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Objective Perturbation of daily rhythm increases cardiovascular risk. The aim of this study was to determine whether obesity alters circadian gene expression and microvascular function in lean mice and obese (db/db) mice. Methods Mice were subjected to normal LD or DD to alter circadian rhythm. Metabolic parameters and microvascular vasoreactivity were evaluated. Array studies were conducted in the am and pm cycles to assess the rhythmicity of the entire genomics. Rhythmic expression of specific clock genes (Bmal1, Clock, Npas2, Per1, Per2, and Cry1), clock output genes (dbp), and vascular relaxation-related genes (eNOS, GTPCH1) were assessed. Results Obesity was associated with metabolic dysfunction and impaired endothelial dilation in the microvasculature. Circadian rhythm of gene expression was suppressed 80% in both macro- and microcirculations of obese mice. Circadian disruption with DD increased fasting serum glucose and HbA1c in obese but not lean mice. Endothelium-dependent dilation was attenuated in obese mice and in lean mice subjected to DD. Rhythmic expression of per1 and dbp was depressed in obesity. Expression of eNOS expression was suppressed and GTPCH1 lost rhythmic expression both in obesity and by constant darkness. Conclusion These results suggest that obesity reduces circadian gene expression in concert with impaired endothelial function. The causal relationship remains to be determined.

Obesity is an emerging epidemic worldwide and threatens cardiovascular health due to the complications of accompanying metabolic dysfunction. One potential mechanism by which these complications are advanced is structural alteration in the microcirculation perfusing target organs. In this brief review, the authors focus on the structural adaptations that occur in the microcirculation, with specific focus on changes in basement membrane thickness and vascular structure. By delineating changes in end-stage disease and recent insights from animal studies, they hope to convince the reader (1) that diabetic disease in the limb is associated with profound changes in arteriolar structure and (2) that parallel changes in microvascular architecture precede the onset of frank type II diabetes.

Objective: To explore Nox1 as a mechanism of microvascular dysfunction in metabolic disease. Methods: Four genotypes were generated by breeding Nox1 knock-out (KO) mice with db/db mice: lean (HdbWn...

1. Obesity is rapidly increasing in Western populations, driving a parallel increase in hypertension, diabetes and vascular disease. Prior to the development of overt diabetes or hypertension, obese patients spend years in a state of progressive insulin resistance and metabolic disease. Mounting evidence suggests that this insulin-resistant state has deleterious effects on the control of blood flow, thus placing organ systems at a higher risk for end-organ damage and increasing cardiovascular mortality. 2. The purpose of the present review is to examine the current literature on the effects of obesity and insulin resistance on the acute control of vascular tone. Effects on nitric oxide (NO)-mediated control of vascular tone are particularly examined with regard to proximal causes and distal mechanisms of the impaired NO-mediation of vasodilation. 3. Finally, novel pathways of impaired control of perfusion are summarized from the recent literature to identify new avenues of exploring impaired vascular function in patients with metabolic disease.

DEY, APARAJITA, ROGER S. WILLIAMS, DAVID M. POLLOCK, DAVID W. STEPP, JOHN W. NEWMAN, BRUCE D. HAMMOCK, AND JOHN D. IMIG. Altered Kidney CYP2C and cyclooxygenase-2 levels are associated with obesity-related albuminuria. Obes Res. 2004;12: 1278 –1289. Objective: To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity-related hypertension and diabetes. Research Methods and Procedures: Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured. Results: Body weight and blood glucose averaged 432 20 grams and 105 5 mg/dl, respectively, in obese Zucker rats as compared with 320 8 grams and 91 5 mg/dl, respectively, in age-matched 10- to 12-week-old lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased 2.3- and 17.0-fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0-fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B2 was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 1.8 vs. 13.4 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age. Discussion: These results suggest that increased CYP4A and COX-2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity-related hypertension and type 2 diabetes.

Increases in muscle mass, as observed with exercise, are positive influences of cardiovascular health. Recent studies from our lab have shown the increase muscle mass via deletion of myostatin improves vasodilation but the underlying mechanisms are unknown. Improving insulin resistance has been shown to improve oxidant stress, specifically via expression of NOX1. Hypothesis: Increasing muscle mass by deletion of muscle growth negative regulator myostatin, improves vascular function in mesenteric arteries from obese db/db mice via reducing NOX-mediated oxidant stress in the endothelium. Myostatin deletion increased muscle mass in both lean (gastrocnemius 57.93%, gluteus maximus 60.95%) and obese mice (gastrocnemius 79.64%, gluteus maximus 112.32%). Fasting glucose, HbA1c and glucose tolerance are improved in obese myostatin null mice. Obese mice demonstrate superoxide-mediated impairment of ACh-induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved ACh-induced vasodilation...

Insulin resistance is a powerful predictor of cardiovascular disease; however, the mechanistic link remains unclear. This study aims to determine if early cardiovascular changes associated with short‐term fructose feeding in the absence of obesity manifest as abnormal blood pressure control. Metabolic dysfunction was induced in Lean Zucker rats by short‐term high‐fructose feeding. Rats were implanted with telemetry devices for the measurement of mean arterial blood pressure (MAP) and subjected to air jet stress at 5 and 8 weeks after feeding. Additional animals were catheterized under anesthesia for the determination of MAP and blood flow responses in the hind limb and mesenteric vascular beds to intravenous injection of isoproterenol (0.001–0.5 μm), a β‐adrenergic agonist. Metabolic dysfunction in high‐fructose rats was not accompanied by changes in 24‐h MAP. Yet, animals fed a high‐fructose diet for 8 weeks exhibited a marked impairment in blood pressure recovery after air‐jet stress. Dose‐dependent decreases in MAP and peripheral blood flow in response to isoproterenol treatment were significantly attenuated in high‐fructose rats. These data suggest that impaired blood pressure recovery to acute mental stress precedes the onset of hypertension in the early stages of insulin resistance. Further, blunted responses to isoproterenol implicate β 2‐adrenergic sensitivity as a possible mechanism responsible for altered blood pressure control after short‐term high‐fructose feeding.