Cardiovascular Abnormalities in Transgenic Mice With Reduced Brown Fat

Cittadini, Antonio; Mantzoros, Christos S.; Hampton, Thomas G.; Travers, Kerry E.; Katz, Sidney; Morgan, James P.; Flier, Jeffrey S.; Douglas, Pamela S.

doi:10.1161/01.cir.100.21.2177

Cited by 54 publications

(45 citation statements)

References 40 publications

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“…18 Another obese mouse model produced by transgenic reduction of brown fat that is hyperinsulinemic and dyslipidemic was also reported to be hypertensive compared with control animals. 19 Our data, together with previous reports, suggest that obesity and the metabolic syndrome in mice with a functional MC4R are associated with increased blood pressure. Thus, a functional MC4R may be necessary for obesity to raise arterial pressure.…”

Section: Cardiovascular Consequences Of Mc4r Deficiencysupporting

confidence: 84%

Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia

et al. 2005

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Abstract-The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (Ϫ/Ϫ) and heterozygous (ϩ/Ϫ) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (nϭ5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (Ϫ/Ϫ) mice were severely obese compared with MC4R (ϩ/Ϫ) and WT mice (body weight 48Ϯ1.5 versus 31Ϯ0.6 and 30Ϯ0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (Ϫ/Ϫ) 110Ϯ3 mm Hg; MC4R (ϩ/Ϫ) 109Ϯ2 mm Hg; WT 114Ϯ2 mm Hg), and HR in MC4R (Ϫ/Ϫ) was lower than in WT (604Ϯ5 versus 645Ϯ9 bpm; PϽ0.05) but not different from MC4R (ϩ/Ϫ) (625Ϯ13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (Ϫ/Ϫ) compared with MC4R (ϩ/Ϫ) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (Ϫ/Ϫ) than in MC4R (ϩ/Ϫ) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (Ϫ/Ϫ) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities. Key Words: obesity Ⅲ insulin resistance Ⅲ hypertension, sodium-dependent Ⅲ arterial pressure Ⅲ renin-angiotensin system E vidence from epidemiological, clinical, and experimental studies has consistently demonstrated that obesity is a major cause of essential hypertension. 1-3 Previous studies show that ␣/␤-adrenergic receptor antagonists and renal denervation significantly blunt the rise in arterial pressure associated with weight gain in diet-induced obese animal models, indicating that increased sympathetic nervous system (SNS) activation is an important cause of obesity-induced hypertension. 3,4 However, the mechanisms that link SNS activation to the development of hypertension in obesity are still unclear.One potential mechanism that could link obesity, SNS activation, and hypertension is the hypothalamic proopiomelanocortin (POMC) pathway. Several studies have indicated that the hypothalamic melanocortin system, acting through the melanocortin-3 receptor (MC3R) and MC4R, is a major regulator of energy balance. ␣-Melanocyte-stimulating hormone (␣-MSH), the proteolytic byproduct of the POMC peptide, activates the hypothalamic MC3/4R to suppress appetite and to increase energy expenditure. 5 Recent studies suggest that the hypothalamic melanocortin system may also be important in cardiovascular regulation. For example, acute intracerebroventricular injections of ␣-MSH increase SNS activity to the kidneys, 6 and chronic activation of MC3/4...

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Section: Cardiovascular Consequences Of Mc4r Deficiencysupporting

confidence: 84%

Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia

et al. 2005

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“…There was no change in cardiac function or left ventricular mass by echocardiographic assessment in the UCP-DTA mice (data not shown), as described previously. 34 Furthermore, at this age, there was no difference in heart weight to body weight ratio and no evidence of hypertension in the UCP-DTA mice compared with NTG controls (data not shown). Transmission electron microscopy was performed on cardiac ventricular samples prepared from insulin-resistant UCP-DTA and NTG littermate control mice.…”

Section: Insulin-resistant Ucp-dta Mice Exhibit Cardiac Mitochondrialmentioning

confidence: 80%

“…To this end, we used UCP-DTA mice, a transgenic model that exhibits many features of metabolic syndrome caused by partial ablation of brown adipose tissue via tissue-specific targeting of a diphtheria toxigene. 24,34 By 3 months of age on standard chow diet, mean body weight was significantly greater in UCP-DTA mice than in NTG littermates ( Table 1). The UCP-DTA mice were normoglycemic but hyperinsulinemic and hypertriglyceridemic at this age (Table 1).…”

Section: Insulin-resistant Ucp-dta Mice Exhibit Cardiac Mitochondrialmentioning

confidence: 99%

Insulin-Resistant Heart Exhibits a Mitochondrial Biogenic Response Driven by the Peroxisome Proliferator-Activated Receptor-α/PGC-1α Gene Regulatory Pathway

