The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes

Adipocyte cell proliferation is an important process in body fat mass development in obesity. Adiponectin or Acrp30 is an adipocytokine exclusively expressed and secreted by adipose tissue that regulates lipid and glucose metabolism and plays a key role in body weight regulation and homeostasis. Adiponectin mRNA expression in adipose tissue and plasma level of adiponectin are decreased in obesity and type 2 diabetes. In obese rodents, the selective CB(1) receptor antagonist rimonabant reduces food intake and body weight and improves lipid and glucose parameters. We have reported previously that rimonabant stimulated adiponectin mRNA expression in adipose tissue of obese fa/fa rats, by a direct effect on adipocytes. We report here that rimonabant (10-400 nM) inhibits cell proliferation of cultured mouse 3T3 F442A preadipocytes in a concentration-dependent manner. In parallel to this inhibitory effect on preadipocyte cell proliferation, rimonabant (25-100 nM) stimulates mRNA expression and protein levels of two late markers of adipocyte differentiation (adiponectin and glyceraldehyde-3-phosphate dehydrogenase) with a maximal effect at 100 nM, without inducing the accumulation of lipid droplets. Furthermore, treatment of mouse 3T3 F442A preadipocytes with rimonabant (100 nM) inhibits basal and serum-induced p42/44 mitogen-activated protein (MAP) kinase activity. These results suggest that inhibition of MAP kinase activity by rimonabant may be one of mechanisms involved in the inhibition of 3T3 F442A preadipocyte cell proliferation and stimulation of adiponectin and GAPDH expression. The inhibition of preadipocyte cell proliferation and the induction of adipocyte late "maturation" may participate in rimonabant-induced antiobesity effects, particularly the reduction of body fat mass.     

Sarsasapogenin improves adipose tissue inflammation and ameliorates insulin resistance in high-fat diet-fed C57BL/6J mice

Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome.Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance.Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals.Sarsasapogenin(ZGY)is one of the metabolites of timosaponin AIII in the gut,which has been shown to exert anti-inflammatory action.In this study,we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice.We showed that pretreatment with ZGY(80 mg·kg^?1·d^?1,ig,for 18 days)significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice.In high-fat diet(HFD)-fed obese mice,oral administration of ZGY(80 mg·kg^?1·d^?1,for 6 weeks)ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages.Furthermore,we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes,but also interrupts the crosstalk between macrophages and adipocytes in vitro,improving adipocyte insulin resistance.The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK/NF-κB and JNK inflammatory signaling pathways in adipocytes.Collectively,our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice,suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.     

Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity

Obesity was first described as a low-grade inflammatory condition more than a decade ago. However, it is only relatively recently that obese individuals have been described with increased macrophage infiltration of adipose tissue, as well as an increase in the number of "M1" or "classically activated" macrophages. Furthermore, macrophages have been identified as the primary source of many of the circulating inflammatory molecules that are detected in the obese state and are postulated to be causal both in the development of insulin resistance and in the progression to type 2 diabetes. There is also novel evidence to suggest that macrophages inhibit adipocyte differentiation, potentially leading to adipocyte hypertrophy, altered secretion of adipokines and ectopic storage of lipid within liver, muscle and other non-adipose tissues. Currently, it is not clear what causes increased macrophage infiltration of adipose tissue in obese individuals. Theories include altered signalling by adipocytes, nutritional induction of metabolic endotoxemia or reduced angiogenesis and local adipose cell hypoxia. Importantly, PPAR-gamma agonists have been shown to alter macrophage phenotype to "M2" or an "alternatively activated" anti-inflammatory phenotype and may induce macrophage specific cell death. Consequently, excitement surrounds the potential for specific inhibition of macrophage infiltration of adipose tissue via pharmacotherapy for obese patients and more particularly as adjunct therapy to improve insulin sensitivity in obese individuals with insulin resistance and overt type 2 diabetes.     

