Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 microgram/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 microgram, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in ! lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexare! lin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

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Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus—Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity

Endocrinology ◽

10.1210/en.2002-221015 ◽

2003 ◽

Vol 144 (7) ◽

pp. 2997-3003 ◽

Cited By ~ 31

Author(s):

Cecilia Mattsson ◽

Maggie Lai ◽

June Noble ◽

Eoin McKinney ◽

Joyce L. Yau ◽

...

Keyword(s):

Hpa Axis ◽

Glucocorticoid Receptors ◽

Hydroxysteroid Dehydrogenase ◽

Male Rats ◽

Zucker Rats ◽

Mrna Levels ◽

Hypothalamic Pituitary Adrenal ◽

Obese Rats ◽

Obese Zucker Rats

Abstract Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) contribute to these changes. In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels. In contrast, in obese rats, 11βHSD1 mRNA levels were reduced in a subpopulation of hippocampal cells in the main neuronal layers (by 37–47%, P < 0.05), whereas 11βHSD1 levels in sparse high-expressing cells did not differ. MR mRNA was decreased in all regions of the hippocampus (by 37–49%, P < 0.05 for CA1–2 and P < 0.01 for dentate gyrus) and in frontal cortex (by 16%, P < 0.05) in obese rats. In whole hippocampal homogenates, however, neither the protein concentration of MR by Western blot nor activity of 11βHSD1 was measurably different between the phenotypes. To test the functional importance of lower central MR expression, groups of lean and obese rats were given spironolactone before restraint stress. In vehicle-treated animals, obese rats had higher plasma corticosterone levels than lean rats after stress (by ANOVA, P < 0.05). Spironolactone markedly increased the corticosterone response in both groups, but the incremental rise was smaller in the obese rats, so that spironolactone abolished the differences between groups. We conclude that lower levels of MR, but not GR, contribute to the increased HPA activity in the obese Zucker rats and that this seems more influential during stress than in the basal state. This may be exacerbated by impaired local regeneration of corticosterone by 11βHSD1. These abnormalities could contribute to the subtle changes in the HPA axis in rodent and human obesity.

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Weight reduction increases adipose but decreases cardiac LPL in reduced-obese Zucker rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.261.2.e246 ◽

1991 ◽

Vol 261 (2) ◽

pp. E246-E251 ◽

Cited By ~ 8

Author(s):

D. H. Bessesen ◽

A. D. Robertson ◽

R. H. Eckel

Keyword(s):

Adipose Tissue ◽

Cardiac Muscle ◽

Weight Reduction ◽

Zucker Rats ◽

Mrna Levels ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Obese Rats ◽

Obese Zucker Rats ◽

Coordinate Changes

Lipoprotein lipase (LPL) activity and mRNA levels were measured in cardiac muscle and adipose tissue from lean, obese, and weight-stable reduced-obese Zucker rats, both fasted and 2 h after feeding. Fasting epididymal fat LPL activity was substantially higher in obese rats relative to lean rats [6.9 vs. 0.2 nmol free fatty acid (FFA).10(6) cells-1.min-1; P = 0.0001], and was higher still in reduced-obese rats (15.7 nmol FFA.10(6) cells-1.min-1; P = 0.002). Adipose tissue LPL increased with feeding in all three groups. In marked contrast, fasting cardiac muscle LPL was lower in obese rats relative to lean (28.8 vs. 38.5 nmol FFA.g-1.min-1; P = 0.0064) and was lower still in reduced-obese rats (14.5 nmol FFA.g-1.min-1; P = 0.0001). LPL mRNA levels increased in adipose tissue along with enzyme activity; however, the magnitude of the changes were relatively small, suggesting that the primary regulatory steps are posttranslational. Weight reduction studies were also carried out in Sprague-Dawley rats with similar results. These studies show that sustained weight reduction results in coordinate changes in tissue-specific LPL, favoring delivery of lipoprotein triglyceride fatty acids to adipose tissue relative to cardiac muscle and the restoration of energy stores.

