Adipocyte Insulin Sensitivity Research Articles

FSP27 interacts with ATGL to regulate lipolysis and insulin sensitivity in human adipocytes (LB60)

In adipocytes, lipolysis is a highly regulated process involving hormonal signals, lipid droplet‐associated proteins and lipases. The discovery of new lipid droplet‐associated proteins added complexity to the current model of lipolysis. In the present study, we used cultured human adipocytes to demonstrate that Fat Specific Protein 27 (FSP27), an abundantly expressed protein in adipocytes, regulates both basal and stimulated lipolysis by interacting with adipose triglyceride lipase (ATGL). We identified a core domain of FSP27, aa 120‐220, that interacts with ATGL to inhibit its lipolytic function and promote triglyceride storage. We also defined the role of FSP27 in free fatty acid‐induced insulin resistance in adipocytes. FSP27 depletion in human adipocytes increased lipolysis and inhibited insulin signaling by decreasing AKT phosphorylation. However, reducing lipolysis by either depletion of ATGL or expression of exogenous full length FSP27 or aa 120‐220 protected human adipocytes against the adverse effects of free fatty acids on insulin signaling. In embryonic fibroblasts derived from ATGL‐KO mice, exogenous free fatty acids did not affect insulin sensitivity. Our results demonstrate a crucial role for FSP27‐ATGL interactions in regulating lipolysis, TG accumulation, and insulin signaling in human adipocytes.Grant Funding Source: Supported by NIH‐NIDDK R56DK094815, NIH‐NIDDK P30DK046200, KL‐2 (8KL2TR000158)

Role for dusp4 in modulating PPARγ activity by covalent modification in adipocytes (1037.12)

Peroxisome proliferator‐activated receptor gamma (PPARγ) is a ligand‐activated transcription factor that plays a prominent role in adipocyte differentiation and insulin sensitivity with aberrant activity linked to obesity and type 2 diabetes. Recent studies have highlighted covalent modification of PPARγ, including phosphorylation, sumoylation and ubiquitylation, as an important mechanisms modulating biological outcome. Phosphorylation of PPARγ by mitogen‐activated protein kinases (MAPKs; ERK, JNK) inhibits transcriptional activity while mice with targeted mutation against the single MAPK‐consensus recognition site are protected against diet‐induced insulin resistance. Others have also shown MAPK‐dependent phosphorylation of PPARγ as an obligatory step in sumoylation‐dependent inhibition of activity. As MAPK activity is modulated by kinases and phosphatases, the objective of this study was to investigate a role for MAPK‐specific phosphatases in modulating PPARγ activity through covalent modification. We examined the expression profile of the 10 known MAPK‐specific phosphatases, collectively referred to as dual‐specificity phosphatases (DUSPs), in insulin‐responsive tissues of genetic‐ and diet‐induced obese mice. We observed that dusp4 was significantly more abundant in white adipose tissue relative to liver, skeletal muscle, and heart in lean mice and that this phosphatase was induced during early stages of obesity and repressed during later stages correlating with the onset of obesity‐induced inflammation. The expression profile of dusp4 was further shown to correlate precisely with PPARγ during differentiation of 3T3‐L1 and F442A adipocytes. Loss‐of‐function studies are underway to support our working model that dusp4 plays a role in modulating biological outcome of PPARγ activity through covalent modification involving phosphorylation by MAPK.Grant Funding Source: Support by NIH‐NIDDK (R15‐DK082799)

P53 Mediates impaired insulin signaling in 3T3‐L1 adipocytes during hyperinsulinemia

Hyperinsulinemia is being implicated in the development of insulin resistance but remains poorly understood. The present study focuses on p53-mediated impaired insulin signaling by hyperinsulinemia in 3T3-L1 adipocytes. Hyperinsulinemia impairs insulin-stimulated glucose uptake and its cellular signaling in a dose- and time-dependent manner. An increased level of reactive oxygen species (ROS) and stress response signals were observed, and quenching of the ROS by an antioxidant N-acetylcysteine (NAC) did not revert impaired insulin sensitivity. The tumor suppressor p53 has emerged as a crucial factor in the metabolic adaptation of cancer cells under nutritional starvation and is being studied in the development of insulin resistance in adipocytes at physiological level. Interestingly, we observed hyperinsulinemia-enhanced p53 level in a time-dependent manner without exhibiting cytotoxicity. Transient knockdown of p53 partially improved insulin sensitivity revealing a novel link between p53 and insulin signaling in adipocytes. The findings suggest that hyperinsulinemia-induced p53 impairs insulin sensitivity in 3T3-L1 adipocytes.