Quantitative comparison of adipocytokine gene expression during adipocyte maturation in non-obese and obese rats

Adipocytokines secreted from adipocytes have been extensively analyzed due to their role as key factors in various complications of obesity, including arterial sclerosis, liver steatosis, insulin resistance, and diabetes. Several in vivo and in vitro studies have suggested that adipocyte maturation is related to fluctuations in adipocytokine secretion. However, the relationship between adipocyte maturation and adipocytokine levels has not been fully elucidated. Therefore, we sought to clarify the link between adipocytokine gene expression and adipocyte maturation through systematic analysis. We quantified mRNA for six adipocytokine genes: adiponectin, resistin, leptin, plasminogen activator inhibitor 1 (PAI-1), heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and visfatin, in adipose tissue, in primary cultured adipocytes obtained from an obese Zucker rat, and in the preadipocyte cell line 3T3-L1. Moreover, to elucidate the role of adipocytokines in adipocyte maturation, adipocytokine expression levels were analyzed during maturation. Although fluctuations in adipocytokine gene expression were heterogeneous, gene expression was highly similar during maturation of primary cultured adipocytes from obese and non-obese rats, suggesting that the maturation process is independent from processes that lead to obesity. Moreover, the expression patterns of adiponectin, resistin and leptin mRNA in 3T3-L1 cells were highly similar to those in primary cultured adipocytes, indicating that these adipocytokines could be common maturation markers for primary cultured adipocytes obtained from obese and non-obese rats, and for preadipocyte cell lines.     

Environmental chemical tributyltin augments adipocyte differentiation

Scientific attention has been drawn to environmental factors that affect obesity and type II diabetes. Previously, acute organotin toxicosis was reported to induce hyperglycemia without morphological abnormalities in islet tissue, suggesting that these compounds have a direct effect on adipose tissue. Therefore, we investigated the effect of tributyltin (TBT) on adipocyte differentiation. When confluent 3T3-L1 cells were incubated with TBT for 2 days in the presence or absence of isobutyl methylxanthine, dexamethasone and insulin (MDI), the lipid accumulation in adipocytes was greatly enhanced. These morphological changes induced by TBT were accompanied by the expression of a differentiation marker for adipocytes in a dose-dependent manner. Co-treatment with the peroxisome proliferator-activated receptor (PPAR)gamma antagonist GW9662 did not inhibit the effect of TBT, suggesting that the observed effect of TBT may not be PPARgamma-dependent. Although TBT was reported to exert androgenic effects and inhibit the activity of aromatase, treatments with dihydrotestosterone or 17beta-estradiol did not influence the aP2 expression in 3T3-L1 cells, suggesting that the TBT effect does not occur via sex-steroids. These findings indicate that TBT may be one of the environmental chemicals that lead to excessive accumulation of adipose tissue, which can result in obesity.     

Factor for adipocyte differentiation 158 gene disruption prevents the body weight gain and insulin resistance induced by a high-fat diet

To clarify the molecular mechanism of adipocyte differentiation, we previously isolated a novel gene, factor for adipocyte differentiation (fad) 158, whose expression was induced during the earliest stages of adipogenesis, and its product was localized to the endoplasmic reticulum. We found that the knockdown of fad158 expression prevented the differentiation of 3T3-L1 cells into adipocytes. In addition, over-expression of fad158 promoted the differentiation of NIH-3T3 cells, which do not usually differentiate into adipocytes. Although these findings strongly suggest that fad158 has a crucial role in regulating adipocyte differentiation, the physiological role of the gene is still unclear. In this study, we generated mice in which fad158 expression was deleted. The fad158-deficient mice did not show remarkable changes in body weight or the weight of white adipose tissue on a chow diet, but had significantly lower body weights and fat mass than wild-type mice when fed a high-fat diet. Furthermore, although the disruption of fad158 did not influence insulin sensitivity on the chow diet, it improved insulin resistance induced by the high-fat diet. These results indicate that fad158 is a key factor in the development of obesity and insulin resistance caused by a high-fat diet.     

Aliskiren reduces body-weight gain,adiposity and plasma leptin during diet-induced obesity

Background and purpose:

Overfeeding increases adipose tissue mass and leptin production and up-regulates the renin-angiotensin system in adipose tissue in rodents. Here, we determined the effect of chronic treatment with the renin inhibitor, aliskiren, in a model of diet-induced obesity in mice, on: (i) body weight, adipose tissue weight and plasma leptin; (ii) food intake and caloric efficiency; and (iii) angiotensin II (Ang II) in adipose tissue.

Experimental approach:

Four-week-old C57BL/6J mice (n= 40) received aliskiren (50 mg·kg⁻¹·day⁻¹; 6 weeks) by means of a subcutaneous osmotic Alzet minipump. Animals were given either a low-fat (10% kcal from fat) or a high-fat diet (45% kcal from fat) during this period. Food-intake and body-weight variation were monitored during treatment.

Key results:

In addition to a decrease of plasma renin activity, aliskiren reduced body-weight gain, adipose pads and plasma leptin concentration, independent of the diet. In adipose tissue, local concentrations of Ang II were also reduced by aliskiren.

