Abstract-The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-␥ (PPAR␥) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPAR␥ have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPAR␥; influence the expression of PPAR␥ target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPAR␥ when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPAR␥ have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations. Key Words: receptors, angiotensin II Ⅲ angiotensin II Ⅲ renin-angiotensin system Ⅲ insulin resistance Ⅲ losartan A ll currently available classes of antihypertensive drugs were developed before it was widely recognized that increased blood pressure is closely associated with insulin resistance and dyslipidemia and well before public health authorities established diagnostic criteria for the metabolic syndrome. 1-3 Thus, the antihypertensive drugs in use today were designed primarily to affect cellular and biochemical mechanisms contributing to increased blood pressure and not to address the disordered carbohydrate and lipid metabolism that often accompany hypertension as part of the metabolic syndrome. Given the major impact of the metabolic syndrome on cardiovascular disease morbidity and mortality, 4 -6 the availability of antihypertensive agents that also improve insulin resistance and dyslipidemia could be of considerable clinical value.Numerous studies have demonstrated that the peroxisome proliferator-activated receptor-␥ (PPAR␥) plays an important role in regulating carbohydrate and lipid metabolism and that ligands for PPAR␥ can improve insulin sensitivity, reduce triglyceride levels, and decrease the risk for atherosclerosis. 7-15 PPAR␥ ligands also have modest antihypertensive effects related at least in part to their ability to promote peripheral vasodilation. 16 -19 Several thiazolidinedione ligands for PPAR␥ have been approved for the treatment of type 2 diabetes; however, these agents have limited capacity to reduce blood pressure and can provoke fluid retention, weight gain, edema, a...

Spontaneously hypertensive rats (SHR) display several features of the human insulin-resistance syndromes. Cd36 deficiency is genetically linked to insulin resistance in SHR. We show that transgenic expression of Cd36 in SHR ameliorates insulin resistance and lowers serum fatty acids. Our results provide direct evidence that Cd36 deficiency can promote defective insulin action and disordered fatty-acid metabolism in spontaneous hypertension.

Increased serum levels of resistin, a molecule secreted by fat cells, have been proposed as a possible mechanistic link between obesity and insulin resistance. To further investigate the effects of resistin on glucose metabolism, we derived a novel transgenic strain of spontaneously hypertensive rats expressing the mouse resistin gene under the control of the fat-specific aP2 promoter and also performed in vitro studies of the effects of recombinant resistin on glucose metabolism in isolated skeletal muscle. Expression of the resistin transgene was detected by Northern blot analysis in adipose tissue and by real-time PCR in skeletal muscle and was associated with increased serum fatty acids and muscle triglycerides, impaired skeletal muscle glucose metabolism, and glucose intolerance in the absence of any changes in serum resistin concentrations. In skeletal muscle isolated from non-transgenic spontaneously hypertensive rats, in vitro incubation with recombinant resistin significantly inhibited insulin-stimulated glycogenesis and reduced glucose oxidation. These findings raise the possibility that autocrine effects of resistin in adipocytes, leading to release of other prodiabetic effector molecules from fat and/or paracrine actions of resistin secreted by adipocytes embedded within skeletal muscle, may contribute to the pathogenesis of disordered skeletal muscle glucose metabolism and impaired glucose tolerance.

Pioglitazone, like other thiazolidinediones, is an insulin-sensitizing agent that activates the peroxisome proliferator-activated receptor ␥ and influences the expression of multiple genes involved in carbohydrate and lipid metabolism. However, it is unknown which of these many target genes play primary roles in determining the antidiabetic and hypolipidemic effects of thiazolidinediones. To specifically investigate the role of the Cd36 fatty acid transporter gene in the insulin-sensitizing actions of thiazolidinediones, we studied the metabolic effects of pioglitazone in spontaneously hypertensive rats (SHR) that harbor a deletion mutation in Cd36 in comparison to congenic and transgenic strains of SHR that express wild-type Cd36. In congenic and transgenic SHR with wild-type Cd36, administration of pioglitazone was associated with significantly lower circulating levels of fatty acids, triglycerides, and insulin as well as lower hepatic triglyceride levels and epididymal fat pad weights than in SHR harboring mutant Cd36. Additionally, insulin-stimulated glucose oxidation in isolated soleus muscle was significantly augmented in pioglitazone-fed rats with wild-type Cd36 versus those with mutant Cd36. The Cd36 genotype had no effect on pioglitazone-induced changes in blood pressure. These findings provide direct pharmacogenetic evidence that in the SHR model, Cd36 is a key determinant of the insulin-sensitizing actions of a thiazolidinedione ligand of peroxisome proliferator-activated receptor ␥.Thiazolidinediones such as pioglitazone and rosiglitazone have attracted considerable attention for the treatment of type II diabetes. The insulin-sensitizing effects of these compounds are believed to be related at least in part to their ability to bind to the peroxisome proliferator activated receptor ␥ (PPAR␥), 1 a nuclear hormone receptor that regulates the expression of multiple genes involved in the control of carbohydrate and lipid metabolism (1-4).Although many genes and metabolic pathways are likely to be involved in the insulin-sensitizing action of PPAR␥ ligands, it has been proposed that the effect of thiazolidinediones on genes regulating free fatty acid (FFA) transport and metabolism may be one of the key mechanisms responsible for the antidiabetic effects of these drugs (2, 3, 5-10). Chronic elevations of FFA levels are a well known determinant of insulin resistance (11)(12)(13)(14). Accordingly, a number of investigators have suggested that thiazolidinediones may attenuate insulin resistance by increasing the metabolic clearance of FFA and decreasing FFA levels in the circulation.The fatty acid transporter CD36 is one of a number of molecules that mediate the uptake of FFA by adipocytes and muscle cells (15-16) and is a well known target of PPAR␥ ligands (17). Mutations in Cd36 have been found to be associated with impaired carbohydrate and lipid metabolism in both humans and laboratory animals (18)(19)(20)(21)(22) Hevener et al. (6) reported that infusion of FFA induces reductions in systemic glucose dis...

