagic Lipolysis in Adipocytes.

Previous studies demonstrated effects of green tea on weight loss; however, green tea-induced modulation of adipocyte function is not fully understood. Here, we investigated effects of the major green tea phytochemical, epigallocatechin-3-gallate (EGCG) on triglyceride contents, lipolysis, mitochondrial function, and autophagy, in adipocytes differentiated from C3H10T1/2 cells and immortalized pre-adipocytes in vitro. EGCG reduced the triglycerol content significantly in adipocytes by 25%, comparable to the nutrient starvation state. EGCG did not affect protein kinase A signaling or brown adipocyte marker expression in adipocytes; however, EGCG increased autophagy, as measured by autophagy flux analysis and immunoblot analysis of LC3B, ATG7, and Beclin1. EGCG treatment reduced mitochondrial membrane potential by 56.8% and intracellular ATP levels by 49.1% compared to controls. Although mammalian target of rapamycin signaling was not upregulated by EGCG treatment, EGCG treatment induced AMP-activated protein kinase phosphorylation, indicating an energy-depleted state. In addition, EGCG increased the association between RAB7 and lipid droplets, suggesting that lipophagy was activated. Finally, knockdown of Rab7 attenuated the EGCG-dependent reduction in lipid contents. Collectively, these results indicated that EGCG upregulated autophagic lipolysis in adipocytes, supporting the therapeutic potential of EGCG as a caloric restriction mimetic to prevent obesity and obesity-related metabolic diseases.

Chardonnay grape seed flour supplemented diets alter intestinal microbiota in diet-induced obese mice

The intestinal microbiota of mice was evaluated after supplementation with flavonoid-rich whole grape seed flour from white winemaking. High-fat (HF)-diet-induced obese (DIO) mice were fed a HF diet supplemented with either 10% partially defatted chardonnay grape seed flour (ChrSd) or microcrystalline cellulose (MCC, control) for 6 weeks. Supplementation with ChrSd reduced HF-diet-induced weight gain, liver and adipose tissue weight, and plasma lipid levels. The results from high-throughput sequencing of the 16S rRNA V3-4 region showed dynamic changes in the intestinal microbiome that are closely associated with the regulation of diet-induced obesity, polyphenol conversion, bile acid and hepatic lipid metabolism, and butyrate production. Body and adipose tissue weight gain and plasma LDL concentration were positively associated with Lactobacillus and negatively associated with Roseburia and Enterococcus. In conclusion, chardonnay grape seed flour ameliorates the effects of a HF diet on plasma lipid concentration and adipose tissue and body weight, possibly via modulation of the intestinal microbiota in DIO mice. Practical applications Construction of a healthy intestinal microbiota via prebiotic action using a flavonoid-rich ChrSd diet may be an effective manner for the prevention of obesity and obesity-related metabolic diseases.

Natural alkaloid bouchardatine ameliorates metabolic disorders in high-fat diet-fed mice by stimulating the sirtuin 1/liver kinase B-1/AMPK axis.

Promoting energy metabolism is known to provide therapeutic effects for obesity and associated metabolic disorders. The present study evaluated the therapeutic effects of the newly identified bouchardatine (Bou) on obesity-associated metabolic disorders and the molecular mechanisms of these effects. The molecular mode of action of Bou for its effects on lipid metabolism was first examined in 3T3-L1 adipocytes and HepG2 cells. This was followed by an evaluation of its metabolic effects in mice fed a high-fat diet for 16weeks with Bou being administered in the last 5weeks. Further mechanistic investigations were conducted in pertinent organs of the mice and relevant cell models. In 3T3-L1 adipocytes, Bou reduced lipid content and increased sirtuin 1 (SIRT1) activity to facilitate liver kinase B1 (LKB1) activation of AMPK. Chronic administration of Bou (50mg∙kg-1 every other day) in mice significantly attenuated high-fat diet-induced increases in body weight gain, dyslipidaemia and fatty liver without affecting food intake and no adverse effects were detected. These metabolic effects were associated with activation of the SIRT1-LKB1-AMPK signalling pathway in adipose tissue and liver. Of particular note, UCP1 expression and mitochondrial biogenesis were increased in both white and brown adipose tissues of Bou-treated mice. Incubation with Bou induced similar changes in primary brown adipocytes isolated from mice. Bou may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues and liver through a mechanism involving the SIRT1-LKB1-AMPK axis.

Methods for quantifying adipose tissue insulin resistance in overweight/obese humans.