Conclusions and implications:

Aliskiren limited the gain of adiposity in young mice. This effect was not due to changes in food intake or caloric efficiency and might be related to a down-regulation of the local renin-angiotensin system in adipose tissue. These effects were accompanied by reduced plasma leptin levels. As Ang II favours differentiation of adipocytes, it is possible that the decreased adipose tissue was linked to changes in adipocyte size and number.     

Direct adipotropic actions of atorvastatin: differentiation state-dependent induction of apoptosis, modulation of endocrine function, and inhibition of glucose uptake

Statins exert anti-inflammatory, anti-atherogenic actions. The mechanisms responsible for these effects remain only partially elucidated. Diabetes and obesity are characterized by low-grade inflammation. Metabolic and endocrine adipocyte dysfunction is known to play a crucial role in the development of these disorders and the related cardiovascular complications. Thus, direct modulation of adipocyte function may represent a mechanism of pleiotropic statin actions. We investigated effects of atorvastatin on apoptosis, differentiation, endocrine, and metabolic functions in murine white and brown adipocyte lines. Direct exposure of differentiating preadipocytes to atorvastatin strongly reduced lipid accumulation and diminished protein expression of the differentiation marker CCAAT/enhancer binding protein-beta (CEBP-beta). In fully differentiated adipocytes, however, lipid accumulation remained unchanged after chronic atorvastatin treatment. Furthermore, cell viability was reduced in response to atorvastatin treatment in proliferating and differentiating preadipocytes, but not in differentiated cells. Moreover, atorvastatin induced apoptosis and inhibited protein kinase B (AKT) phosphorylation in proliferating and differentiating preadipocytes, but not in differentiated adipocytes. On the endocrine level, direct atorvastatin treatment of differentiated white adipocytes enhanced expression of the pro-inflammatory adipokine interleukin-6 (IL-6), and downregulated expression of the insulin-mimetic and anti-inflammatory adipokines visfatin and adiponectin. Finally, these direct adipotropic endocrine effects of atorvastatin were paralleled by the acute inhibition of insulin-induced glucose uptake in differentiated white adipocytes, while protein expression of the thermogenic uncoupling protein-1 (UCP-1) in brown adipocytes remained unchanged. Taken together, our data for the first time demonstrate direct differentiation state-dependent effects of atorvastatin including apoptosis, modulation of pro-inflammatory and glucostatic adipokine expression, and insulin resistance in adipose cells. These differential interactions may explain variable clinical observations.     

The anti-angiogenic herbal extracts Ob-X from Morus alba,Melissa officinalis,and Artemisia capillaris suppresses adipogenesis in 3T3-L1 adipocytes

Context: Growing adipose tissue is thought to require adipogenesis, angiogenesis, and extracellular matrix (ECM) remodeling. Close examination of developing adipose tissue microvasculature reveals that angiogenesis often precedes adipogenesis. Since our previous study demonstrated that Ob-X, the anti-angiogenic herbal composition composed of Melissa officinalis L. (Labiatae), Morus alba L. (Moraceae), and Artemisia capillaris Thunb. (Compositae), reduced adipose tissue mass in obese mice, we hypothesized that adipogenesis can be inhibited by Ob-X.

Objective: To investigate the effects of the anti-angiogenic herbal extracts Ob-X on adipogenesis in 3T3-L1 adipocytes.

Materials and methods: After differentiated 3T3-L1 adipocytes were treated with Ob-X, we studied the effects of Ob-X on triglyceride accumulation and expression of genes involved in adipogenesis, angiogenesis, and ECM remodeling.

Results: Treatment of cells with Ob-X inhibited lipid accumulation and adipocyte-specific gene expression caused by troglitazone or monocyte differentiation-inducing (MDI) mix. Ob-X reduced mRNA levels of angiogenic factors (vascular endothelial growth factor-A, -B, -C, -D, and fibroblast growth factor-2) and matrix metalloproteinases (MMPs; MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenic inhibitors [(thrombospondin-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2)] in differentiated cells. MMP-2 and MMP-9 activities were also decreased in Ob-X-treated cells.

Discussion and conclusion: These results suggest that the anti-angiogenic herbal composition Ob-X inhibits differentiation of preadipocytes into adipocytes. These events may be mediated by changes in the expression of genes involved in lipogenesis, angiogenesis, and the MMP system. Thus, by reducing adipogenesis, anti-angiogenic Ob-X provides a possible therapeutic approach for the prevention and treatment of human obesity and its related disorders.     

