PPARγ In Adipose Tissue Research Articles

Mulberry and Hippophae-based solid beverage promotes weight loss in rats by antagonizing white adipose tissue PPARγ and FGFR1 signaling.

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated ina high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.

355-OR: Targeting a Lipid Droplet Hydrolase-Mediated Lipid Signaling for Treatment of Type 2 Diabetes

Lipid droplets (LDs) are cytosolic organelles that serve as the major energy reservoir in adipocytes. Excessive accumulation of neutral lipids in LDs has been linked to obesity-associated type 2 diabetes. The dynamics of LDs is regulated by multiple proteins bound to their surfaces. Recently, carboxylesterase 1d (Ces1d) was identified as a LD-targeting lipid hydrolase. It has been showed that blockage of Ces1d in adipose tissue led to not only decreased lipolysis, but also impaired β-adrenergic signaling-stimulated thermogenesis. The goal of the current study is to define the mechanism governing the function of Ces1d on lipid metabolism. The hypothesis is that the LD-targeting Ces1d generates free fatty acids (FFA) “third messenger” that trigger specific lipid signaling in adipose tissue which further affect the whole-body metabolic homeostasis. To test this hypothesis, an adipose tissue specific Ces1d knockout mouse model (Adipo-Ces1d KO) was generated. Mass Spectrometry analysis revealed that circulating docosahexaenoic acid (DHA, C22:6 n=3), an established PPARγ ligand, was dramatically decreased in Adipo-Ces1d KO mice. The production of DHA was confirmed by an in vitro lipid digestion assay on the recombinant Ces1d. Lack of DHA signaling further led to decreased transactivation of PPARγ in adipose tissue of the Adipo-Ces1d KO mice. As a result, the expression of thermogenic gene, UCP1 was significantly downregulated. The result agrees with previous observation that Adipo-Ces1d KO mice lost their ability to defense body temperature when exposed to coldness. More interestingly, the Adipo-Ces1d KO mice gained more body weight with increased fat mass during a HFD challenge, suggesting they experienced decreased energy expenditure in the whole process. The findings thus highlight the key role of a novel lipid signaling pathway mediated by Ces1d in energy expenditure and hence pinpoint it as a potential target for treatment of obesity-induced type 2 diabetes. Disclosure X.Li: None. K.Sun: None. Funding National Institutes of Health (R56DK124419, R01DK129815)

Brown Adipose Tissue PPARγ Is Required for the Insulin-Sensitizing Action of Thiazolidinediones.

Brown adipose tissue (BAT) plays a critical role in metabolic homeostasis. BAT dysfunction is associated with the development of obesity through an imbalance between energy expenditure and energy intake. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulator of adipogenesis. However, the roles of PPARγ and thiazolidinediones (TZDs) in the regulation of BAT metabolism remain unclear. TZDs, which are selective PPARγ activators, improve systemic insulin resistance in animals and humans. In the present study, we generated brown adipocyte-specific PPARγ-deficient mice (BATγKO) to examine the in vivo roles of PPARγ and TZDs in BAT metabolism. In electron microscopic examinations, brown adipocyte-specific PPARγ deletion promoted severe whitening of brown fat and morphological alteration of mitochondria. Brown adipocyte-specific PPARγ deletion also reduced mRNA expression of BATselective genes. Although there was no difference in energy expenditure between control and BATγKO mice in calorimetry, norepinephrine-induced thermogenesis was impaired in BATγKO mice. Moreover, pioglitazone treatment improved diet-induced insulin resistance in the control mice but not in the BATγKO mice. These findings suggest that BAT PPARγ is necessary for the maintenance of brown adipocyte function and for the insulin-sensitizing action of TZDs.

Antihyperglycemic Effects and Mode of Actions of Musa paradisiaca Leaf and Fruit Peel Hydroethanolic Extracts in Nicotinamide/Streptozotocin‐Induced Diabetic Rats