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Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

AJP Renal Physiology ◽

10.1152/ajprenal.00604.2009 ◽

2010 ◽

Vol 299 (5) ◽

pp. F1164-F1170 ◽

Cited By ~ 11

Author(s):

Xiaoyan Wang ◽

Fengmin Li ◽

Pedro A. Jose ◽

Carolyn M. Ecelbarger

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Receptor Expression ◽

Female Rats ◽

Male Rats ◽

Zucker Rats ◽

Protein Levels ◽

Obese Rats ◽

Obese Zucker Rats

Dopamine produced by renal proximal tubules increases sodium excretion via a decrease in renal sodium reabsorption. Dopamine natriuresis is impaired in obese Zucker rats; however, the mechanism is not fully understood. To test the hypothesis that renal expression of one or more of the subtypes are altered in these rats, we measured whole kidney protein levels by immunoblotting of D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) dopamine receptors in both male and female obese and lean Zucker rats. In obese males on 1% NaCl diet, D1R, D2R, D4R, and D5R were decreased, while D3R was increased, relative to lean rats. Under a 4% NaCl diet, D2R and D3R levels in obese rats were restored to lean levels. 4% NaCl diet reduced D5R in both body types, relative to 1% NaCl diet. Female rats had higher expression of D1R and D3R than did male; however, the sex difference for D1R was markedly blunted in obese rats. In obese rats, dietary candesartan (angiotensin II type 1 receptor blocker) normalized downregulated D1R and D2R, but either decreased (D3R), did not affect (D4R), or further downregulated (D5R) the other subtypes. Candesartan also decreased D4R in lean rats. In summary, reduced renal protein levels of D1R, D2R, D4R, and D5R in obese Zucker rats could induce salt sensitivity and elevate blood pressure. Increased angiotensin II type 1 receptor activity may be mechanistically involved in the decreased expression of D1R and D2R in obese rats. Finally, reduced D1R and D3R in male rats may contribute to sex differences in blood pressure.

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Corticosterone-dependent metabolic and neuroendocrine abnormalities in obese Zucker rats in relation to feeding

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00087.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. E254-E266 ◽

Cited By ~ 18

Author(s):

Martine Duclos ◽

Elena Timofeeva ◽

Chantal Michel ◽

Denis Richard

Keyword(s):

Food Deprivation ◽

Hpa Axis ◽

Stress Reaction ◽

Whole Body ◽

Zucker Rats ◽

Mrna Levels ◽

Experimental Conditions ◽

Metabolic Defects ◽

Obese Rats ◽

Obese Zucker Rats

The obese Zucker ( fa/fa) rat is characterized by hyperphagia, hyperinsulinemia, an increase in fat deposition, and a hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis in fa/fa rats is hypersensitive to stressful experimental conditions. Food deprivation even leads to a stress reaction in obese fa/fa rats. The present study was conducted to investigate the role of corticosterone in obese rats on the basal, fasting, and postprandial metabolic rate as well as on the central expression of the thyrotropin-releasing hormone (TRH) in these conditions. In addition, the study was aimed at clarifying whether the high levels of corticosterone in obese rats are responsible for the induction of the stress reaction to food deprivation in these animals. The present results demonstrate that whole body fat oxidation and postprandial metabolic responses in obese Zucker rats were improved by adrenalectomy (ADX). At the level of the central nervous system, ADX reversed a decrease in TRH mRNA expression in the paraventricular hypothalamus (PVH) detected in fasting animals. Considering all feeding conditions, the obese rats demonstrated lower TRH mRNA levels compared with lean animals. ADX resulted in an enhanced postprandial activation of the parvocellular PVH. In contrast, the magnocellular part of the PVH was less responsive to refeeding in ADX animals. Finally, ADX failed to prevent the stress response of obese rats to food deprivation. The present results provide evidence that the removal of adrenals resolve some of the metabolic defects encountered in obese Zucker rats. They also demonstrate that not all the abnormalities of the obese Zucker rats are attributable to the hyperactivity of the HPA axis.

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Reduced adipsin mRNA and circulating adipsin protein are modulated by adrenal steroids in obese Zucker rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.259.1.r184 ◽

1990 ◽

Vol 259 (1) ◽

pp. R184-R188 ◽

Cited By ~ 1

Author(s):

P. R. Johnson ◽

B. Spiegelman ◽

B. Rosen ◽

I. Turkenkopf ◽

H. Ree ◽

...

