Effect of experimental obesity and subsequent weight reduction upon circulating atrial natriuretic peptide

The effect of obesity and weight reduction upon circulating concentrations of atrial natriuretic peptide was assessed in an experimental model of the disease. Obese rats weighing in excess of 750 g were compared with formerly obese animals subjected to a 15-week period of caloric restriction resulting in a 40% reduction in body weight. Mean adipocyte size was significantly reduced with weight loss, as was estimated body fat. Mean arterial blood pressure remained normotensive for both groups, but a significant reduction in heart rate was associated with weight reduction. Circulating atrial natriuretic peptide was significantly elevated in the lean rats, which also exhibited decreased plasma renin activity and a negative sodium balance. Analysis of heart to body weight ratios implied that an obesity-associated, volume-induced cardiac hypertrophy remained even after the normalization of body fat. These results suggest that the diuresis and natriuresis accompanying weight reduction may be facilitated by atrial natriuretic peptide, which was elevated in part due to a persistent left ventricular hypertrophy following the transition from the obese to lean condition.     

Gender-specific effects of thyroid hormones on cardiopulmonary function in SHHF rats.

Spontaneously hypertensive heart failure (SHHF) rats develop hypertension and heart failure. We hypothesized that induction of hyperthyroidism should accelerate development of heart failure in male SHHF rats. Male and female SHHF rats received diets containing desiccated thyroid glands (DTG) or a control diet for 8 wk. Male and female Wistar-Kyoto rats were used as normotensive controls. DTG treatment reduced body weight in male, but not female, SHHF rats but increased body temperature and heart weight-to-body weight ratio in both genders. In DTG-treated male SHHF rats, serum triiodothyronine levels doubled relative to SHHF controls, whereas O2 consumption increased in DTG-treated SHHF rats. Frequency of breathing in air increased in DTG-treated female rats, and ventilation increased in DTG-treated male rats. Ventilatory equivalents exhibited gender differences in SHHF rats, were decreased in both genders by DTG treatment, and reached levels similar to those of Wistar-Kyoto rats. DTG increased heart rate, right ventricular pressure, and contractility in both genders and increased left ventricular pressure in SHHF male rats. These results refute our hypothesis and suggest that cardiopulmonary function of SHHF male rats may be improved by DTG treatment.     

The influence of body composition, fat distribution, and sustained weight loss on left ventricular mass and geometry in obesity

Alterations in left ventricular mass and geometry vary along with the degree of obesity, but mechanisms underlying such covariation are not clear. In a case–control study, we examined how body composition and fat distribution relate to left ventricular structure and examine how sustained weight loss affects left ventricular mass and geometry. At the 10‐year follow‐up of the Swedish obese subjects (SOS) study cohort, we identified 44 patients with sustained weight losses after bariatric surgery (surgery group) and 44 matched obese control patients who remained weight stable (obese group). We also recruited 44 matched normal weight subjects (lean group). Dual‐energy X‐ray absorptiometry, computed tomography, and echocardiography were performed to evaluate body composition, fat distribution, and left ventricular structure. BMI was 42.5 kg/m², 31.5 kg/m², and 24.4 kg/m² for the obese, surgery, and lean groups, respectively. Corresponding values for left ventricular mass were 201.4 g, 157.7 g, and 133.9 g (P < 0.001). In multivariate analyses, left ventricular diastolic dimension was predicted by lean body mass (β = 0.03, P < 0.001); left ventricular wall thickness by visceral adipose tissue (β = 0.11, P < 0.001) and systolic blood pressure (β = 0.02, P = 0.019); left ventricular mass by lean body mass (β = 1.23, P < 0.001), total body fat (β = 1.15, P < 0.001) and systolic blood pressure (β = 2.72, P = 0.047); and relative wall thickness by visceral adipose tissue (β = 0.02, P < 0.001). Left ventricular adjustment to body size is dependent on body composition and fat distribution, regardless of blood pressure levels. Obesity is associated with concentric left ventricular remodeling and sustained 10‐year weight loss results in lower cavity size, wall thickness and mass.     