Insulin resistance of adipose tissue is an important feature of obesity-related metabolic disease. However, assessment of lipolysis in humans requires labor-intensive and expensive methods, and there is limited validation of simplified measurement methods. We aimed to validate simplified methods for the quantification of adipose tissue insulin resistance against the assessment of insulin sensitivity of lipolysis suppression during hyperinsulinemic-euglycemic clamp studies. We assessed the insulin-mediated suppression of lipolysis by tracer-dilution of [1,1,2,3,3-2H5]glycerol during hyperinsulinemic-euglycemic clamp studies in 125 overweight or obese adults (85 men, 40 women; age 50±11 years; body mass index 38±7 kg m-2). Seven indices of adipose tissue insulin resistance were validated against the reference measurement method. Low-dose insulin infusion resulted in suppression of the glycerol rate of appearance ranging from 4% (most resistant) to 85% (most sensitive), indicating a good range of adipose tissue insulin sensitivity in the study population. The reference method correlated with (1) insulin-mediated suppression of plasma glycerol concentrations (r=0.960, P<0.001), (2) suppression of plasma non-esterified fatty acid (NEFA) concentrations (r=0.899, P<0.001), (3) the Adipose tissue Insulin Resistance (Adipo-IR) index (fasting plasma insulin-NEFA product; r=-0.526, P<0.001), (4) the fasting plasma insulin-glycerol product (r=-0.467, P<0.001), (5) the Adipose Tissue Insulin Resistance Index (fasting plasma insulin-basal lipolysis product; r=0.460, P<0.001), (6) the Quantitative Insulin Sensitivity Check Index (QUICKI)-NEFA index (r=0.621, P<0.001), and (7) the QUICKI-glycerol index (r=0.671, P<0.001). Bland-Altman plots showed no systematic errors for the suppression indices but proportional errors for all fasting indices. Receiver-operator characteristic curves confirmed that all indices were able to detect adipose tissue insulin resistance (area under the curve ⩾0.801, P<0.001). Adipose tissue insulin sensitivity (that is, the antilipolytic action of insulin) can be reliably quantified in overweight and obese humans by simplified index methods. The sensitivity and specificity of the Adipo-IR index and the fasting plasma insulin-glycerol product, combined with their simplicity and acceptable agreement, suggest that these may be most useful in clinical practice.

A novel role for the Wnt inhibitor APCDD1 in adipocyte differentiation: Implications for diet-induced obesity

Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli down-regulated 1 (APCDD1) has recently been identified as an inhibitor of Wnt signaling, a key regulator of adipogenic differentiation. Here we report a novel role for APCDD1 in adipogenic differentiation via repression of Wnt signaling and an epigenetic linkage between miR-130 and APCDD1 in DIO. APCDD1 expression was significantly up-regulated in mature adipocytes compared with undifferentiated preadipocytes in both human and mouse subcutaneous adipose tissues. siRNA-based silencing of APCDD1 in 3T3-L1 preadipocytes markedly increased the expression of Wnt signaling proteins (Wnt3a, Wnt5a, Wnt10b, LRP5, and β-catenin) and inhibited the expression of adipocyte differentiation markers (CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ)) and lipid droplet accumulation, whereas adenovirus-mediated overexpression of APCDD1 enhanced adipogenic differentiation. Notably, DIO mice exhibited reduced APCDD1 expression and increased Wnt expression in both subcutaneous and visceral adipose tissues and impaired adipogenic differentiation in vitro Mechanistically, we found that miR-130, whose expression is up-regulated in adipose tissues of DIO mice, could directly target the 3'-untranslated region of the APCDD1 gene. Furthermore, transfection of an miR-130 inhibitor in preadipocytes enhanced, whereas an miR-130 mimic blunted, adipogenic differentiation, suggesting that miR-130 contributes to impaired adipogenic differentiation during DIO by repressing APCDD1 expression. Finally, human subcutaneous adipose tissues isolated from obese individuals exhibited reduced expression of APCDD1, C/EBPα, and PPARγ compared with those from non-obese subjects. Taken together, these novel findings suggest that APCDD1 positively regulates adipogenic differentiation and that its down-regulation by miR-130 during DIO may contribute to impaired adipogenic differentiation and obesity-related metabolic disease.