et al. 2007

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Background-Obesity and diabetes mellitus are complex metabolic problems of pandemic proportion, contributing to significant cardiovascular mortality. Recent studies have shown altered mitochondrial function in the hearts of diabetic animals. We hypothesized that regulatory events involved in the control of mitochondrial function are activated in the prediabetic, insulin-resistant stage. Methods and Results-Morphometric analyses demonstrated that cardiac myocyte mitochondrial volume density was increased in insulin-resistant uncoupling protein-diptheria toxin A (UCP-DTA) transgenic mice, a murine model of metabolic syndrome, compared with littermate controls. Mitochondrial DNA content and expression of genes involved in multiple mitochondrial pathways were also increased in insulin-resistant UCP-DTA hearts. The nuclear receptor, peroxisome proliferator-activated receptor-␣ (PPAR␣), is known to activate metabolic genes in the diabetic heart. Therefore, we evaluated the role of PPAR␣ in the observed mitochondrial biogenesis response in the insulin-resistant heart. Insulin-resistant UCP-DTA mice crossed into a PPAR␣-null background did not exhibit evidence of mitochondrial biogenesis or induction of mitochondrial gene expression. Conversely, transgenic mice with cardiac-specific overexpression of PPAR␣ exhibited signatures of cardiac mitochondrial biogenesis. A screen for candidate mediators of the PPAR␣-driven mitochondrial biogenic response revealed that expression of PPAR␥ coactivator-1␣ (PGC-1␣), a known regulator of mitochondrial biogenesis, was activated in wild-type UCP-DTA mice but not in PPAR␣-deficient UCP-DTA mice. Conclusions-These

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“…Zucker diabetic fatty (ZDF) rats showed a modest decrease in FS (from 43% to 36%) with unchanged LV mass at 20 wk of age (42), similar to results for db/db mice ( Table 2). On the other hand, echocardiography in obese mice with insulin resistance due to reduced brown fat revealed a very different cardiac phenotype, consisting of LV dilation and hypertrophy with increased cardiac output (9).…”

Section: Discussionmentioning

confidence: 99%

Echocardiographic assessment of cardiac function in diabeticdb/db and transgenic db/db-hGLUT4 mice

Semeniuk¹,

Kryski

Severson³

2002

American Journal of Physiology-Heart and Circulatory Physiology

240

182

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Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. Am J Physiol Heart Circ Physiol 283: H976-H982, 2002; 10.1152/ ajpheart.00088.2002.-Control db/ϩ and diabetic db/db mice at 6 and 12 wk of age were subjected to echocardiography to determine whether contractile function was reduced in vivo and restored in transgenic db/db-human glucose transporter 4 (hGLUT4) mice (12 wk old) in which cardiac metabolism has been normalized. Systolic function was unchanged in 6-wk-old db/db mice, but fractional shortening and velocity of circumferential fiber shortening were reduced in 12-wk-old db/db mice (43.8 Ϯ 2.1% and 8.3 Ϯ 0.5 circs/s, respectively) relative to db/ϩ control mice (59.5 Ϯ 2.3% and 11.8 Ϯ 0.4 circs/s, respectively). Doppler flow measurements were unchanged in 6-wk-old db/db mice. The ratio of E and A transmitral flows was reduced from 3.56 Ϯ 0.29 in db/ϩ mice to 2.40 Ϯ 0.20 in 12-wk-old db/db mice, indicating diastolic dysfunction. Thus a diabetic cardiomyopathy with systolic and diastolic dysfunction was evident in 12-wk-old diabetic db/db mice. Cardiac function was normalized in transgenic db/db-hGLUT4 mice, indicating that altered cardiac metabolism can produce contractile dysfunction in diabetic db/db hearts. echocardiography; human glucose transporter 4 THE MOST PREVALENT FORM (90%) of diabetes mellitus is Type 2 (non-insulin-dependent) diabetes, resulting from the combination of insulin resistance and a ␤-cell secretory defect (6). Increased cardiovascular disease is the most common complication of diabetes (18,19). Cardiac complications associated with type 2 diabetes are due to 1) increased coronary heart disease secondary to accelerated atherosclerosis because of associated risk factors (20) such as hypertension, obesity, and dyslipidemia (metabolic syndrome); and 2) a diabetic cardiomyopathy producing abnormalities in ventricular function in the absence of coronary heart disease or hypertension (31,36).Experimental studies with rodent models of diabetes allow assessment of direct deleterious effects of a diabetic cardiomyopathy without contributions from atherosclerotic coronary heart disease. However, most reports of diabetes-induced cardiac dysfunction have used insulin-deficient (Type 1) models (28,35,40). Relatively few studies on cardiac function have been conducted with type 2 diabetic animal models (29). Diabetic db/db mice provide an animal model of Type 2 diabetes (24). The natural history of the diabetic progression in db/db mice, with initial insulin resistance followed by an insulin secretion defect (37), is similar to the pathogenesis of Type 2 diabetes in humans (6).Recently, we examined contractile function and metabolism using isolated perfused (ex vivo) working hearts from diabetic db/db mice (10-14 wk of age) compared with hearts from control (db/ϩ) heterozygotes (2). Cardiac mechanical performance was significantly reduced with an increase in left ventricular (LV) end-diastolic pressure, decreased LV developed pressure, and reductio...

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Cardiovascular Abnormalities in Transgenic Mice With Reduced Brown Fat

Cited by 54 publications

References 40 publications

Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia

Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia

Insulin-Resistant Heart Exhibits a Mitochondrial Biogenic Response Driven by the Peroxisome Proliferator-Activated Receptor-α/PGC-1α Gene Regulatory Pathway

Echocardiographic assessment of cardiac function in diabeticdb/db and transgenic db/db-hGLUT4 mice

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