Developmental aspects of the Adipose tissue renin-angiotensin system: Therapeutic implications

Adipose tissue possesses considerable growth potential, and excess adipose tissue mass is associated with noninsulin dependent diabetes mellitus (NIDDM). Adipose tissue is a significant source of angiotensinogen, the precursor of angiotensin II (All), a vasoactive peptide with in vitro mitogenic effects. The renin-angiotensin system remains only partially identified in adipose tissue, however, and knowledge of whether All has a physiologic role in this tissue is dependent in part upon other components of the system being characterized. We have chosen to further investigate aspects of the renin-angiotensin system in separate adipose tissue depots of rats during growth and development of the tissue. Either epididymal or retroperitoneal adipose tissue was examined in young lean, or adult obese male Sprague-Dawley rats. Adipose tissue was subjected to collagenase digestion, yielding separate vascular and fat cell fractions. Each fraction was analyzed for angiotensin converting enzyme (ACE) activity and All receptor binding capacity. ACE activity was significantly greater when expressed per gram of adipose tissue in the young lean rats. Vascular and fat cell fractions exhibited All receptors of high affinity, with a greater density of receptors observed in the epididymal adipose tissue fractions. Incubation of adipocytes with exogenous All was associated with the release of prostaglandin into the medium, and analyses of adipocyte cytosol indicated the presence of angiotensinogen. Growing rats given oral losartan, an All receptor antagonist, once daily (15 mg/kg) for 2 weeks exhibited reductions in body weight gain, fat mass, fat cell volume, and All receptor number. These data further document the presence of a peripheral renin-angiotensin system in anatomically distinct adipose tissue depots at different stages of growth. While the characterization of the effects of All upon adipose tissue development remains incomplete, future investigations with agents affecting the adipocyte renin-angiotensin system could provide additional information on the role of this system in adipose tissue growth.     

Differentiation of embryonic stem cells for pharmacological studies on adipose cells.

The ongoing global explosion in the incidence of obesity has focused attention on the development of adipose cells. Severe obesity is the result of an increase in fat cell size in combination with increased fat cell number. New fat cells arise from a pre-existing pool of adipose stem cells that are present irrespective of age. The development of established preadipocyte cell lines has facilitated the study of different steps leading to terminal differentiation. However, these systems are limited for studying early events of differentiation as they represent cells which are already determined for the adipogenic lineage. In vitro differentiation of mouse embryonic stem (ES) cells towards the adipogenic lineage provides an alternative source of adipocytes for study in tissue culture and offers the possibility to investigate regulation of the first steps of adipose cell development. In this review, we describe the sequential requirement of retinoic acid and PPARgamma during adipogenesis in ES cells. Stimulation of ES cells with synthetic retinoids which are selective ligands of the retinoic acid receptor isotypes allowed the investigation of the contribution of the different retinoic receptors on the RA-dependent differentiation. The effects of thiazolidinediones, a new class of pharmacological agents used for the treatment of type 2 diabetes, and of statins, drugs used in therapy for lowering cholesterol, on the differentiation of ES cells into adipocytes or osteoblasts are described. Finally, we propose a model in which PPARgamma plays a key role in the decision of stem cells to undergo differentiation into adipocytes or osteoblasts, two closely related lineages.     

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β₃-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.     

Adipocyte-derived exosomal miR-27a induces insulin resistance in skeletal muscle through repression of PPARγ

OBJECTIVE To explore increasingly exosomal serum miR-27 a derived from adipocytes could be taken up by skeletal muscle tissue and induce insulin resistance in skeletal muscle in obese state. METHODS The association between miR-27 a and insulin resistance in skeletal muscle was determined in obese children,high-fat diet-induced miR-27 a knockdown obese mice,db/db mice and C2C12 cells overexpressing miR-27 a.The crosstalk mediated by exosomal miR-27 a between adipose tissue and skeletal muscle was determined in C2C12 cel s incubated with conditioned medium prepared from palmitate-treated 3 T3-L1 adipocytes. RESULTS After knockdown miR-27 a in obese insulin resistance mice,impaired insulin resistance, glucose intolerance and insulin resistance of skeletal muscle were partly restored. In high-fat diet group, the expressions of IRS-1 and GLUT4 in glucose uptake signal pathway of skeletal muscle were significantly decreased, while the expression of IRS-1 and GLUT4 was restored after miR-27 a knockdown. The content of FABP4, a marker specific for exosomes from adipocytes, was detected in sera, skeletal muscle, supernatant of adipocytes and co-cultured C2C12 cells; furthermore,exosomal miR-27 a in serum and adipocyte supernatants were detect, and fluorescence co-localization experiments were conducted to detect whether the exosomal miR-27 a in serum is mainly derived from adipocyte; finally,we used the supernatant of adipose tissue to construct conditioned media to treat with C2C12 cells, and detected whether adipocytes derived exosomal miR-27 a could impaired glucose uptake signaling pathway of skeletal muscle. the expressions of PPARγ silencing high-fat diet induced C57 BL/6 J obese mouse model and adenovirus intervention miR-27 a knockdown model were examined,and a C2C12 cell model overexpressing miR-27 a in the absence or presence with rosiglitazone(PPARγ activator)were established to test glucose consumption, glucose uptake, and glucose uptake signaling pathways of skeletal muscle cells. CONCLUSION These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27 a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle.     

Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells

There is growing evidence to suggest that reservoirs of stem cells may reside in several types of adult tissue. These cells may retain the potential to transdifferentiate from one phenotype to another, presenting exciting possibilities for cellular therapies. Recent discoveries in the area of neural differentiation are particularly exciting given the limited capacity of neural tissue for intrinsic repair and regeneration. Adult adipose tissue is a rich source of mesenchymal stem cells, providing an abundant and accessible source of adult stem cells. These cells have been termed adipose derived stem cells (ASC). The characterization of these ASCs has defined a population similar to marrow-derived and skeletal muscle-derived stem cells. The success seen in differentiating ASC into various mesenchymal lineages has generated interest in using ASC for neuronal differentiation. Initial in vitro studies characterized the morphology and protein expression of ASC after exposure to neural induction agents. Additional in vitro data suggests the possibility that ASCs are capable of neuronal activity. Progress in the in vitro characterization of ASCs has led to in vivo modeling to determine the survival, migration, and engraftment of transplanted ASCs. While work to define the mechanisms behind the transdifferentiation of ASCs continues, their application to neurological diseases and injuries should also progress. The subject of this review is the capacity of adipose derived stem cells (ASC) for neural transdifferentiation and their application to the treatment of various neurologic disorders.     

In vivo imaging reveals adipose tissue inflammation in obesity and multi-cellular processes of developing thrombus

The metabolic syndrome is a major risk factor of cardiovascular events, and obese visceral adipose tissue remodeling based on chronic inflammation plays a central role. To assess dynamic interplay between multiple cell types in obese adipose tissue, a visualization technique in vivo was developed. By this technique we identified inflammatory cell clusters associated with angiogenesis and adipogenesis in obese adipose tissue. We also found increased leukocyte-platelet-endothelial cell interactions in obese adipose tissue microcirculation, which were indicative of local chronic inflammation. Moreover, we found that large numbers of CD8(+) effector T cells infiltrated into obese adipose tissue. Immunological and genetic depletion of CD8(+) T cells reduced inflammatory (M1) macrophage infiltration and adipose tissue inflammation, and ameliorated systemic insulin resistance. Infiltration of CD8(+) T cells is essential for inflammatory macrophage recruitment into obese adipose tissue, and the initiation and development of inflammation therein. Our results clearly demonstrate the power of our imaging technique to analyze complex cellular interplay in vivo, especially parenchymal and stromal cell crosstalk, and to evaluate new therapeutic interventions against conditions arising from these interactions.     

Effect of gelatinase inhibition on adipogenesis and adipose tissue development

1. The potential of the matrix metalloproteinase (MMP) inhibitor ABT-518 to affect pre-adipocyte differentiation in vitro and adipose tissue development in vivo was investigated using mouse models of adipogenesis and obesity. 2. Differentiation of 3T3-F442A pre-adipocytes into mature adipocytes was enhanced in a dose-dependent manner by the addition of ABT-518 (0-100 μmol/L). This was associated with increased expression of the adipogenic markers adipocyte fatty acid-binding protein 2 (AP2), peroxisome proliferator-activated receptor γ and adiponectin. 3. Feeding 5-week-old male wild-type mice with a high-fat diet, with or without ABT-518 (to achieve a dose of 100 mg/kg per day), for 16 weeks resulted in a significant reduction in bodyweight throughout the experimental period. Magnetic resonance spectroscopy revealed that the lipid : water ratio was significantly lower in ABT-518-treated mice. The total weight of isolated subcutaneous or gonadal fat depots did not differ significantly following ABT-518 treatment, but adipocyte and blood vessel size were significantly reduced in the gonadal fat. 4. Administration of ABT-518-2 (100 mg/kg per day for 10 weeks) to 5-week-old male wild-type mice with established obesity maintained on a high-fat diet had no effect on total bodyweight at the end of the experiment, but was associated with reduced blood vessel size in the fat depots. 5. Thus, the MMP inhibitor ABT-518 stimulates differentiation of 3T3-F442A pre-adipocytes in vitro. It mildly reduces bodyweight gain in a murine model of diet-induced obesity, but does not affect established obesity.     