Novel LC/MS/MS and High-Throughput Mass Spectrometric Assays for Monoacylglycerol Acyltransferase Inhibitors

Monoacylglycerol acyltransferase enzymes (MGAT1, MGAT2, and MGAT3) convert monoacylglycerol to diacylglycerol (DAG). MGAT1 and MGAT2 are both implicated in obesity-related metabolic diseases. Conventional MGAT enzyme assays use radioactive substrates, wherein the product of the MGAT-catalyzed reaction is usually resolved by time-consuming thin layer chromatography (TLC) analysis. Furthermore, microsomal membrane preparations typically contain endogenous diacylglycerol acyltransferase (DGAT) from the host cells, and these DGAT activities can further acylate DAG to form triglyceride (TG). Our mass spectrometry (liquid chromatography–tandem mass spectrometry, or LC/MS/MS) MGAT2 assay measures human recombinant MGAT2-catalyzed formation of didecanoyl-glycerol from 1-decanoyl-rac-glycerol and decanoyl-CoA, to produce predominantly 1,3-didecanoyl-glycerol. Unlike 1,2-DAG, 1,3-didecanoyl-glycerol is proved to be not susceptible to further acylation to TG. 1,3-Didecanoyl-glycerol product can be readily solubilized and directly subjected to high-throughput mass spectrometry (HTMS) without further extraction in a 384-well format. We also have established the LC/MS/MS MGAT activity assay in the intestinal microsomes from various species. Our assay is proved to be highly sensitive, and thus it allows measurement of endogenous MGAT activity in cell lysates and tissue preparations. The implementation of the HTMS MGAT activity assay has facilitated the robust screening and evaluation of MGAT inhibitors for the treatment of metabolic diseases.

ATF4/ATG5 Signaling in Hypothalamic Proopiomelanocortin Neurons Regulates Fat Mass via Affecting Energy Expenditure.

Although many biological functions of activating transcription factor 4 (ATF4) have been identified, a role of hypothalamic ATF4 in the regulation of energy homeostasis is poorly understood. In this study, we showed that hypothalamic proopiomelanocortin (POMC) neuron-specific ATF4 knockout (PAKO) mice are lean and have higher energy expenditure. Furthermore, PAKO mice were resistant to high-fat diet-induced obesity, glucose intolerance, and leptin resistance. Moreover, the expression of autophagy protein 5 (ATG5) was increased or decreased by ATF4 knockdown or overexpression, respectively, and ATF4 inhibited the transcription of ATG5 by binding to the basic zipper-containing protein sites on its promoter. Importantly, mice with double knockout of ATF4 and ATG5 in POMC neurons gained more fat mass and reduced energy expenditure compared with PAKO mice under a high-fat diet. Finally, the effect of ATF4 deletion in POMC neurons was possibly mediated via enhanced ATG5-dependent autophagy and α-melanocyte-stimulating hormone production in the hypothalamus. Taken together, these results identify the beneficial role of hypothalamic ATF4/ATG5 axis in the regulation of energy expenditure, obesity, and obesity-related metabolic disorders, which suggests that ATF4/ATG5 axis in the hypothalamus may be a new potential therapeutic target for treating obesity and obesity-related metabolic diseases.

5-aminolevulinic acid combined with ferrous ion reduces adiposity and improves glucose tolerance in diet-induced obese mice via enhancing mitochondrial function

BackgroundMitochondrial dysfunction is associated with obesity and various obesity-associated pathological conditions including glucose intolerance. 5-Aminolevulinic acid (ALA), a precursor of heme metabolites, is a natural amino acid synthesized in the mitochondria, and various types of cytochromes containing heme contribute to aerobic energy metabolism. Thus, ALA might have beneficial effects on the reduction of adiposity and improvement of glucose tolerance through its promotion of heme synthesis. In the present study, we investigated the effects of ALA combined with sodium ferrous citrate (SFC) on obesity and glucose intolerance in diet-induced obese mice.MethodsWe used 20-weeks-old male C57BL/6J diet-induced obesity (DIO) mice that had been fed high-fat diet from 4th week or wild-type C57BL/6J mice. The DIO mice were orally administered ALA combined with SFC (ALA/SFC) for 6 weeks. At the 4th and 5th week during ALA/SFC administration, mice were fasted for 5 h and overnight, respectively and used for oral glucose tolerance test. After the ALA/SFC administration, the plasma glucose levels, weight of white adipose tissue, and expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes were examined. Furthermore, the effects of ALA/SFC on lipid content and glucose uptake were examined in vitro.ResultsOral administration of ALA/SFC for 6 weeks reduced the body weight by about 10% and the weight of white adipose tissues in these animals. In vitro, ALA/SFC reduced lipid content in mouse 3T3-L1 adipocytes in a dose dependent manner, and enhanced glucose uptake in 3T3-L1 adipocytes by 70–90% and rat L6 myoblasts by 30% at 6 h. Additionally, oral administration of ALA/SFC reduced plasma glucose levels and improved glucose tolerance in DIO mice. Furthermore, ALA/SFC enhanced the expression of OXPHOS complexes III, IV, and V by 40–70% in white adipose tissues of DIO mice, improving mitochondrial function.ConclusionsOur findings indicate that ALA/SFC is effective in the reduction of adiposity and improvement of glucose tolerance, and that the induction of mitochondrial OXPHOS complex III, IV, and V by ALA/SFC might be an essential component of the molecular mechanisms underlying these effects. ALA/SFC might be a useful supplement for obesity and obesity-related metabolic disease such as type 2 diabetes mellitus.