内源性一氧化氮在高血压心肌肥厚中的作用

目的和方法：本实验用Ｌ精氨酸和一氧化氮合酶（ＮＯＳ）抑制剂ＬＮＡＭＥ观察内源性一氧化氮（ＮＯ）在高血压性心肌肥厚中的作用。结果：腹主动脉缩窄引起大鼠动脉血压显著升高,左心室重量／体重比值显著增加,左心室ＮＯ含量显著下降;Ｌ精氨酸不影响主动脉缩窄大鼠动脉血压,但减轻左心室重量／体重比值,明显升高左心室ＮＯ含量,加入ＬＮＡＭＥ可消除Ｌ精氨酸的上述作用;主动脉缩窄大鼠给予ＬＮＡＭＥ,动脉血压和左心室／体重比值并没有进一步增加;假手术大鼠给予ＬＮＡＭＥ,血压明显升高,左心室重量／体重比值轻度增加;主动脉缩窄大鼠不论是服用Ｌ精氨酸还是ＬＮＡＭＥ,左心室ｃＧＭＰ含量都明显增加。结论：口服Ｌ精氨酸可减轻主动脉缩窄大鼠心肌肥厚但不影响动脉血压,此作用可能是通过Ｌ精氨酸ＮＯ途径实现的,与ｃＧＭＰ机制无关。     

Composition of Dietary Fat Affects Blood Pressure and Insulin Responses to Dietary Obesity in the Dog

Cardiovascular and metabolic parameters were evaluated in 15 female spayed dogs before and after they became obese on either a saturated fat (LD, lard, n=8) or unsaturated fat (CO, corn oil, n=7) diet. Body weight and body fat increased significantly in both groups, although no differences occurred between diet groups. Dogs receiving the LD diet exhibited a greater increase in mean arterial pressure than those receiving the CO diet (p<0. 01; 15. 9 ± 2. 1 vs. 9. 8 ± 3. 3 mm Hg increase). The CO diet stimulated a greater increase in heart rate than the LD diet (p<0. 05; 32. 8 ± 7. 8 vs. 14. 1 ± 5. 8 bpm increase). Ganglionic blockade with chlorisondamine caused an increase in HR in both lean groups and in the obese CO group, but not the obese LD group, consistent with a decrease in parasympathetic tone to the heart in the dogs overfed saturated fat. Obesity enhanced the heart rate response to β-badrenergic stimulation by isoproterenol in the LD, but not CO group. The LD diet increased circulating insulin and decreased insulin sensitivity, whereas the CO diet had no effect on either parameter. These findings suggest that the composition of dietary fat can modulate the autonomic and metabolic adaptations induced by dietary obesity.     

Left ventricular hypertrophy in obese hypertensives: is it really eccentric? (An echocardiographic study)

In order to study left ventricular hypertrophy patterns in obese hypertensives, we examined 132 patients with essential hypertension by 2D, M-mode and Doppler echocardiography. The patients were classified in four comparable groups, corresponding to the values of Quetelet's body mass index (BMI) and grades of obesity. More obese hypertensives had on average larger left ventricles with thicker walls and larger left atria than less obese, or lean ones. Left ventricular mass increased significantly and progressively with advancing grades of obesity, but relative wall thickness (wall thickness/cavity size ratio) did not diminish. Doppler echocardiography revealed significantly higher prevalence of left ventricular diastolic dysfunction among obese than among lean hypertensives. In the second part of our study, we analyzed the subgroups defined by the severity of hypertension and the age of the patients. The correlation of the indices of left ventricular and left atrial hypertrophy with the BMI values was considerably better in the group of moderate than in the group of mild hypertension. The r values were 0.62 vs. 0.22 for left ventricular mass and 0.64 vs. 0.26 for left atrial dimension. The group of patients with severe hypertension was characterized by left ventricular cavity enlargement in correlation with increasing BMI values, but without corresponding left ventricular wall thickening. So called left ventricular "eccentricity index", as the reverse value of relative wall thickness, correlated well (r = 0.76) with the BMI values. The indices of left ventricular hypertrophy correlated with the BMI values slightly better in middle age groups than in the groups of the youngest (< or = 30 years) or the eldest (> or = 61 years) hypertensives. In conclusion, eccentric left ventricular hypertrophy does not seem to be a distinctive feature of hypertensive heart disease in obesity. There is only some tendency toward the "eccentricity" of left ventricular geometry which becomes more apparent in more severe forms of hypertension, especially in very obese persons.     