The present study aimed to evaluate the antihyperglycemic effects of Musa paradisiaca (M. paradisiaca) leaf and fruit peel hydroethanolic extracts and to suggest their probable mode of actions in nicotinamide (NA)/streptozotocin (STZ)-induced diabetic rats. The leaf and fruit peel hydroethanolic extracts were analyzed by GC-MS that indicated the presence of phytol, octadecatrienoic acid, hexadecanoic acid, and octadecadienoic acid as major components in the leaf extract and vitamin E, octadecenamide, β-sitosterol, and stigmasterol as major phytochemicals in the fruit peel extract. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (60 mg/kg body weight) dissolved in citrate buffer (pH 4.5), 15 minutes after intraperitoneal injection of NA (120 mg/kg body weight). The NA/STZ-induced diabetic rats were, respectively, treated with M. paradisiaca leaf and fruit peel hydroethanolic extracts at a dose of 100 mg/kg body weight/day by oral administration for 28 days. The treatment of NA/STZ-induced diabetic rats with leaf and fruit peel extracts significantly improved the impaired oral glucose tolerance and significantly increased the lowered serum insulin and C-peptide levels. The HOMA-IR (as the index of insulin resistance) and QUICKI (as a marker for insulin sensitivity), as well as HOMA-β cell function were significantly alleviated as a result of treatment of diabetic rats with leaf and fruit peel extracts. In association, the elevated serum-free fatty acids, TNF-α, and IL-6 levels were significantly decreased. In addition, the suppressed adipose tissue PPARγ, GLUT4, adiponectin, and insulin receptor β-subunit mRNA expressions were upregulated while the elevated adipose tissue resistin expression was downregulated in diabetic rats as a result of treatment with the leaf and peel extract. Based on these results, it can be concluded that M. paradisiaca leaf and fruit peel hydroethanolic extracts have antihyperglycemic effects which may be mediated via their insulinotropic and insulin-sensitizing effects.

Effect of Dietary Calcium on Adipogenesis Program and Its Role in Adipocyte Dysfunction in Male Wistar Rats

Dietary calcium influences obesity-related adipocyte dysfunction by modulating body weight. The molecular mechanism behind this weight management is under intense investigation. In the present study, the authors investigated the effect of dietary calcium on peroxisome proliferator-activated receptor-γ (PPAR-γ)-mediated adipogenesis program and its role in adipocyte dysfunction by measuring the inflammatory and oxidative markers within the adipose tissue of male albino rats. Healthy male rats were fed with a control diet based on AIN-93, and either low-calcium (0.25%) or high-calcium (1.0%) diet for 90 days. A significant inverse (p < 0.05) relationship exists between the calcium intake and anthropometric parameters like adipose tissue mass and body weight. Adipose tissue PPAR-γ activity along with its downstream enzyme activities like glyceraldehydes 3 phosphate dehydrogenase, lipoprotein lipase as well as the protein expression of fatty acid-binding protein 4 and calcium-sensing receptor were significantly increased (p < 0.05) in the low-calcium-fed rats which in turn promoted the adipogenesis program. At the same time, protein expression of inflammatory markers like tumor necrosis factor-α and interleukin-6 and oxidative stress markers like lipid peroxidation and protein carbonylation were significantly increased (p < 0.05) in low-calcium-fed rats. These deleterious effects were suppressed by the high-calcium diet by preventing the activation of the adipogenesis program. Thus, the present study showed the involvement of dietary calcium against the PPAR-γ-mediated adipogenesis program as well as its role in adipocyte dysfunction by regulating the inflammatory and oxidative stress.

Constitutive androstane receptor mediates PCB-induced disruption of retinoid homeostasis

Environmental exposure to polychlorinated biphenyls (PCBs) is associated with an increased risk of incidence of metabolic disease, however the molecular mechanisms underlying this phenomenon are not fully understood. Our study provides new insights into molecular interactions between PCBs and retinoids (vitamin A and its metabolites) by defining a role for constitutive androstane receptor (CAR) in the disruption of retinoid homeostasis by non-coplanar 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153). Administration of four weekly 50 mg/kg doses of PCB153 to C57BL/6 male mice resulted in a significant decline in the tissue concentrations of retinyl esters, retinol and all-trans-retinoic acid (atRA), while no decline in hepatic and adipose tissue retinoid levels were detected in Car-null littermates. Our data imply that disrupted retinoid homeostasis occurs as a consequence of PCB153-induced activation of CAR, and raise the possibility that CAR signaling can affect atRA homeostasis in vivo. A strong correlation between the changes in retinoid metabolism and extensive upregulation of hepatic CAR-driven Cyp2b10 expression implicates this CYP isoform as contributing to retinoid homeostasis disruption via atRA oxidation during PCB153 exposure. In response to PCB153-induced CAR activation and disruption of retinoid homeostasis, expression of hepatic Pepck, Cd36 and adipose tissue Pparγ, Cd36, Adipoq, and Rbp4 were altered; however, this was reversed by administration of exogenous dietary retinoids (300 IU daily for 4 weeks). Our study establishes that PCB153 exposure enables a significant disruption of retinoid homeostasis in a CAR-dependent manner. We propose that this contributes to the obesogenic properties of PCB153 and may contribute to the predisposition to the metabolic disease.