Triglyceride dependent differentiation of obesity in adipose tissues by FTIR spectroscopy coupled with chemometrics.

The excess deposition of triglycerides in adipose tissue is the main reason of obesity and causes excess release of fatty acids to the circulatory system resulting in obesity and insulin resistance. Body mass index and waist circumference are not precise measure of obesity and obesity related metabolic diseases. Therefore, in the current study, it was aimed to propose triglyceride bands located at 1770-1720 cm-1 spectral region as a more sensitive obesity related biomarker using the diagnostic potential of Fourier Transform Infrared (FTIR) spectroscopy in subcutaneous (SCAT) and visceral (VAT) adipose tissues. The adipose tissue samples were obtained from 10weeks old male control (DBA/2J) (n = 6) and four different obese BFMI mice lines (n = 6 per group). FTIR spectroscopy coupled with hierarchical cluster analysis (HCA) and principal component analysis (PCA) was applied to the spectra of triglyceride bands as a diagnostic tool in the discrimination of the samples. Successful discrimination of the obese, obesity related insulin resistant and control groups were achieved with high sensitivity and specificity. The results revealed the power of FTIR spectroscopy coupled with chemometric approaches in internal diagnosis of abdominal obesity based on the spectral differences in the triglyceride region that can be used as a spectral marker.

Phosphodiesterase-4B as a Therapeutic Target for Cognitive Impairment and Obesity-Related Metabolic Diseases.

People in modern, affluent societies are living longer but also becoming increasingly overweight. With increased life expectancy comes increased risk of developing age-related cognitive decline and neurodegenerative diseases, such that an increasing proportion of life may be lived with cognitive impairment as age increases. Obesity is associated with poorer cognitive function in elderly subjects, and often leads to ill-health arising from various complications such as metabolic syndrome and type-2 diabetes mellitus. This chapter provides an overview of the effects of administering pan-phosphodiesterase-4 (PDE4) inhibitors to animal models of cognitive ageing, Alzheimer's disease, frontotemporal dementia, fragile X syndrome, obesity and diabetes. Inhibition of the PDE4B subtype specifically is discussed as an approach to avoid the emetic side effects of pan-PDE4 inhibitors, whilst retaining their therapeutic effects. Finally, the findings of rodent studies that employ genetic and pharmacological approaches to specifically target PDE4B are discussed in relation to the potential utility of PDE4B-selective inhibitors for the treatment of cognitive impairment and obesity-related metabolic diseases.

Gene Expression and Histological Analysis of Activated Brown Adipocytes in Adipose Tissue.

With the rediscovery of brown adipose tissue in adult humans, identification and characterization of brown adipocytes have been topics of great interest in the field of adipose tissue research. In particular, identification of the molecular mechanisms that activate thermogenic adipocytes suggests promising targets for increasing energy expenditure and ultimately combatting obesity and obesity-related metabolic disease. Thus, the methodology for identifying brown adipocytes in vivo is important for the precise determination of the metabolic activity of brown adipose tissue and de novo brown adipogenesis in white adipose tissue. In addition, in vivo analysis of brown adipocytes in combination with lineage tracing is essential to investigate the cellular origins of brown adipocytes. This chapter first provides a brief overview of lineage tracing studies performed in the search for the cellular origins of brown adipocytes. The chapter then describes the immunohistochemistry methodology for identifying brown adipocytes in adipose tissue, including analyses in histologic tissue sections and whole mount tissue. Lastly, it discusses flow cytometric analysis of dissociated cells from adipose tissue, and isolation of live adipocytes for subsequent gene expression profiling using fluorescence-activated cell sorting.