Superantigen activates the gp130 receptor on adipocytes resulting in altered adipocyte metabolism

ObjectiveThe bacteria Staphylococcus aureus is part of the normal bacterial flora and produces a repertoire of enterotoxins which can cause food poisoning and toxic shock and might contribute to the pathogenesis of inflammatory diseases. These enterotoxins directly cross-link the T cell receptor with MHC class II, activating large amounts of T cells and are therefore called superantigens. It was recently discovered that the superantigen SEA binds to the cytokine receptor gp130. As obesity and type 2 diabetes are highly associated with inflammation of the adipose tissue and gp130 has been shown to play an important role in adipocytes, we wanted to investigate the effect of SEA on adipocyte signaling and function. Materials/methodsBinding of SEA to gp130 was examined using surface plasmon resonance in a cell free system. Effects of SEA on adipocyte signaling, insulin sensitivity and function were studied using western blotting and biological assays for lipolysis, lipogenesis and glucose uptake. ResultsWe demonstrate that SEA binds to gp130 with a medium affinity. Furthermore, SEA induces phosphorylation of a key downstream target, STAT3, in adipocytes. SEA also inhibits insulin-induced activation of PKB and PKB downstream signaling which was associated with reduced basal and insulin induced glucose uptake, reduced lipogenesis as well as reduced ability of insulin to inhibit lipolysis. ConclusionsSEA inhibits insulin signaling as well as insulin biological responses in adipocytes supporting that bacterial infection might contribute to the development of insulin resistance and type 2 diabetes.

In Preeclampsia, Maternal Third Trimester Subcutaneous Adipocyte Lipolysis Is More Resistant to Suppression by Insulin Than in Healthy Pregnancy

Obesity increases preeclampsia risk, and maternal dyslipidemia may result from exaggerated adipocyte lipolysis. We compared adipocyte function in preeclampsia with healthy pregnancy to establish whether there is increased lipolysis. Subcutaneous and visceral adipose tissue biopsies were collected at caesarean section from healthy (n=31) and preeclampsia (n=13) mothers. Lipolysis in response to isoproterenol (200 nmol/L) and insulin (10 nmol/L) was assessed. In healthy pregnancy, subcutaneous adipocytes had higher diameter than visceral adipocytes (P<0.001). Subcutaneous and visceral adipocyte mean diameter in preeclampsia was similar to that in healthy pregnant controls, but cell distribution was shifted toward smaller cell diameter in preeclampsia. Total lipolysis rates under all conditions were lower in healthy visceral than subcutaneous adipocytes but did not differ after normalization for cell diameter. Visceral adipocyte insulin sensitivity was lower than subcutaneous in healthy pregnancy and inversely correlated with plasma triglyceride (r=-0.50; P=0.004). Visceral adipose tissue had lower ADRB3, LPL, and leptin and higher insulin receptor messenger RNA expression than subcutaneous adipose tissue. There was no difference in subcutaneous adipocyte lipolysis rates between preeclampsia and healthy controls, but subcutaneous adipocytes had lower sensitivity to insulin in preeclampsia, independent of cell diameter (P<0.05). In preeclampsia, visceral adipose tissue had higher LPL messenger RNA expression than subcutaneous. In conclusion, in healthy pregnancy, the larger total mass of subcutaneous adipose tissue may release more fatty acids into the circulation than visceral adipose tissue. Reduced insulin suppression of subcutaneous adipocyte lipolysis may increase the burden of plasma fatty acids that the mother has to process in preeclampsia.