Weight reduction in the management of hypertension: epidemiologic and mechanistic evidence

A number of studies have established a close association between increased body mass and elevated blood pressure. The presence of obesity in hypertensive subjects is associated with some hemodynamic, metabolic, and endocrinic characteristics: an increased intravascular volume with a high intracellular body water/interstitial fluid volume ratio, increased cardiac output, stroke volume, and left ventricular work while peripheral resistance was reduced or normal. Weight loss of at least 10 kg can reduce blood pressure independently of changes in sodium intake in obese persons of both sexes with mild, moderate, or severe high blood pressure. The fall in arterial pressure in obese hypertensives after weight loss may reverse many of the previously mentioned altered findings and underscore previous epidemiological studies that have shown that weight control could be an important measure in the treatment of hypertension.     

Effects of Obesity and Weight Loss on Cardiac Function and Valvular Performance

KARASON, KRISTJAN, INGEMAR WALLENTIN, BO LARSSON, LARS SJOSTROM. Effects of obesity and weight loss on cardiac function and valvular performance. Obes Res. 1998;6:422–429. Objective : To study the consequences of long-standing obesity on myocardial function and valvular performance and to determine the effects of weight loss on these cardiovascular features. Research Methods and Procedures : We included 41 patients with obesity referred for weight-reducing gastroplasty, 31 patients with obesity who received dietary recommendations, and 43 lean subjects. Body weight and blood pressure were measured, and cardiac function and valvular performance were estimated echocardiographically. Left ventricular ejection fraction was used to assess systolic heart function, and the ratio of transmitral early to atrial (E/A) peak flow velocity was used as an estimate of diastolic filling. All three study groups were investigated at baseline, and the two groups with obesity were re-examined at 1-year follow-up. Results : Patients with obesity had higher blood pressure, greater cardiac output, lower ejection fraction, and reduced E/A ratio, compared with lean subjects (p<0.01). Surgical treatment of obesity led to significant decreases in body weight, whereas body weight remained unchanged in the group treated with dietary recommendations (p<0.001). In the weight loss group, blood pressure and cardiac output decreased and the E/A ratio increased (p<0.001). Left ventricular ejection fraction tended to increase in the weight loss group and decrease in the obese control group p<0.01). No significant valvular disease was observed in any of the subjects with obesity at baseline or after weight loss. Discussion : We conclude that weight reduction in subjects with obesity is associated with improvements in left ventricular diastolic filling and has favorable effects on left ventricular ejection fraction. Neither obesity nor weight loss seem to promote valvular heart disease.     

Influence of a diet rich in fish oil on blood pressure, body weight and cardiac hypertrophy in spontaneously hypertensive rats

The effects of a diet rich in fish oil on arterial blood pressure, body weight, left ventricular weight and heart rate have been investigated in 8 month old spontaneously hypertensive male rats (SHR) as compared to age-matched hypertensive controls. A diet containing 10% fish oil decreased blood pressure by about 40 mmHg within 20 days of starting the experiment, and this effect persisted over the observation period of 80 days. Permitting the animals free access to food, the body weight of the diet group increased by 25%. The degree of hypertrophy as evaluated by relating left ventricular weight to tibial length was significantly reduced (10%) in the diet fed group. Heart rate was increased by 53%. The study demonstrates that a diet rich in fish oil can lower arterial blood pressure over several weeks without a recognizable loss in function despite a considerable increase in body weight. It can be assumed that a more marked regression of left ventricular hypertrophy is counteracted by a reflex increase in sympathetic efferentation to the heart.     