Carnosic Acid Modulates Increased Hepatic Lipogenesis and Adipocytes Differentiation in Ovariectomized Mice Fed Normal or High-Fat Diets.

As postmenopausal women experience a rapid increase in cardiovascular disease (CVD) risk with an increase in abdominal fat, dietary interventions to reduce CVD risk have been emphasized. This study was aimed at investigating the effect of a high-fat diet (HFD) in combination with an ovariectomy on liver and adipose tissue fat metabolism. The efficacy of carnosic acid (CA) supplementation in the suppression of HFD- and ovariectomy-induced obesity was also evaluated. Ovariectomized (OVX) or sham-operated mice at eight weeks of age were fed with a normal diet (ND), HFD, ND and 0.02% CA, or HFD and 0.02% CA for 12 weeks. All of the animals were sacrificed at the age of 20 weeks. The blood and tissue markers of the lipogenesis and adipocyte differentiation were measured. As expected, ovariectomy decreased the uterus weight and serum 17β-estradiol concentration. The HFD and ovariectomy significantly contributed to increases in the body weight and total fat mass, which were effectively inhibited by CA supplementation. The circulating concentrations of insulin, leptin, and TG (triglyceride) were significantly higher in the HFD group, and the concentrations were two to five times higher in the OVX and HFD group compared with those of the ND group. The CA supplementation significantly lowered the insulin, leptin, and TG concentrations in the OVX and HFD mice. The hepatic protein expressions of pAMPK and pACC were up-regulated by CA supplementation in OVX mice fed either ND or HFD. The expressions of hepatic SREBP1c and FAS mRNA were the highest in the OVX and HFD group, which were suppressed by CA supplementation. The adipose tissue PPARγ, aP2, and lipoprotein lipase (LPL) mRNA expressions were up-regulated by a HFD or ovariectomy, while they were significantly reduced in the mice fed a CA supplemented diet. The TNF-α and IL-6 mRNA levels in the adipose tissue were decreased by providing CA in the OVX groups. These results suggest that HFD and ovariectomy independently contribute to body fat accumulation, and CA effectively alleviated the ovariectomy-induced increases in lipogenesis and adipocyte differentiation. Further human trials are required in order to evaluate the efficacy of rosemary-derive CA as natural anti-adipogenic compounds, especially in postmenopausal women.

Metabolic Remodeling in Diabetic Cardiomyopathy.

Diabetes is a risk factor for heart failure and cardiovascular mortality with specific changes to myocardial metabolism, energetics, structure, and function. The gradual impairment of insulin production and signalling in diabetes is associated with elevated plasma fatty acids and increased myocardial free fatty acid uptake and activation of the transcription factor PPARα. The increased free fatty acid uptake results in accumulation of toxic metabolites, such as ceramide and diacylglycerol, activation of protein kinase C, and elevation of uncoupling protein-3. Insulin signalling and glucose uptake/oxidation become further impaired, and mitochondrial function and ATP production become compromised. Increased oxidative stress also impairs mitochondrial function and disrupts metabolic pathways. The diabetic heart relies on free fatty acids (FFA) as the major substrate for oxidative phosphorylation and is unable to increase glucose oxidation during ischaemia or hypoxia, thereby increasing myocardial injury, especially in ageing female diabetic animals. Pharmacological activation of PPARγ in adipose tissue may lower plasma FFA and improve recovery from myocardial ischaemic injury in diabetes. Not only is the diabetic heart energetically-impaired, it also has early diastolic dysfunction and concentric remodelling. The contractile function of the diabetic myocardium negatively correlates with epicardial adipose tissue, which secretes proinflammatory cytokines, resulting in interstitial fibrosis. Novel pharmacological strategies targeting oxidative stress seem promising in preventing progression of diabetic cardiomyopathy, although clinical evidence is lacking. Metabolic agents that lower plasma FFA or glucose, including PPARγ agonism and SGLT2 inhibition, may therefore be promising options.