Lipopolysaccharide impairs insulin sensitivity via activation of phosphoinositide 3-kinase in adipocytes

The effect of lipopolysaccharide (LPS) on insulin sensitivity in adipocytes were examined by using differentiated 3T3-L1 adipocytes. Insulin-mediated activation of insulin receptor substrate (IRS) 1/2 was inhibited in LPS-pretreated adipocytes and IRS1/2-mediated Akt activation was also attenuated in those cells. LPS inhibited activation of glycogen synthase kinase 3 as a negative regulator of glycogenesis and impaired the glycogen synthesis in response to insulin. LPS-induced activation of phosphoinositide 3-kinase (PI3K) in adipocytes. Involvement of suppressor of cytokine signaling 3 (SOCS3) in LPS-induced IRS1/2 inhibition was excluded. Considering that both insulin and LPS were able to activate the PI3K/Akt signaling pathway, LPS was suggested to impair insulin sensitivity of adipocytes through down-regulating insulin-mediated PI3K/Akt activation.

Endothelial Cells From Visceral Adipose Tissue Disrupt Adipocyte Functions in a Three-Dimensional Setting: Partial Rescue by Angiopoietin-1

During obesity, chronic inflammation of human white adipose tissue (WAT) is associated with metabolic and vascular alterations. Endothelial cells from visceral WAT (VAT-ECs) exhibit a proinflammatory and senescent phenotype and could alter adipocyte functions. We aimed to determine the contribution of VAT-ECs to adipocyte dysfunction related to inflammation and to rescue these alterations by anti-inflammatory strategies. We developed an original three-dimensional setting allowing maintenance of unilocular adipocyte functions. Coculture experiments demonstrated that VAT-ECs provoked a decrease in the lipolytic activity, adipokine secretion, and insulin sensitivity of adipocytes from obese subjects, as well as an increased production of several inflammatory molecules. Interleukin (IL)-6 and IL-1β were identified as potential actors in these adipocyte alterations. The inflammatory burst was not observed in cocultured cells from lean subjects. Interestingly, pericytes, in functional interactions with ECs, exhibited a proinflammatory phenotype with diminished angiopoietin-1 (Ang-1) secretion in WAT from obese subjects. Using the anti-inflammatory Ang-1, we corrected some deleterious effects of WAT-ECs on adipocytes, improving lipolytic activity and insulin sensitivity and reducing the secretion of proinflammatory molecules. In conclusion, we identified a negative impact of VAT-ECs on adipocyte functions during human obesity. Therapeutic options targeting EC inflammation could prevent adipocyte alterations that contribute to obesity comorbidities.

The Total Phenolic Fraction of Anemarrhena asphodeloides Inhibits Inflammation and Reduces Insulin Resistance in Adipocytes via Regulation of AMP-Kinase Activity

Anemarrhena asphodeloides is widely used for treatment of metabolic disorders in traditional Chinese medicine. This study investigated the effects of the total phenolic fraction of Anemarrhena asphodeloides on regulation of insulin sensitivity in adipocytes. Through treatment with macrophage-derived conditioned medium, insulin resistance was induced in adipocytes with IKKβ activation and dysregulation of adipokine production. However, these changes were reversed by treatment with the total phenolic fraction of A.asphodeloides (1, 10, 50 µg/mL). It regulated serine/tyrosine phosphorylation of insulin receptor substrate-1 and subsequently restored Akt phosphorylation in response to insulin, thereby leading to the improvement of insulin-mediated glucose uptake. The total phenolic fraction of A.asphodeloides enhanced AMP-activated protein kinase phosphorylation, and this action contributed to the inhibition of inflammation implicated in insulin resistance. In conclusion, the total phenolic fraction of A.asphodeloides attenuated insulin resistance in adipocytes by inhibition of inflammation in an AMP-activated protein kinase-dependent manner.

Herbal medicine as an alternative medicine for treating diabetes: the global burden.

Herbal medicine as an alternative medicine for treating diabetes: the global burden.

Abstract 18773: Discovery and Translation of Novel Long Intergenic Non-Coding RNAs in Inflammatory Cardio-Metabolic Disorders