Linkage studies in segregating populations derived from the spontaneously hypertensive rat (SHR) indicate that a blood pressure quantitative trait locus exists on rat chromosome 1 in the vicinity of the Sa gene. On the basis of these findings and the observation of increased renal expression of the Sa gene in SHR versus normotensive rats, the Sa gene has been proposed as a candidate gene for spontaneous hypertension. In SHR congenic strains, we and others have found that replacement of a segment of SHR chromosome 1 that contains the Sa gene with the corresponding chromosome segment from a normotensive Brown Norway (BN) rat or Wistar-Kyoto rat can reduce blood pressure. To test whether the Sa gene is necessary for the effect of this region of chromosome 1 on blood pressure, we studied a new SHR congenic subline that harbors a smaller segment of BN chromosome 1 that does not include the Sa gene. Transfer of this subregion of chromosome 1 from the BN rat onto the SHR background was associated with significant reductions in blood pressure comparable to those previously observed on transfer of a larger region of chromosome 1 that included the Sa gene. Thus, in the SHR-BN model of hypertension, the results of these mapping studies (1) demonstrate that molecular variation in the Sa gene is not required for the effect of this region of chromosome 1 on blood pressure and (2) should direct attention toward other candidate genes within the differential chromosome segment of the new congenic subline.

To evaluate the importance of volume in the development of hypertension in inbred Dahl salt-sensitive rats (SS/Jr), we measured the changes in blood pressure (BP) that occurred with oral intake of food (salt) and water in rats whose body weight was permitted to increase versus those in which body weight was maintained constant with a servo-control system. We hypothesized that if volume expansion is essential in the development of hypertension, then BP would not increase if body weight was held constant. We found that oral presentation of chow containing 4% salt to SS/Jr rats caused BP to increase 32.2 +/- 2.9 mmHg over 4 days when body weight was controlled at its initial value. Plasma sodium increased from 142.0 to 145.2 meq/l during 4 days of high salt. Neither plasma volume, hematocrit, nor central venous pressure changed significantly on the high-salt diet. In contrast, the inbred Dahl salt-resistant rats (SR/Jr) did not increase their BP during body weight control when given 4% salt. This demonstrates that volume expansion is not an obligatory step in the pressure response to increased salt in SS/Jr rats. Our results obtained with oral presentation of salt, in contrast to intravenous, represent a physiological evaluation of the significance of volume changes in response to dietary salt because no potential regulatory reflexes have been bypassed.

To investigate the prevalence and assess the zoonotic transmission burden of Cryptosporidium species in domestic pigeons in Guangdong Province, Southern China, 244 fecal samples were collected from four pigeon breeding farms between June 2012 and March 2013. Cryptosporidium oocysts were purified by Sheather's sugar flotation technique and characterized by DNA sequencing of small subunit ribosomal RNA (SSU rRNA) gene. Cryptosporidium species were determined by comparison of sequences with corresponding Cryptosporidium sequences in GenBank and phylogenetic analysis using neighbor-joining (NJ) in MEGA5.2. The overall prevalence of Cryptosporidium infection in domestic pigeons in Guangdong Province was 0.82% (2/244). Two Cryptosporidium species, namely Cryptosporidium baileyi and Cryptosporidium meleagridis, were identified in Huizhou and Chaozhou farm, respectively. These findings confirmed the existence of C. meleagridis infection in domestic pigeons in China for the first time and provided base-line information for further studies to evaluate the public health risk from pigeon to human.

Abstract-Previous studies with chromosome-Y consomic strains of spontaneously hypertensive rats (SHR) andWistar-Kyoto rats suggest that a quantitative trait locus for blood pressure regulation exists on chromosome Y. To test this hypothesis in the SHR-Brown Norway (BN) model and to study the effects of chromosome Y on lipid and carbohydrate metabolism, we produced a new consomic strain of SHR carrying the Y chromosome transferred from the BN rat. We found that replacing the SHR Y chromosome with the BN Y chromosome resulted in significant decreases in systolic and diastolic blood pressures in the SHR.BN-Y consomic strain (PϽ0.05). To elicit possible dietary-induced variation in lipid and glucose metabolism between the SHR progenitor and chromosome-Y consomic strains, we fed rats a high-fructose diet for 15 days in addition to the normal diet. On the high-fructose diet, the SHR.BN-Y consomic rats exhibited significantly increased levels of serum triglycerides and decreased levels of serum HDL cholesterol versus the SHR progenitor rats. Glucose tolerance and insulin/glucose ratios, however, were similar in both strains on both normal and high-fructose diets. These findings provide direct evidence that a gene or genes on chromosome Y contribute to the pathogenesis of spontaneous hypertension in the SHR-BN model. These results also indicate that transfer of the Y chromosome from the BN rat onto the SHR background exacerbates dietary-induced dyslipidemia in SHR. Thus, genetic variation in genes on the Y chromosome may contribute to variation in blood pressure and lipid levels and may influence the risk for cardiovascular disease.