Integrated regulation of the cellular metabolism and function of immune cells in adipose tissue

Obesity is known to associate with low‐grade, sustained, systemic inflammation, which is considered to be a key pathological basis for obesity‐associated diseases such as diabetes and atherosclerosis. Immune cells, including both lymphocytes and macrophages, play physiological and pathological roles in adipose tissue. They increasingly infiltrate obese adipose tissue as body weight is gained, after which the infiltrated cells promote adipose tissue inflammation and strongly impact systemic metabolism. Recent studies have shown that the immune and metabolic systems are highly integrated with one another. This recognition has provided new insight into the mechanisms of metabolic diseases. In addition to the link at the tissue level, studies have shown that immune cell function is coordinately regulated with cellular metabolism. This review summarizes the current understanding of the specific metabolic signatures adopted by lymphocytes and macrophages to mediate proper effecter function. These findings will be related to the regulation of adipose tissue homeostasis and inflammation.     

Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target

Fat cells or adipocytes are distributed ubiquitously throughout the body and are often regarded purely as energy stores. However, recently it has become clear that these adipocytes are engine rooms producing large numbers of metabolically active substances with both endocrine and paracrine actions. White adipocytes surround almost every blood vessel in the human body and are collectively termed perivascular adipose tissue (PVAT). It is now well recognized that PVAT not only provides mechanical support for any blood vessels it invests, but also secretes vasoactive and metabolically essential cytokines known as adipokines, which regulate vascular function. The emergence of obesity as a major challenge to our healthcare systems has contributed to the growing interest in adipocyte dysfunction with a view to discovering new pharmacotherapeutic agents to help rescue compromised PVAT function. Very few PVAT studies have been carried out on human tissue. This review will discuss these and the hypotheses generated from such research, as well as highlight the most significant and clinically relevant animal studies showing the most pharmacological promise. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.     

Chemerin与糖脂代谢关系的研究进展

Chemerin是新发现的一种脂肪因子,在脂肪组织中高度表达,它能通过自分泌途径,作用于自身受体CMKLR1,促进脂肪细胞分化及葡萄糖转运,并可通过自分泌或旁分泌途径,对脂肪组织及脂质代谢产生一系列影响。近期研究发现,Chemerin除具有炎症因子的趋化作用外,还与肥胖、胰岛素抵抗和代谢综合征有密切关系。     

Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes

The immune system is closely linked to human metabolic diseases. Serum levels of IL-6 increase with obesity and insulin resistance. Not only does IL-6 decrease the insulin sensitivity of human cells such as adipocytes, but it also regulates the lineage commitment of naïve T cells into interleukin (IL)-17A-producing CD4(+) T (Th17) cells. Although IL-17A exerts a variety of effects on somatic tissues, its functional role in human adipocytes has not been identified. In this work, we show that IL-17A inhibits adipocyte differentiation in human bone marrow mesenchymal stem cells (hBM-MSCs), while promoting lipolysis of differentiated adipocytes. We find that IL-17A increases both mRNA and protein secretion of IL-6 and IL-8 during adipocyte differentiation in hBM-MSCs. IL-17A up-regulates cyclooxygenase (COX)-2 gene expression and thereby increases the level of prostaglandin (PG) E₂ in differentiated adipocyes. The suppression of anti-adipogenic PGE₂ by COX inhibitors such as aspirin and NS-398 partially blocked the effect of IL-17A on adipocyte differentiation in hBM-MSCs. Therefore, IL-17A exhibits its inhibitory effect in part via the COX-2 induction in differentiated adipocytes. In addition, treatment with anti-IL-17A antibody neutralizes IL-17A-mediated effects on adipocyte differentiation and function. These results suggest that IL-17A plays a regulatory role in both the metabolic and inflammatory processes of human adipocytes, similar to other pro-inflammatory cytokines such as IL-1, IFNγ, and TNFα.