Arthrospira platensis improves macrophages arginine metabolism and prevents insulin resistance in Psammomys obesus

Introduction: Chronic low grade inflammation is generally linked to the development of obesity-related metabolic diseases and tissue-resident macrophages play a major role in the regulation of the inflammation markers in the tissues. The cyanobacterium Arthrospira platensis also named spirulina is a blue green microalgae which has anti-inflammatory and anti diabetic properties. This study aimed to evaluate its potential therapeutic benefits on insulin resistance and peritoneal macrophages arginine metabolism in experimental gerbils named Psammomys obesus. Methods: A control group was fed its vegetable -based low caloric diet (halophilic plants). Two experimental groups were fed a high caloric diet for 12 weeks. Spirulina, or its vehicle (0.9% NaCl solution) were administrated daily by gastric intubation during 12 weeks. At the end of experiments, serum was collected to assess biochemical parameters and arginine metabolism was studied from isolated peritoneal macrophages. Results: Spirulina attenuated hyperlipidemia and prevented hyperinsulinemia, avoiding metabolic disturbances. Psammomys fed a high caloric diet displayed macrophages arginine metabolism toward pro-inflammatory phenotype while spirulina supplementation maintained peritoneal macrophages’ iNOS activity similar to that of the control group. Conclusion: Our study suggests that Arthrospira platensis is effective in improving insulin sensitivity by regulating peritoneal macrophages’ arginine metabolism.

Sex differences in sympathetic innervation and browning of white adipose tissue of mice

BackgroundThe higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in β3-adrenergic remodeling of WAT in mice.MethodsEffects of the β3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15 days.ResultsWe found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate.ConclusionsCollectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen-dependent sympathetic innervation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0121-7) contains supplementary material, which is available to authorized users.

Long-Term Effects of Radiation Exposure and Metabolic Status on Telomere Length of Peripheral Blood T Cells in Atomic Bomb Survivors.

In a series of studies of atomic bomb survivors, radiation-dose-dependent alterations in peripheral T-cell populations have been reported. For example, reduced size in naïve T-cell pools and impaired proliferation ability of T cells were observed. Because these alterations are also generally observed with human aging, we hypothesized that radiation exposure may accelerate the aging process of the T-cell immune system. To further test this hypothesis, we conducted cross-sectional analyses of telomere length, a hallmark of cellular aging, of naïve and memory CD4 T cells and total CD8 T cells in the peripheral blood of 620 atomic bomb survivors as it relates to age and radiation dose, using fluorescence in situ hybridization with flow cytometry. Since telomere shortening has been recently demonstrated in obesity-related metabolic abnormalities and diseases, the modifying effects of metabolic status were also examined. Our results indicated nonlinear relationships between T-cell telomere length and prior radiation exposure, i.e., longer telomeres with lower dose exposure and a decreasing trend of telomere length with individuals exposed to doses higher than 0.5 Gy. There were associations between shorter T-cell telomeres and higher hemoglobin Alc levels or fatty liver development. In naïve and memory CD4 T cells, radiation dose and high-density lipoprotein (HDL) cholesterol were found to positively interact with telomere length, suggesting that the decreasing trend of telomere length from a higher radiation dose was less conspicuous in individuals with a higher HDL cholesterol. It is therefore likely that radiation exposure perturbs T-cell homeostasis involving telomere length maintenance by multiple biological mechanisms, depending on dose, and that long-term-radiation-induced effects on the maintenance of T-cell telomeres may be modified by the subsequent metabolic conditions of individuals.

Effect of the Capsicoside G-rich Fraction from Pepper (Capsicum annuum L.) Seeds on High-fat Diet-induced Obesity in Mice.

Obesity is one of the most common metabolic syndromes and is a major threat to human health worldwide. Given the size of this problem, there is growing interest in natural agents that may decrease obesity. In this study, we investigated the anti-obesity effect of a capsicoside G-rich fraction (CRF; 13.35% capsicoside G) isolated from pepper seeds in diet-induced obese mice. C57BL/6J mice were fed either a normal diet or a high-fat diet (HFD), with or without CRF (HFD + CRF; 10 and 100 mg/kg body weight). The body weight and food efficiency ratio of mice fed HFD + CRF were lower in comparison to that of mice fed only an HFD. Epididymal adipose tissue weight and adipocyte hypertrophy were significantly lower in HFD + CRF mice than in HFD mice. The fat deposition in the liver of mice fed HFD + CRF was lower compared to that of mice fed only an HFD. CRF significantly reversed the HFD-induced elevation of the expression of key adipocyte differentiation regulators, including peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, sterol regulatory element binding protein 1c, and their target genes. These results suggest that CRF could be used as dietary therapy for the prevention of obesity and obesity-related metabolic diseases. Copyright © 2016 John Wiley & Sons, Ltd.

Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure.

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways.

Background:A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals’ effects on adult adipose tissue.Objectives:Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes.Methods:We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes.Results:Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor’s activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression.Conclusions:Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ.Citation:Manteiga S, Lee K. 2017. Monoethylhexyl phthalate elicits an inflammatory response in adipocytes characterized by alterations in lipid and cytokine pathways. Environ Health Perspect 125:615–622; http://dx.doi.org/10.1289/EHP464

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans.

The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases.