The mechanisms by which PPARgamma and adiponectin regulate glucose and lipid metabolism

Obesity, a state of increased adipose tissue mass, is a major cause for type 2 diabetes, hyperlipidemia, and hypertension, resulting in clustering of risk factors for atherosclerosis. Heterozygous PPARgamma knockout mice and KKA(y) mice administered with a PPARgamma antagonist were protected from high-fat diet-induced adipocyte hypertrophy and insulin resistance. Moderate reduction of PPARgamma activity prevented adipocyte hypertrophy, thereby diminution of TNFalpha, resistin, and FFA and upregulation of adiponectin and leptin. These alterations led to reduction of tissue TG content in muscle/liver, thereby ameliorating insulin resistance. Insulin resistance in the lipoatrophic mice and KKA(y) mice were ameliorated by replenishment of adiponectin. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes, but not the obesity of ob/ob mice. Furthermore, targeted disruption of the adiponectin gene caused moderate insulin resistance and glucose intolerance. In muscle, adiponectin activated AMP kinase and PPARgamma pathways, thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated muscle insulin resistance. In the liver, adiponectin also activated AMPK, thereby downregulating PEPCK and G6Pase, leading to decreased glucose output from the liver. In conclusion, PPARgamma plays a central role in the regulation of adipocyte hypertrophy and insulin sensitivity. The upregulation of the adiponectin pathway by PPARgamma may play a role in the increased insulin sensitivity of heterozygous PPARgamma knockout mice, and activation of adiponectin pathway may provide novel therapeutic strategies for obesity-linked disorders such as type 2 diabetes and metabolic syndrome.     

Are decreased AdipoR1 mRNA levels associated with adiponectin resistance in coronary artery disease patients?

The aim of the present study was to investigate if circulating adiponectin levels and the expression of AdipoR1 and AdipoR2 in peripheral blood mononuclear cells (PBMC) are altered in coronary artery disease (CAD) patients, with and without significant stenosis, compared to healthy patients. The present study included 69 patients with presenting symptoms of CAD (26 patients with significant stenosis and 43 patients without significant stenosis). The control group (CG) consisted of 33 healthy patients. Circulating adiponectin levels were measured by enzyme‐linked immunosorbent assay, whereas AdipoR1 and AdipoR2 mRNA levels in PBMC were determined by real‐time polymerase chain reaction. Adiponectin levels were significantly higher in patients with and without significant stenosis compared to the CG (P < 0.001 vs P = 0.006, respectively). Both patient groups had lower AdipoR1 levels compared to the CG (P < 0.001 vs P < 0.001, respectively). There were no significant differences in these parameters between the two patient groups. Adiponectin negatively correlated with body mass index, triglycerides, insulin and homeostasis model assessment of insulin resistance index (HOMA IR), and positively with high‐denisty lipoprotein cholesterol in the CG. Glucose, insulin, and the HOMA IR index negatively correlated with adiponectin in patients. A positive correlation between adiponectin receptors was found in patients and the CG. Decreased AdipoR1 mRNA levels and increased circulating adiponectin in advanced stages of CAD, as well as in patients without significant stenosis, compared to the CG, implies that CAD could be related to ‘adiponectin resistance’. Despite increased adiponectin, its protective effects could be diminished even in early stages of atherosclerosis.     

妊娠期糖尿病患者胎盘和腹部皮下脂肪组织中脂联素受体2的表达分析

目的 探讨脂联素受体2 (adioponectin receptor2,AdipoR 2)在妊娠期糖尿病患者胎盘及腹部皮下脂肪组织中的表达情况.方法 收集正常妊娠妇女及妊娠期糖尿病患者各20例皮下脂肪组织及胎盘组织,分别采用逆转录聚合酶链反应技术(RT-PCR)及蛋白免疫印迹法(Western bolt)检测AdipoR 2 mRNA及其蛋白质的表达情况.结果 与正常妊娠妇女相比较,妊娠期糖尿病患者胎盘组织中AdipoR 2 mRNA及其蛋白质表达均升高,皮下脂肪组织中AdipoR2 mRNA及其蛋白质表达均降低.结论 AdipoR2在胎盘组织及皮下脂肪组织中表达异常,可能在妊娠期糖尿病的发病机制中起到重要作用.     

替米沙坦对2型糖尿病大鼠心肌脂联素受体2葡萄糖转运蛋白4表达的影响

目的探讨替米沙坦对2型糖尿病大鼠心肌组织脂联素受体2(AdipoR2)及葡萄糖转运蛋白4(GluT4)表达的影响。方法30只雄性Wistar大鼠,随机分为3组:健康对照组(A组),糖尿病组(B组)和糖尿病替米沙坦治疗组(C组),每组各10只。采用高糖高脂饮食加小剂量链脲佐菌素(STZ)的方法诱导糖尿病模型。用逆转录-聚合酶链反应(RT—PCR)的方法测定大鼠心肌AdipoR2mRNA、GluT4mRNA的表达,用免疫组织化学法检测AdipoR2蛋白在心肌组织中的表达,用放射免疫法检测血浆脂联素水平。结果与A组比较,B组糖尿病大鼠心质量/体质量增加,血浆脂联素水平、心肌AdipoR2mRNA和蛋白表达以及GluT4mRNA表达均显著降低。替米沙坦治疗后,C组糖尿病大鼠心质量/体质量降低,血浆脂联素水平、心肌AdipoR2mRNA和蛋白表达以及GluT4mRNA表达均显著升高。结论2型糖尿病大鼠心肌AdipoR2及GluT4表达水平降低。替米沙坦上调2型糖尿病大鼠心肌AdipoR2及GluT4表达,促进心肌葡萄糖氧化,减轻心脏肥大,产生心脏保护作用。     

Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice

Non-selective inhibition of cyclooxygenase (COX) has been reported to reduce atherosclerosis in both rabbit and murine models. In contrast, selective inhibition of COX-2 has been shown to suppress early atherosclerosis in LDL-receptor null mice but not more advanced lesions in apoE deficient (apoE(-/-)) mice. We investigated the efficacy of the novel COX inhibitor indomethacin phenethylamide (INDO-PA) on the development of different stages of atherosclerotic lesion formation in female apoE(-/-) mice. INDO-PA, which is highly selective for COX-2 in vitro, reduced platelet thromboxane production by 61% in vivo, indicating partial inhibition of COX-1 in vivo. Treatment of female apoE(-/-) mice with 5mg/kg INDO-PA significantly reduced early to intermediate aortic atherosclerotic lesion formation (44 and 53%, respectively) in both the aortic sinus and aorta en face compared to controls. Interestingly, there was no difference in the extent of atherosclerosis in the proximal aorta in apoE(-/-) mice treated from 11 to 21 weeks of age with INDO-PA, yet there was a striking (76%) reduction in lesion size by en face analysis in these mice. These studies demonstrate the ability of non-selective COX inhibition with INDO-PA to reduce early to intermediate atherosclerotic lesion formation in apoE(-/-) mice, supporting a role for anti-inflammatory approaches in the prevention of atherosclerosis.     

The effects of beta(3)-adrenoceptor agonist CL-316,243 on adiponectin, adiponectin receptors and tumor necrosis factor-alpha expressions in adipose tissues of obese diabetic KKAy mice

We investigated the effects of beta(3)-adrenoceptor agonist, 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316,243) in obese diabetic KKAy mice. Two weeks' subcutaneous administration of CL-316,243 reduced serum levels of glucose, insulin, triglyceride, free fatty acid and tumor necrosis factor-alpha (TNF-alpha), and increased adiponectin. Adiponectin, adiponectin receptors and beta(3)-adrenoceptor mRNA expressions were reduced in epididymal white adipose tissue in KKAy mice, and CL-316,243 recovered these mRNA expressions. Meanwhile, CL-316,243 suppressed the overexpressed mRNA level of TNF-alpha in both epididymal white adipose tissue and brown adipose tissue. These data suggest that the normalization of adiponectin, adiponectin receptors and TNF-alpha may result in the amelioration of obesity-induced insulin resistance.     

Adiponectin and its potential in the treatment of obesity, diabetes and insulin resistance

Adiponectin is a protein hormone produced exclusively by adipocytes. Its circulating levels are decreased in individuals with obesity, atherosclerosis and insulin resistance, suggesting that its deficiency may have a causal role in the etiopathogenesis of these diseases. Studies have shown that adiponectin administration in rodents has insulin-sensitizing, anti-atherogenic and anti-inflammatory effects and under certain settings also decreases body weight. Therefore, adiponectin replacement in humans may represent a promising approach to prevent and/or treat obesity, insulin resistance and type 2 diabetes; however, clinical studies with adiponectin administration need to be conducted to confirm this hypothesis. Current experimental and clinical data regarding adiponectin physiology and pathophysiology are detailed in this review.     

脂联素受体1基因-102T/G多态位点与山西省汉族人2型糖尿病的关系

目的研究脂联素受体1(AdipoR1)基因-102T/G多态位点与山西汉族人2型糖尿病的关系。方法应用序列特异性引物-聚合酶链反应技术(PCR-SSP)检测50例2型糖尿病患者和50名健康对照者AdipoR1-102T/G单核苷酸多态性位点基因型,并测定所选人群的临床指标。结果①基因型及等位基因频率分布在2型糖尿病患者和健康对照组人群中差异无统计学意义(P>0.05)。②健康对照组人群中,G等位基因携带者空腹血糖较TT基因型者低(P<0.01)。③2型糖尿病患者中,G等位基因携带者空腹胰岛素(P<0.01)、胰岛素抵抗指数(P<0.05)及空腹血糖(P<0.05)较TT基因型者低。结论AdipoR1基因与山西汉族人群糖代谢及胰岛素抵抗相关,与2型糖尿病无关。     

Retinol-binding protein 4 : a possible role in cardiovascular complications

BACKGROUND AND PURPOSE

Retinol-binding protein 4 (RBP4) is an adipocyte-secreted hormone proposed to link obesity with insulin resistance. However, the role of RBP4 in cardiovascular complications is yet to be fully understood. The present study is aimed to decipher the association between RBP4 with pro-inflammatory cytokines and low-density lipoprotein (LDL) cholesterol in diet-induced obese and hyperlipidaemic mice. To understand the correlation, rimonabant, an anti-obesity drug, has been used to relieve the atherosclerotic predisposition.

EXPERIMENTAL APPROACH

Adipose and/or aortic tissue expressions of RBP4, pro-inflammatory cytokine genes and circulating LDL levels were measured in high fat (HF)-fed female C57BL/6 and high cholesterol (HC)-fed apolipoprotein E3 (ApoE3) Leiden mice.

KEY RESULTS

Mice fed a HF diet had a significantly increased adipose expression of RBP4, TNF-α and monocyte chemoattractant protein 1 (MCP-1) and down-regulated adiponectin mRNA levels. A significant increase in aortic RBP4 and MCP-1 expression and circulating levels of LDL and C-reactive protein (CRP) was found in the ApoE3 mice fed a HC diet. Interestingly, rimonabant treatment lowered the elevated aortic RBP4, MCP-1 expressions and significantly reduced the serum levels of LDL, CRP, RBP4 and MCP-1.

CONCLUSION AND IMPLICATIONS

Our results indicate that RBP4 is positively associated with markers of inflammation in obese and pro-atherogenic conditions and could play a role in a predisposition to atherosclerosis. Furthermore, our results indicate that rimonabant may improve vascular function by modulating RBP4 along with pro-inflammatory cytokines.     

Adiponectin and its receptors: Partners contributing to the “vicious circle” leading to the metabolic syndrome?

Although already described five years ago, it is only from year 2000, following intensive research in the field of genetics that the adiponectin protein was related with insulin sensitivity, type 2 diabetes and the metabolic syndrome. The story began with a paradox as this protein exclusively secreted by fat tissue was dramatically decreased in patients presenting an excess of fat mass. Later this decrease was reported with insulin resistance and metabolic syndrome associated phenotypes. The search for genetic variants in the adiponectin encoding ACDC gene and epidemio genetic investigations allowed to associate genetic variations of the gene and phenotypic traits of the metabolic syndrome. One of the major points was the correlation of the levels of circulating adiponectin with insulin sensitivity, leading to a better knowledge of the role of adiponectin. Indeed it is now clearly admitted that adiponectin is an insulin sensitizing cytokine. Recently two adiponectin receptors were described and genetic variations in their genes were associated with features of the metabolic syndrome. Interactions of adiponectin with various partners are discussed in view of a better understanding of adiponectin resistance and insulin resistance.     

BDE-153对胰岛素抵抗和脂肪因子的影响及机制初探

目的 研究2,2',4,4',5,5'-六溴联苯醚(2,2',4,4',5,5'-Hexabromodiphenyl ether,BDE-153)对C57BL/6小鼠胰岛素抵抗和脂肪因子的影响,并初步探讨其可能的机制.方法 雄性C57BL/6小鼠随机分为对照组、BDE-153染毒高、中和低剂量组.利用腹腔注射葡萄糖耐量...     

Adiponectin and its role in cardiovascular diseases

Studies performed during the last decade indicate that adipose tissue is not only a site of triglyceride storage but also an active endocrine organ which secretes many biologically active mediators referred to as "adipokines". In contrast to many adipokines which are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism and cardiovascular system, such as leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, resistin, etc., adiponectin seems to be a unique adipokine which is produced in lower amounts in obese than in lean subjects and possesses predominantly beneficial activities, i.e. increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reaction and induces endothelium-dependent nitric oxide-mediated vasorelaxation. Adiponectin binds two receptors, AdipoR1 and AdipoR2. Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium-dependent vasorelaxation and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Raising endogenous adiponectin level or increasing the sensitivity to this hormone may be a promising therapeutic strategy for patients with metabolic and cardiovascular diseases. Among currently used drugs, thiazolidinediones (peroxisome proliferator activated receptor gamma agonists) are most effective in elevating adiponectin level.     

The glutathione transferase kappa family

Glutathione transferase (GST) kappa, also named mitochondrial GST, is a very ancient protein family with orthologs in bacteria and eukaryotes. Both the structure and the subcellular localization of GSTK1-1, in mitochondria and peroxisomes, make this enzyme distinct from cytosolic GSTs. Rodent and human GSTK1 exhibit activity towards a number of model GST substrates and, in Caenorhabditis elegans, this enzyme may be involved in energy and lipid metabolism, two functions related to mitochondria and peroxisomes. Interestingly, GST kappa is also a key regulator of adiponectin biosynthesis and multimerization suggesting that it might function as a chaperone to facilitate correct folding and assembly of proteins. Since adiponectin expression has been correlated with insulin resistance, obesity and diabetes, GSTK1 expression level which is negatively correlated with obesity in mice and human adipose tissues may be an important factor in these metabolic disorders. Furthermore, a polymorphism in the hGSTK1 promoter has been associated with insulin secretion and fat deposition.     

Myocardial insulin resistance and cardiac complications of diabetes

Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery disease. Indeed, diabetes is an independent risk factor for the development of heart failure and the mechanisms responsible remain to be clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver are widely recognized features of obesity and type 2 diabetes, and contribute to the pathogenesis of impaired glucose homeostasis. Insulin resistance has also been described in the vasculature, and may contribute to endothelial dysfunction and atherosclerosis. The heart is an insulin responsive organ and less is known about whether or not the heart becomes insulin resistant in diabetes and what the pathogenic consequences of this might be. This review will discuss the currently available evidence from human and animal studies, that the heart may become insulin resistant in obesity and type 2 diabetes. The potential consequences of this on cardiac structure, function and metabolism will be discussed as well as recent data from transgenic mice with perturbed cardiac insulin sensitivity that have shed interesting new insight into potential mechanisms linking cardiac insulin resistance with myocardial dysfunction in diabetes.     

Adiponectin and its receptors: Partners contributing to the “vicious circle” leading to the metabolic syndrome?