Conjugated Linoleic Acid Isomers Exert Differential Effects on an Adipocyte Model of HIV-associated Lipodystrophy.

HIV-associated lipodystrophy is associated with decreased expression of PPAR-γ in adipose tissue. Conjugated linoleic acid (CLA) isomers (cis9, trans11 and trans10, cis12) are putative PPAR-γ agonists, but have not previously been investigated in the context of HIVassociated lipodystrophy. 3T3-L1 pre-adipocytes were differentiated in the presence of ritonavir (20 μM as per previous experimental models) and 100 μM cis9,trans11, trans10,cis12 or vehicle control, DMSO. Microarray analysis, RT-PCR, DNA binding ELISA and Oil Red O staining were used to investigate adipocyte gene expression and binding, protein secretion and triglyceride storage. trans10, cis12 + ritonavir altered the expression of 2160 gene transcripts greater than 1.5-fold compared with control, while 257 gene transcripts were altered by cis9,trans11 + ritonavir (P<0.001). trans10,cis12 + ritonavir down-regulated Pparg (-1.55) and Adipoq (-2.95), as well as differentiation (Fcor (-4.78-fold), Arl4a (-4.84), Itga6 (-2.45), Id4 (-2.01)) and triglyceride storage genes (Mrap (- 8.25), Scd1 (-4.34), Lipin1 (-2.52)). Changes in Adipoq were confirmed by RT-PCR (P=0.038) and adiponectin secretion by ELISA (P= 0.003). cis9,trans11 + ritonavir increased PPAR-γ nuclear binding to its gene response element (P=0.038). Both isomers increased triglyceride storage in the presence of ritonavir (P<0.001). In the presence of ritonavir, trans10, cis12 appears to be detrimental, while cis9, trans11 was beneficial and may mediate its effects via PPAR-γ. Further research is required to determine the potential role of CLA isomers as therapeutic agents in the management of HIV-associated lipodystrophy.

Modulatory effect of berberine on adipose tissue PPARγ, adipocytokines and oxidative stress in high fat diet/ streptozotocin-induced diabetic rats

Modulatory effect of berberine on adipose tissue PPARγ, adipocytokines and oxidative stress in high fat diet/ streptozotocin-induced diabetic rats

Inhibition of adipose tissue PPARγ prevents increased adipocyte expansion after lipectomy and exacerbates a glucose-intolerant phenotype.

Adipose tissue plays a fundamental role in glucose homeostasis. For example, fat removal (lipectomy, LipX) in lean mice, resulting in a compensatory 50% increase in total fat mass, is associated with significant improvement in glucose tolerance. This study was designed to further examine the link between fat removal, adipose tissue compensation and glucose homeostasis using a peroxisome proliferator-activated receptor γ (PPAR γ; activator of adipogenesis) knockout mouse. The study involved PPARγ knockout (FKOγ) or control mice (CON), subdivided into groups that received LipX or Sham surgery. We reasoned that as the ability of adipose tissue to expand in response to LipX would be compromised in FKOγ mice, so would improvements in glucose homeostasis. In CON mice, LipX increased total adipose depot mass (~60%), adipocyte number (~45%) and changed adipocyte distribution to smaller cells. Glucose tolerance was improved (~30%) in LipX CON mice compared to Shams. In FKOγ mice, LipX did not result in any significant changes in adipose depot mass, adipocyte number or distribution. LipX FKOγ mice were also characterized by reduction of glucose tolerance (~30%) compared to shams. Inhibition of adipose tissue PPARγ prevented LipX-induced increases in adipocyte expansion and produced a glucose-intolerant phenotype. These data support the notion that adipose tissue expansion is critical to maintain and/or improvement in glucose homeostasis.