Objective: The purpose of this study is to identify long intergenic non-coding RNAs (LincRNAs) modulated by inflammation utilizing human experimental endotoxemia and to explore their association with cardiometabolic traits. Methods and results: We performed deep high-throughput RNAseq (~500 million reads per sample) in adipose tissue and whole blood of a healthy subject before and after endotoxin (LPS 1 ng/Kg) administration. Of 8,179 LincRNAs identified by Cabili et al (Gene &amp; Development 2011. 25:1915-1927), we detected 514 present in adipose and 266 in blood, with 69 (13.6%) and 56 (21.2%) LincRNAs respectively modulated by LPS with just six LPS-modulated lincRNAs overlapping in both tissues. In both tissues, LincRNAs had lower expression and more tissue specificity than protein coding RNAs. RNAseq of adipose and blood in 2 additional individuals during endotoxemia was used to confirm findings and qPCR used to validate top findings in an additional 7 study participants. Linc-ARFIP1-4 and Linc-CMC1-2 were consistently reduced by LPS in blood, but not in adipose. Interestingly, Linc-DMRT2 and Linc-TP53I13, the top adipose LPS-modulated LincRNA, was more abundant in human primary adipocytes than monocyte and macrophage cultured in vitro while adipose samples obtained from obese subjects exhibited lower Linc-DMRT2 and Linc-TP63I13 expression (77% and 50% lower respectively, P&lt;0.05) compared to lean individuals (N=10/group). To further investigate biological roles, we generated lentiviral-vectors with short hairpin RNAs (shRNAs) targeting Linc-DMRT2 and Linc-TP53I13 as well as Linc-AQPEP, the top expressed adipose-specific LincRNA. Preliminary studies demonstrated more than 50% knockdown of these lincRNAs in human adipocytes with shRNA application and functional studies are ongoing to characterize their impact on adipocyte differentiation, lipid storage and insulin sensitivity. Conclusion: These novel data from a human endotoxemia experiment suggest that inflammatory modulation of adipose LincRNAs might modulate adipose functions in cardio-metabolic disorders.

Modulation of liver function, antioxidant responses, insulin resistance and glucose transport by Oroxylum indicum stem bark in STZ induced diabetic rats

A decoction of stem bark of Oroxylum indicum Vent. (OI) is taken (2–3times/day) by the tribal people of Sikkim, India to treat diabetes but scientific validation of its overall potential is lacking. Present study was aimed to assess in vitro antihyperglycemic activity of standardized OI extract using inhibition of α-glucosidase, BSA glycation and enhancement of insulin sensitivity. Antidiabetic and antioxidant modulatory effects of OI extract along with the blood biomarkers of toxic response were studied in streptozotocin (STZ) induced diabetic rats. In vitro analysis showed strong antioxidant capacity of OI -and potential to inhibit BSA glycation and α-glucosidase activity which was comparable to standard counterparts. Extract also improved insulin sensitivity in mature 3T3-L1 adipocytes. In vivo effects of OI extract (oral 250mg/kg b.wt.) on STZ induced type II diabetic rats normalized the antioxidant status (p⩽0.01). Analysis of blood biomarkers of toxic response indicated its safety. Lowering of total cholesterol and HDL levels (p⩽0.05) and restoration of glycated Hb (p⩽0.01) were also found in OI treated diabetic rats. HOMA-IR, QUICKI analysis along with area under the curve analysis showed the capacity of OI extract to enhance the insulin sensitivity significantly (p⩽0.01) which was confirmed by increased GLUT-4 translocation in skeletal muscles.

6-Mercaptopurine augments glucose transport activity in skeletal muscle cells in part via a mechanism dependent upon orphan nuclear receptor NR4A3

The purine anti-metabolite 6-mercaptopurine (6-MP) is widely used for the treatment of leukemia and inflammatory diseases. The cellular effects of 6-MP on metabolism remain unknown; however, 6-MP was recently found to activate the orphan nuclear receptor NR4A3 in skeletal muscle cell lines. We have reported previously that NR4A3 (also known as NOR-1, MINOR) is a positive regulator of insulin sensitivity in adipocytes. To further explore the role of NR4A3 activation in insulin action, we explored whether 6-MP activation of NR4A3 could modulate glucose transport system activity in L6 skeletal muscle cells. We found that 6-MP increased both NR4A3 expression and NR4A3 transcriptional activity and enhanced glucose transport activity via increasing GLUT4 translocation in both basal and insulin-stimulated L6 cells in an NR4A3-dependent manner. Furthermore, 6-MP increased levels of phospho-AS160, although this effect was not modulated by NR4A3 overexpression or knockdown. These primary findings provide a novel proof of principle that 6-MP, a small molecule NR4A3 agonist, can augment glucose uptake in insulin target cells, although this occurs via both NR4A3-dependent and -independent actions; the latter is related to an increase in phospho-AS160. These results establish a novel target for development of new treatments for insulin resistance.

Rosiglitazone attenuates the severity of hyperlipidemic severe acute pancreatitis in rats

Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand regulates adipocyte differentiation and insulin sensitivity, and exerts antihyperlipidemic and anti-inflammatory effects. However, the mechanisms by which PPAR-γ ligands affect hyperlipidemia with severe acute pancreatitis (SAP) have not been fully elucidated. The present study investigated the effects of rosiglitazone, a PPAR-γ ligand, on hyperlipidemia with SAP in a rat model. The hyperlipidemia was induced with a high-fat diet and SAP was induced by the administration of sodium taurocholate (TCA). The hyperlipidemia was shown to aggravate the severity of the sodium taurocholate-induced SAP. However, rosiglitazone demonstrated significant antihyperlipidemic and anti-inflammatory effects in the rats with high-lipid diet-induced hyperlipidemia and SAP.

MicroRNA miR-378 regulates adipocytokine fate by targeting transcriptional factors in human visceral and subctaneous adipose tissue

Purpose: MicroRNAs (miRNA), single-stranded non-protein coding gene products, regulate gene expression through post-transcriptional inhibition, and known to be involved in essential biological processes including obesity and insulin resistance. miR-378 and miR-378*, which are encoded by PGC-1β gene and counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. We conducted to elucidate the role of miR378 expression in human adiposity and adipose tissue inflammation. Methods: Pair samples were obtained from subcutaneous (SAT) and visceral adipose tissue (VAT) during elective operation in 71 men and 42 women. Mature miRNA levels were determined by qRT-PCR and normalized to levels of U6 small nuclear ribonucleoprotein. Subcutaneous (SFA) and visceral fat area (VFA) was determined by abdominal multidetector CT scanning. Adipocyte sizing was determined by the osmium-fixed method on a Coulter counter. Results: Study 1 (clinical study): SFA were larger than VFA, and the mean size of adipocytes was greater in SAT than in VAT. In VAT, level of log(miR100) was positively correlated with level of adiponectin, TLR4 and HMGB1, while negatively correlated with CD68, NOX4 and with mean size of adipocyte. In SAT, level of log(miR100) was positively correlated with level of IL18, TLR4 and HMGB1, while negatively correlated with NOX4. Study 2 (in vitro study): expression levels of miR100 as well as PPARγ2 and PGC1α were increased in adipocyte-like 3T3L1 cells during differentiation. Levels of PPARγ2 and PGC1α were inhibited by antisense miRNA transfection. The expression levels of computer-predicted target genes, ACSL1, acyl-CoA synthetase long-chain family member 1 and AGPAT6, 1-acylglycerol-3-phosphate O-acyltransferase 6 (lysophosphatidic acid acyltransferase ζ), were partially inhibited by anti-sense miR-378 overexpression. Conclusion: Adipose tissue miR378 is derived mostly from adipocytes and may play a role in regulating expressions of adipocyte inflammatory cytokines and insulin sensitivity in human. Results suggested that mir-378 regulates adipocytokine expression by targeting transcriptional factors and controls adipose tissue inflammation in human.

Fgf21 Impairs Adipocyte Insulin Sensitivity in Mice Fed a Low-Carbohydrate, High-Fat Ketogenic Diet

BackgroundA low-carbohydrate, high-fat ketogenic diet (KD) induces hepatic ketogenesis and is believed to affect energy metabolism in mice. As hepatic Fgf21 expression was markedly induced in mice fed KD, we examined the effects of KD feeding on metabolism and the roles of Fgf21 in metabolism in mice fed KD using Fgf21 knockout mice.Methodology/Principal FindingsWe examined C57BL/6 mice fed KD for 6 or 14 days. Blood β-hydroxybutyrate levels were greatly increased at 6 days, indicating that hepatic ketogenesis was induced effectively by KD feeding for 6 days. KD feeding for 6 and 14 days impaired glucose tolerance and insulin sensitivity, although it did not affect body weight, blood NEFA, and triglyceride levels. Hepatic Fgf21 expression and blood Fgf21 levels were markedly increased in mice fed KD for 6 days. Blood β-hydroxybutyrate levels in the knockout mice fed KD for 6 days were comparable to those in wild-type mice fed KD, indicating that Fgf21 is not required for ketogenesis. However, the impaired glucose tolerance and insulin sensitivity caused by KD feeding were improved in the knockout mice. Insulin-stimulated Akt phosphorylation was significantly decreased in the white adipose tissue in wild-type mice fed KD compared with those fed normal chow, but not in the muscle and liver. Its phosphorylation in the white adipose tissue was significantly increased in the knockout mice fed KD compared with wild-type mice fed KD. In contrast, hepatic gluconeogenic gene expression in Fgf21 knockout mice fed KD was comparable to those in the wild-type mice fed KD.Conclusions/SignificanceThe present findings indicate that KD feeding impairs insulin sensitivity in mice due to insulin resistance in white adipose tissue. In addition, our findings indicate that Fgf21 induced to express by KD is a negative regulator of adipocyte insulin sensitivity in adaptation to a low-carbohydrate malnutritional state.

Importance of estrogen receptors in adipose tissue function

Adipose tissue dysfunction belongs to the primary defects in obesity and may link excessive fat accumulation to several health problems including increased risk of insulin resistance, type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, atherosclerosis, dementia, and certain forms of cancer [1]. Symptoms of adipose tissue (AT) dysfunction include ectopic fat deposition in visceral depots, adipocyte hypertrophy, increased number of immune cells infiltrating AT, impaired insulin sensitivity and lipolysis in adipocytes, and the production of a proinflammatory, atherogenic, and diabetogenic adipokine pattern [1]. In this context, it is important to note that approximately 10–15% of obese individuals are protected against obesity-associated metabolic and cardiovascular diseases and therefore called metabolically healthy or insulin sensitive obese [2]. Metabolically healthy obesity may result from preserved adipose tissue function and is more frequently observed in pre-menopausal women compared to both postmenopausal women and men [1]. Moreover, there are significant differences in fat distribution, adipocyte and AT function between men and women, which may, to a large extent, result from gender differences in estrogen receptor expression [3]. In postmenopausal women, decreased circulating estrogens may contribute to the development of visceral obesity and subsequent metabolic disorders—a phenomenon, which can be partly reversed by estrogen replacement therapy [4]. Visceral and subcutaneous abdominal fat distribution (often referred to as male type of fat distribution) is commonly associated with metabolic complications of obesity, whereas lower-body fat (gluteal-femoral), which is considered the typical “female fat distribution”, may be protective. Investigating metabolic properties of adipose tissue, in order to better understand the mechanisms that regulate AT function distinctly in men and women, is a goal of current research endeavors. During the past decades, it has become clear that there are gender-dependent differences in AT biology, including adipogenesis, adipose tissue developmental patterning, the storage and release of fatty acids, as well as AT's secretory function. The well recognized effects of estrogens in the regulation of glucose homeostasis and lipid metabolism may at least in part be due to their action in adipose tissue. In this issue of Molecular Metabolism, Davis and co-workers provide novel experimental evidence that AT and adipocyte estrogen receptor alpha (ERα) play an important role in maintaining AT function and protecting AT against inflammatory damage [5]. The first notion that estrogen/ERα signaling may be associated with obesity and the development of AT comes from studies of ERα whole body knockout

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that regulates cellular redox potential. In this study, we demonstrate that macrophage G6PD plays an important role in the modulation of proinflammatory responses and oxidative stress. The G6PD levels in macrophages in the adipose tissue of obese animals were elevated, and G6PD mRNA levels positively correlated with those of proinflammatory genes. Lipopolysaccharide (LPS) and free fatty acids, which initiate proinflammatory signals, stimulated macrophage G6PD. Overexpression of macrophage G6PD potentiated the expression of proinflammatory and pro-oxidative genes responsible for the aggravation of insulin sensitivity in adipocytes. In contrast, when macrophage G6PD was inhibited or suppressed via chemical inhibitors or small interfering RNA (siRNA), respectively, basal and LPS-induced proinflammatory gene expression was attenuated. Furthermore, macrophage G6PD increased activation of the p38 mitogen-activated protein kinase (MAPK) and NF-κB pathways, which may lead to a vicious cycle of oxidative stress and proinflammatory cascade. Together, these data suggest that an abnormal increase of G6PD in macrophages promotes oxidative stress and inflammatory responses in the adipose tissue of obese animals.

PPAR-γ: A Master Metabolic Nuclear Receptor

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of metabolic nuclear receptors called PPARs, which regulate all facets of the fatty acid metabolism including transport, synthesis, storage, mobilization, activation and oxidation of fatty acids. Hence, this receptor could be a drug target for metabolic syndrome-related noncommunicable diseases (NCD) like obesity, diabetes, cardiovascular disease and cancers. The PPAR-γ gene has different size and transcriptional variants in different species. The major transcriptional variants (PPAR-γ1 and PPAR-γ2) encode proteins with 475/477 and 505 amino acids, respectively. Transcriptional regulation of PPAR-γ is mainly due to combinatorial activity of several transcription factors, chromatin remodelers and non-coding RNA at its promoters and enhancers during energy-surplus state. The miR-130a/b could be a major miRNA regulating PPAR-γ transcripts at post-transcriptional levels. Its protein has a large ligand-binding pocket to bind a wide range of endogenous and exogenous natural (e.g., dietary lipids) and synthetic ligands (TZDs). Along with its obligate partner RXR, and other co-activators, it exerts its action by DNA binding at DR1 and DR2 repeats and also by chromatin remodeling at the promoters and enhancers of its target genes. It has important physiological roles in adipocyte differentiation, inflammation, insulin sensitivity and reproduction. By enhancing the transcription of genes related to lipid uptake, triglyceride synthesis and glucose metabolism, PPAR-γ sequesters the plasma-free fatty acids into adipose tissue and, thereby, it plays a greater role of promoting systemic insulin sensitivity. Hence, it is a key target for anti-diabetic drugs like TZDs. Due to many side effects for classical PPAR-γ-targeting drugs like TZDs, selective PPAR-γ modulators are gaining a great lot of attention. Future studies need to be carried out to understand its transcriptional and post-transcriptional regulation in non-adipose tissues adopting advanced omics approaches. Such studies will be helpful in designing selective PPAR-γ modulators with limited side effects.

Botanical extracts modulate adipocyte function and insulin sensitivity in vitro and in vivo

Historically, many drugs have been developed from plant extracts. The study of botanical extracts is an emerging area in obesity and T2DM research. Botanical extracts are a rich source of molecules capable of modulating adipocyte development and function. Thus, botanicals which alter the properties of fat cells could be protective or causative of obesity, metabolic syndrome and/or T2DM. We used 3T3‐L1 cells and C57BL/6 mice to study the effects of botanicals on adipocytes and adipose tissue. We examined adipogenesis in vitro and insulin action and adipokine secretion in mice. In a screen of botanical extracts for potential novel therapeutic modulators of adipocytes, we identified several positive regulators of fat cell development from the genus Artemisia. Our studies revealed that extracts of several Artemisia species promote differentiation of 3T3‐L1 fat cells and increase adiponectin secretion in mature adipocytes. Additionally, in C57BL/6 mice maintained on a 60% high fat diet, administration of the Artemisia extracts improved insulin‐sensitive Akt serine phosphorylation within white adipose tissue and increased circulating adiponectin levels. In summary, we have in vitro and in vivo data to demonstrate that Artemisia extracts have a beneficial impact on metabolic syndrome by improving adipocyte development and function. Support: PBRC BRC Pilot funding and NIH grant P50AT002776–06 from ODS and NCAAM.

Association of an oral formulation of angiotensin-(1–7) with atenolol improves lipid metabolism in hypertensive rats

The β-adrenergic blockers and antagonists of the renin-angiotensin system (RAS) are among the drugs that present better results in the control of cardio-metabolic diseases. The aim of the present study was to evaluate the effect of the association of the β-blocker, atenolol, and an oral formulation of Ang-(1–7) on lipid metabolism in spontaneously hypertensive rats (SHR). The main results showed that SHR treated with oral formulation of Ang-(1–7) in combination to atenolol have an improvement of lipid metabolism with a reduction of total plasma cholesterol, improvement of oral fat load tolerance and an increase in the lipolytic response stimulated by the β-adrenergic agonist, isoproterenol, without modification of resting glucose or insulin sensitivity in adipocytes. In conclusion, we showed that administration of an Ang-(1–7) oral formulation in association with a β-blocker induces beneficial effects on dyslipidemia treatment associated with hypertension.