Although already described five years ago, it is only from year 2000, following intensive research in the field of genetics that the adiponectin protein was related with insulin sensitivity, type 2 diabetes and the metabolic syndrome. The story began with a paradox as this protein exclusively secreted by fat tissue was dramatically decreased in patients presenting an excess of fat mass. Later this decrease was reported with insulin resistance and metabolic syndrome associated phenotypes. The search for genetic variants in the adiponectin encoding ACDC gene and epidemio genetic investigations allowed to associate genetic variations of the gene and phenotypic traits of the metabolic syndrome. One of the major points was the correlation of the levels of circulating adiponectin with insulin sensitivity, leading to a better knowledge of the role of adiponectin. Indeed it is now clearly admitted that adiponectin is an insulin sensitizing cytokine. Recently two adiponectin receptors were described and genetic variations in their genes were associated with features of the metabolic syndrome. Interactions of adiponectin with various partners are discussed in view of a better understanding of adiponectin resistance and insulin resistance.     

糖尿病合并甲状腺功能亢进患者血清胰岛素抵抗和脂联素表达水平及其与甲状腺激素的相关性分析

目的 探讨糖尿病合并甲状腺功能亢进(甲亢)患者血清胰岛素抵抗(IR)指数和脂联素表达水平及其与甲状腺激素的相关性.方法 选择2012年6月-2014年10月收治的50例糖尿病合并甲亢患者作为研究组,选取同期50例单纯糖尿病作为对照组.观察2组IR指数、脂联素、游离三碘甲状腺原氨酸(FT3)、促甲状腺激素(TSH)、游离甲状腺素(FT4)水平,并分析其相关性.结果 研究组IR、脂联素、TSH、FT3、FT4水平均高于对照组(P＜0.05).研究组血清FT3和脂联素、IR指数呈正相关(r=0.4579、0.5874,P=0.015、0.026),血清FT4与脂联素和IR指数呈正相关(r=0.3578、0.4325,P=0.010、0.013),TSH与脂联素和IR指数呈正相关(r=0.4342、0.5012,P=0.014、0.021),IR指数与脂联素也呈正相关(r=0.5745,P=0.024).结论 IR指数和脂联素在糖尿病合并甲亢患者中存在异常增高表达,且其与甲状腺激素水平呈正相关,表明糖尿病合并甲亢患者IR指数及脂联素与甲亢的病变过程有相关关系.     

脂联素与胰岛素抵抗的关系探讨

目的探讨血清脂联素与胰岛素抵抗以及2型糖尿病的关系。方法选择2型糖尿病患者76例,分为非肥胖组34例,肥胖组42例,正常对照组30名,采用酶联免疫分析法检测空腹血糖、胰岛素和脂联素水平。结果正常对照组和糖尿病非肥胖组相比,体重指数(BMI)相同,但稳态模式评估法的胰岛素抵抗指数(HOMA-IR)后者明显大于前者;糖尿病非肥胖组的脂联素水平明显低于正常对照组。糖尿病肥胖组和正常对照组以及糖尿病非肥胖组相比,不论BMI和HOMA-IR,还是脂联素水平差异均有统计学意义。结论2型糖尿病患者血清脂联素水平越降低,胰岛素抵抗越严重;脂联素水平的降低对胰岛素抵抗和糖尿病的发生发展具有促进作用。     

Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin

Type 2 diabetes mellitus (T2DM) is a disease characterized by inadequate beta-cell response due to progressive insulin resistance that typically accompanies physical inactivity and weight gain. T2DM is associated with substantial morbidity and mortality related to the associated atherosclerotic cardiovascular risks and diabetic vasculopathies, including microangiopathies (e.g., blindness and renal failure) and macroangiopathies (atherosclerosis). The increasing global prevalence of T2DM is linked to the rising rates of obesity, especially abdominal obesity. Visceral fat accumulation is upstream of obesity-related disorders including atherosclerotic cardiovascular disease (ACVD), and is associated with impaired insulin sensitivity and atherosclerosis through dysregulated production of adipocytokines, especially hypoadiponectinemia. This review article discusses the pathophysiological mechanisms responsible for T2DM and atherosclerosis, focusing on adiponectin. Clinical and experimental studies have shown that hypoadiponectinemia contributes to a variety of life style-related diseases including T2DM and atherosclerosis. It is likely that life-style modification, visceral fat reduction and use of medications that increase serum adiponectin levels (e.g., rimonabant, thiazolidinediones, fibrates, angiotensin receptor blocker and mineralocorticoid receptor blockade) when provided in combination can improve hypoadiponectinemia and thus prevent the development of life style-related diseases including T2DM and ACVD.