Keyword(s):

Blot Analysis ◽

Plasma Insulin ◽

Northern Blot Analysis ◽

Zucker Rats ◽

Epididymal Adipose Tissue ◽

Mrna Levels ◽

Adrenal Steroids ◽

Slot Blot ◽

Obese Rats ◽

Obese Zucker Rats

We investigated expression of the adipose-specific serine protease adipsin in genetically obese Zucker rats and whether adrenalectomy modifies expression. Adipsin mRNA levels were determined by slot blot and Northern blot analysis of total RNA samples extracted from epididymal adipose tissue and isolated retroperitoneal adipocytes of obese (fa/fa) and homozygous lean (Fa/Fa) Zucker rats. Both 30-day-old and 4-mo-old animals were analyzed in experiment 1. In experiment 2, 10-wk-old obese and lean rats were either bilaterally adrenalectomized or sham operated, and adipsin mRNA levels were determined on tissue and cell samples 2 wk postsurgery. In both experiments, serum adipsin protein was determined by Western blot analysis and plasma insulin by radioimmunoassay. The data show that both adipsin mRNA and adipsin protein are reduced in obese compared with lean rats and that adrenalectomy restores these values toward normal in obese rats. The data thus suggest that adrenal steroids are involved in modulating adipsin expression in obese Zucker rats and that insulin may be an intermediary factor in such modulation.

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High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT2R-MasR axis in obese Zucker rats

AJP Renal Physiology ◽

10.1152/ajprenal.00097.2012 ◽

2012 ◽

Vol 303 (3) ◽

pp. F412-F419 ◽

Cited By ~ 24

Author(s):

Preethi Samuel ◽

Quaisar Ali ◽

Rifat Sabuhi ◽

Yonnie Wu ◽

Tahir Hussain

Keyword(s):

Sodium Intake ◽

Zucker Rats ◽

Kidney Cortex ◽

Complex Nature ◽

Ang Ii ◽

Pronounced Increase ◽

High Sodium ◽

High Sodium Intake ◽

Obese Rats ◽

Obese Zucker Rats

High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT1R) vs. AT2-ACE2-angiotensinogen (Ang) (1–7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT1A/BR, ACE, AT2R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT1BR increased, renin decreased, and ACE2, AT2R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT2R, and MasR, and no changes in renin and AT1R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT2R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT1R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension.

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Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

Acta Endocrinologica ◽

10.1530/eje.1.02046 ◽

2005 ◽

Vol 153 (6) ◽

pp. 963-969 ◽

Cited By ~ 53

Author(s):

Dorte X Gram ◽

Anker J Hansen ◽

Michael Wilken ◽

Torben Elm ◽

Ove Svendsen ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Sensory Nerve ◽

Zucker Rats ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Nerve Activity ◽

Calcitonin Gene ◽

Obese Rats ◽

Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

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Adipose-tissue-specific increase in glyceraldehyde-3-phosphate dehydrogenase activity and mRNA amounts in suckling pre-obese Zucker rats. Effect of weaning

Biochemical Journal ◽

10.1042/bj2540483 ◽

1988 ◽

Vol 254 (2) ◽

pp. 483-487 ◽

Cited By ~ 21

Author(s):

I Dugail ◽

A Quignard-Boulange ◽

R Bazin ◽

X Le Liepvre ◽

M Lavau

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Zucker Rats ◽

Tissue Specific ◽

Gapdh Gene ◽

Gapdh Activity ◽

Weanling Rats ◽

Obese Rats ◽

Specific Increase ◽

Obese Zucker Rats

The regulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression was studied during the onset of obesity in the genetically obese (fa/fa) rat by determination of GAPDH activity and hybridizable mRNA amounts in adipose tissue and liver from suckling and weanling rats. GADPH activity remained low throughout the suckling period, and a burst of activity occurred after weaning in both lean and obese pups. As early as 7 days of age, adipose tissue from pre-obese rats displayed a significant increase in enzyme activity, whereas no difference could be detected in the liver. In both suckling (16 days of age) and weanling (30 days of age) obese rats a proportionate increase in GAPDH activity and mRNA amounts was observed in adipose tissue, but not in liver. It is concluded that the obese genotype influences GAPDH gene expression at a pretranslational level and in a tissue-specific manner. This phenomenon could partly contribute to the hyperactive fat accretion in the obese rat, since glycolysis is the major metabolic pathway for lipogenic substrates in adipose tissue.