Role of the adipose PPAR\u03b3-adiponectin axis in susceptibility to stress and depression/anxiety-related behaviors

Adaptive responses to stressful stimuli involving behavioral, emotional and metabolic changes are orchestrated by the nervous and endocrine systems. Adipose tissue has been recognized as a highly active metabolic and endocrine organ, secreting adipokines that operate as hormones to mediate the crosstalk with other organs including the brain. The role of adipose tissue in sensing and responding to emotional stress and in behavioral regulation, however, remains largely unknown. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a key transcriptional factor controlling adipokine gene expression. Here we show that chronic social defeat stress decreases messenger RNA and protein levels of PPARγ in adipose tissue of susceptible but not resilient mice, which was correlated with social avoidance behavior. A corresponding reduction in adipose adiponectin production was observed in susceptible mice. Rosiglitazone, a blood–brain barrier-impermeant PPARγ-selective agonist, elicited antidepressant- and anxiolytic-like behavioral effects in wild-type mice, with a concurrent increase in plasma adiponectin levels. These effects of rosiglitazone were absent in mice lacking adiponectin but having normal PPARγ expression in adipose tissue and brain. Moreover, pretreatment with the PPARγ-selective antagonist GW9662 blocked rosiglitazone-induced adiponectin expression and antidepressant/anxiolytic-like effects. Together, these results suggest that the behavioral responses to rosiglitazone are mediated through PPARγ-dependent induction of adiponectin. Our findings support an important role for the adipose PPARγ-adiponectin axis in susceptibility to stress and negative emotion-related behaviors. Selectively targeting PPARγ in adipose tissue may offer novel strategies for combating depression and anxiety.

Epigenomic and transcriptional control of insulin resistance.

Insulin resistance is one of the defining features of type 2 diabetes and the metabolic syndrome and accompanies many other clinical conditions, ranging from obesity to lipodystrophy to glucocorticoid excess. Extraordinary efforts have gone into defining the mechanisms that underlie insulin resistance, with most attention focused on altered signalling as well as mitochondrial and endoplasmic reticulum stress. Here, nuclear mechanisms of insulin resistance, including transcriptional and epigenomic effects, will be discussed. Three levels of control involving transcription factors, transcriptional cofactors, and chromatin-modifying enzymes will be considered. Well-studied examples of the first include PPAR-γ in adipose tissue and the glucocorticoid receptor and FoxO1 in a variety of insulin-sensitive tissues. These proteins work in concert with cofactors such as PGC-1α and CRTC2, and chromatin-modifying enzymes including DNA methyltransferases and histone acetyltransferases, to regulate key genes that promote insulin-stimulated glucose uptake, gluconeogenesis or other pathways that affect systemic insulin action. Furthermore, genetic variation associated with increased risk of type 2 diabetes is often related to altered transcription factor binding, either by affecting the transcription factor itself, or more commonly by changing the binding affinity of a noncoding regulatory region. Finally, several avenues for therapeutic exploitation in the battle against metabolic disease will be discussed, including small-molecule inhibitors and activators of these factors and their related pathways.

Glucose intolerance after chronic stress is related with downregulated PPAR-γ in adipose tissue

BackgroundChronic stress is associated with increased risk of glucose intolerance and cardiovascular diseases, albeit through undefined mechanisms. With the aim of gaining insights into the latter, this study examined the metabolic profile of young adult male rats that were exposed to chronic unpredictable stress.MethodsYoung adult male rats were submitted to 4 weeks of chronic unpredictable stress and allowed to recover for 5 weeks. An extensive analysis including of morphologic, biochemical and molecular parameters was carried out both after chronic unpredictable stress and after recovery from stress.ResultsAfter 28 days of chronic unpredictable stress (CUS) the animals submitted to this protocol displayed less weight gain than control animals. After 5 weeks of recovery the weight gain rebounded to similar values of controls. In addition, following CUS, fasting insulin levels were increased and were accompanied by signs of impaired glucose tolerance and elevated serum corticosteroid levels. This biochemical profile persisted into the post-stress recovery period, despite the restoration of baseline corticosteroid levels. The mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-γ and lipocalin-2 in white adipose tissue were, respectively, down- and up-regulated.ConclusionsReduction of PPAR-γ expression and generation of a pro-inflammatory environment by increased lipocalin-2 expression in white adipose tissue may contribute to stress-induced glucose intolerance.