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Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00075.2011 ◽

2011 ◽

Vol 301 (1) ◽

pp. H230-H240 ◽

Cited By ~ 33

Author(s):

Domitila A. Huber ◽

Ann M. Schreihofer

Keyword(s):

Sympathetic Nerve Activity ◽

Nucleus Tractus Solitarius ◽

Excitatory Input ◽

Rostral Ventrolateral Medulla ◽

Male Rats ◽

Ventrolateral Medulla ◽

Zucker Rats ◽

Caudal Ventrolateral Medulla ◽

Obese Zucker Rats ◽

Altered Regulation

Obese Zucker rats (OZR) have elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) compared with lean Zucker rats (LZR). We examined whether altered tonic glutamatergic, angiotensinergic, or GABAergic inputs to the rostral ventrolateral medulla (RVLM) contribute to elevated SNA and MAP in OZR. Male rats (14–18 wk) were anesthetized with urethane (1.5 g/kg iv), ventilated, and paralyzed to record splanchnic SNA, heart rate (HR), and MAP. Inhibition of the RVLM by microinjections of muscimol eliminated SNA and evoked greater decreases in MAP in OZR vs. LZR ( P < 0.05). Antagonism of angiotensin AT1 receptors in RVLM with losartan yielded modest decreases in SNA and MAP in OZR but not LZR ( P < 0.05). However, antagonism of ionotropic glutamate receptors in RVLM with kynurenate produced comparable decreases in SNA, HR, and MAP in OZR and LZR. Antagonism of GABAA receptors in RVLM with gabazine evoked smaller rises in SNA, HR, and MAP in OZR vs. LZR ( P < 0.05), whereas responses to microinjections of GABA into RVLM were comparable. Inhibition of the caudal ventrolateral medulla, a major source of GABA to the RVLM, evoked attenuated rises in SNA and HR in OZR ( P <0.05). Likewise, inhibition of nucleus tractus solitarius, the major excitatory input to caudal ventrolateral medulla, produced smaller rises in SNA and HR in OZR. These results suggest the elevated SNA and MAP in OZR is derived from the RVLM and that enhanced angiotensinergic activation and reduced GABAergic inhibition of the RVLM may contribute to the elevated SNA and MAP in the OZR.

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The age-related increase in renal clusterin mRNA is accelerated in obese Zucker rats.

Journal of the American Society of Nephrology ◽

10.1681/asn.v9138 ◽

1998 ◽

Vol 9 (1) ◽

pp. 38-45 ◽

Cited By ~ 2

Author(s):

N J Laping ◽

B A Olson ◽

J R Day ◽

B M Brickson ◽

L C Contino ◽

...

Keyword(s):

Mrna Expression ◽

Tissue Injury ◽

Rat Kidney ◽

Zucker Rats ◽

Mrna Levels ◽

Zucker Rat ◽

Age Related ◽

Obese Zucker Rat ◽

Obese Zucker Rats ◽

F344 Rats

Clusterin is a multifunctional glycoprotein associated with development and tissue injury. Because renal function decreases with advancing age in the obese Zucker rat, clusterin mRNA expression was examined in the kidney of young adult Zucker rats and compared with age-related changes in renal clusterin mRNA expression in Fischer 344 (F344) rats. Renal clusterin mRNA levels in the obese Zucker rat were 2.5-fold higher by 3 mo of age and fourfold higher at 5 mo of age compared with the lean strain. In comparison, renal clusterin mRNA in 12-mo-old F344 rats was twofold higher than in 3-mo-old animals and was tenfold higher at 24 mo of age. Clusterin mRNA was positively correlated with urinary protein excretion and negatively correlated with creatinine clearance in Zucker rats. Clusterin was increased in select nephrons of the obese Zucker rat kidney and in 24-mo-old F344 rat kidney as assessed by in situ hybridization. Increased expression of clusterin mRNA occurred mostly in the tubular epithelium of dilated, convoluted proximal tubules. These data indicate that renal clusterin mRNA levels increase as a function of age and that age-related increases in renal clusterin and the associated tubular abnormalities are accelerated in obese Zucker rats.

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