PPARγ UPREGULATION MEDIATES THE ANTIDIABETIC POTENTIAL OF KAEMPFEROL IN HIGH FAT DIET/STREPTOZOTOCIN-INDUCED DIABETIC RATS

Type 2 diabetes mellitus is a heterogeneous disorders characterized by impaired insulin sensitivity and/or insulin secretion. The aim of the present study was to assess the effect of the flavonoid kaempferol (3, 5, 7, 4'-tetrahydroxyflavone) as compared with rosiglitazone maleate on adipose tissue PPARγ, adiponectin and resistin in diabetic rats. After being fed a high-fat diet (HFD) for two weeks, rats were intraperitoneally injected with streptozotocin (STZ, 35 mg/kg body weight). An oral dose of 75 mg/kg kaempferol or 4 mg/kg rosiglitazone was daily given for rats for 4 weeks after diabetes induction. In HFD/STZ diabetic group, levels of glucose and glycosylated hemoglobin (HbA1c %), resistin, TNF-α and IL-6 were significantly increased, while serum insulin and adiponectin were decreased. Both kaempferol and rosiglitazone supplementation significantly ameliorate these alterations. In addition, both tested agents reversed the decline in adipose tissue PPARγ and adiponectin in conjunction with downregulated resistin expression. These results demonstrate that kaempferol may be a naturally occurring anti-diabetic agent improving peripheral insulin sensitivity by modulating some adipose tissue genes.

Antidiabetic effect of total saponins from Polygonatum kingianum in streptozotocin-induced daibetic rats

BackgroundPolygonatum kingianum has been used in the prevention and treatment of diabetes, hyperlipidemia and related metabolic syndrome in Asian counties for centuries. In this study, the blood glucose regulation activity and mechanism of total saponins from P. kingianum (TSPK) were investigated in streptozotocin (STZ)-induced diabetic rats in this research. MethodsTSPK (0.025g/kg and 0.1mg/kg) was administrated by gavage to STZ-induced diabetic rats for 8 weeks. Changes of body weight, food intakes, blood glucose, serum insulin and lipid indexes were observed. Genome-wide expression profiling was applied to explore the gene expression alternation after treated with TSPK. Expressions of adenosine monophosphate activated protein kinase (AMPK), phosphoenolpyruvate carboxykinase (PEPCK), the relative transcript level of glucose kinase and glucose-6-phosphatase (GK/G6P) in the liver were investigated. Meanwhile, contents of AMPK, and glucose transporter subtype-4 (GLUT4) in skeletal muscle, and peroxysome proliferator-activated receptor (PPAR-γ) in adipose tissue were investigated. ResultsTSPK could effectively alleviate hyperglycemia and hyperlipidemia in diabetic rats. Genome-wide expression profiling showed that TSPK up-regulated the expression of GLUT4 while down-regulated the expression of G6P in insulin signal pathway. In the liver, the expression of AMPK and GK are increased. Further more, TSPK promoted the expressions of GLUT4 in skeletal muscle, and PPAR-γ in adipose tissue, respectively. ConclusionThese results provide possible mechanisms for the antidiabetic effects of TSPK. TSPK could promote not only glycogenesis but also glucose utilization in peripheral tissue. Our results suggested that TSPK may be used as adjuvant therapy to control blood glucose and insulin resistance in type 2 diabetic individuals.

A Moderate Low-Carbohydrate Low-Calorie Diet Improves Lipid Profile, Insulin Sensitivity and Adiponectin Expression in Rats.

Calorie restriction (CR) via manipulating dietary carbohydrates has attracted increasing interest in the prevention and treatment of metabolic syndrome. There is little consensus about the extent of carbohydrate restriction to elicit optimal results in controlling metabolic parameters. Our study will identify a better carbohydrate-restricted diet using rat models. Rats were fed with one of the following diets for 12 weeks: Control diet, 80% energy (34% carbohydrate-reduced) and 60% energy (68% carbohydrate-reduced) of the control diet. Changes in metabolic parameters and expressions of adiponectin and peroxisome proliferator activator receptor γ (PPARγ) were identified. Compared to the control diet, 68% carbohydrate-reduced diet led to a decrease in serum triglyceride and increases inlow density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C) and total cholesterol; a 34% carbohydrate-reduced diet resulted in a decrease in triglycerides and an increase in HDL-cholesterol, no changes however, were shown in LDL-cholesterol and total cholesterol; reductions in HOMA-IR were observed in both CR groups. Gene expressions of adiponectin and PPARγ in adipose tissues were found proportionally elevated with an increased degree of energy restriction. Our study for the first time ever identified that a moderate-carbohydrate restricted diet is not only effective in raising gene expressions of adiponectin and PPARγ which potentially lead to better metabolic conditions but is better at improving lipid profiles than a low-carbohydrate diet in rats.

Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo.

Circulating levels of the adipokine adipocyte fatty acid-binding protein (AFABP) are increased in obesity. However, the influence of circulating AFABP on insulin sensitivity in vivo remains unclear. C57BL/6NTac mice (10 weeks) were treated over 8 weeks i.p. with saline (control) or recombinant AFABP (0.5 mg/kg/d). A comprehensive characterization of metabolic parameters, body composition, and energy expenditure was performed. Furthermore, the effect of AFABP on pancreatic β-cell responsiveness, hepatic glycogen content, and peroxisome proliferator-activated receptor (PPAR) γ protein expression was elucidated. In male mice, AFABP treatment induced insulin resistance with significantly increased fasting insulin, C-peptide, and homeostasis model assessment of insulin resistance. In female animals, a similar trend was observed. In both genders, no difference in body weight, lipid parameters, body composition, or energy expenditure could be detected between AFABP-treated and control mice. Insulin resistance in male AFABP-treated mice was accompanied by decreased PPARγ protein content in perigonadal adipose tissue and diminished circulating adiponectin. AFABP treatment did not affect pancreatic β-cell responsiveness and hepatic glycogen content. Circulating AFABP induces insulin resistance in male mice. AFABP-mediated degradation of PPARγ in adipose tissue and subsequently decreased expression of insulin-sensitizing adiponectin are potential mechanisms for this effect.

Effects of High Fat Diets on Metabolic Gene Expression in the Liver and Adipose of the Offspring through Multi‐generations via Epigenetic Alterations

The epigenetic modification is established and altered in a sensitive manner to environment factors such as diet during development. The modification is long-lasting through the life cycle and even can be transmitted to offspring. Here, we show that paternal high fat diet (HFD) induce metabolic disturbance as well as epigenetic changes in gametes and the effects are transmitted to the next two generations. The founder (F0) male mice were exposed to HFD for 13 weeks from 5wk of age, resulting in glucose intolerance and insulin resistance, and were bred with female mice fed with control diet. F1 female progeny of HFD F0 showed high fasting glucose at 8wk of age and glucose intolerance at 18wk, although all the progeny were fed with control diet. Even stronger phenotypes of impaired glucose metabolism appeared in F2 female progeny born to the F1 female. The transmission of metabolic phenotypes was associated with changes in expression of metabolic regulating genes. In both HFD F0 and F1 female there were increased glucose and fatty acid metabolism-related gene such as Gck, Fasn, and Pparα in liver and decreased Pparγ in adipose tissue, which means progressing insulin resistance and decreased fat storage capacity, respectively. In order to understand the underlying mechanism, DNA methylation status of F0 sperm was analyzed. A HFD reduced global DNA methylation in sperms, indicated by DNA methylation levels in repetitive elements. In conclusion, paternal exposure to HFD induced transgenerational effects on impaired glucose intolerance and altered metabolic gene expression in liver and adipose through multi-generations, possibly through epigenetic alterations in gametes.

Adipo8, a high-affinity DNA aptamer, can differentiate among adipocytes and inhibit intracellular lipid accumulation in vitro

Obesity is primarily caused by the excessive accumulation of white adipose tissues (WAT). We previously obtained an adipocyte-specific aptamer termed Adipo8 in vitro . In this present study, this adipocyte-specific aptamer Adipo8 was first chemically modified by introduction of phosphorothioate linkages (PS-linkages) and then conjugated to polyethylene glycol (PEG), we tested whether this modified aptamer could distinguish mature white adipocytes from 3T3-L1 preadipocytes or brown adipocytes. To verify the binding affinity of this aptamer to mature white adipocytes in vivo as well as in vitro , we tested whether modified Adipo8 could specifically bind to the WAT of Diet-Induced Obesity (DIO) C57BL/6 mice. Finally, we examined the effect of Adipo8 on the adipogenic differentiation of mature white adipocytes. Based on our results, PS-modified aptamer demonstrated its high binding affinity and specificity, and was able to distinguish white adipocytes from 3T3-L1 preadipocytes or brown adipocytes in vitro . PS-modified Adipo8 also demonstrated more biostability and prolonged binding time in biological fluids. Additionally, Adipo8 could inhibit adipogenic differentiation of adipose tissue, possibly by inhibiting the expression of PPAR-γ in adipose tissue. This modified aptamer holds great promise as a stable molecular recognition tool for targeted delivery to adipocytes and has potential in the treatment of obesity.