Chronic high-carbohydrate, high-fat feeding in rats induces reversible metabolic, cardiovascular, and liver changes

Age-related physiological changes develop at the same time as the increase in metabolic syndrome in humans after young adulthood. There is a paucity of data in models mimicking chronic diet-induced changes in human middle age and interventions to reverse these changes. This study measured the changes during chronic consumption of a high-carbohydrate (as cornstarch), low-fat (C) diet and a high-carbohydrate (as fructose and sucrose), high-fat (H) diet in rats for 32 wk. C diet feeding induced changes without metabolic syndrome, such as disproportionate increases in total body lean and fat mass, reduced bone mineral content, cardiovascular remodeling with increased systolic blood pressure, left ventricular and arterial stiffness, and increased plasma markers of liver injury. H diet feeding induced visceral adiposity with reduced lean mass, increased lipid infiltration in the skeletal muscle, impaired glucose and insulin tolerance, cardiovascular remodeling, hepatic steatosis, and increased infiltration of inflammatory cells in the heart and the liver. Chia seed supplementation for 24 wk attenuated most structural and functional modifications induced by age or H diet, including increased whole body lean mass and lipid redistribution from the abdominal area, and normalized the chronic low-grade inflammation induced by H diet feeding; these effects may be mediated by increased metabolism of anti-inflammatory n-3 fatty acids from chia seed. These results suggest that chronic H diet feeding for 32 wk mimics the diet-induced cardiovascular and metabolic changes in middle age and that chia seed may serve as an alternative dietary strategy in the management of these changes.     

Preferential loss of body fat during starvation in dietary obese rats.

This study was undertaken to examine whether diet-induced obesity alters the amount and/or composition of weight lost during starvation. The amount and composition of weight lost during a 4-day period of starvation was determined before and at 17, 30 and 42 weeks after rats (350 g of body weight) were given a high fat diet (HFD). To control for effects of aging, a second group of rats, fed standard laboratory chow, was also subjected to similar periods of starvation. Although total weight loss during starvation was never greater for HFD rats than for chow-fed rats, the former group showed a clear patter of increasing loss of body fat and total energy and conservation of fat-free tissues with periods of starvation later in life. In addition, chow-fed rats showed substantial energy conservation during each period of starvation (i.e. they lost less energy each day than their pre-starvation energy requirements). In contrast, HFD rats demonstrated substantial energy conservation only at 17 weeks and not at 30 or 42 weeks; during the last period of starvation, their average daily loss of carcass energy exceeded their pre-starvation energy requirements. This suggests the increased fat mass of these rats may have led to increased fuel availability and to an increased metabolic rate during starvation. If these results are applicable to humans, the more obese subjects are likely to show greater total loss of energy than lean subjects, but show a lesser loss of lean body mass, at least initially. If protein requirements are reflected by the ability to mobilize protein during food restriction, protein requirements would be substantially lower in the dietary obese rats than in controls. In summary, diet-induced obesity leads to preferential loss of body fat and conservation of lean mass during starvation.     

A cardiac electric field on the body surface in rats with left ventricular hypertrophy caused by experimental renovascular hypertension

The dynamics of potential distribution of cardiac electric field on the body surface was studied in renovascular hypertensive rats (Goldblatt type) during the ventricular activity. Three inversions of the mutual location of positive and negative areas of the cardiac electric field on the body surface were found in normotensive and hypertensive rats during the QRS-T period. Left ventricular hypertrophy of the heart in rats caused by renovascular hypertension results in changes of temporal and amplitude characteristics of the body surface potential distribution during the initial and terminal ventricular activity. The shifting trajectory of the positive and negative areas and their extremal ranges on the body surface does not change during the ventricular activity in rats with left ventricular hypertrophy of the heart as compared to the initial normotensive state.     

Age-related cardiovascular responses of rats to coronary artery ligation

The cardiovascular responses of rats of different ages, ranging from 4-15 weeks (body weight 115-490 g), to acute left coronary artery ligation under pentobarbitone anaesthesia were studied. In older animals, the responses included the occurrence of ventricular tachycardia and/or fibrillation, decrease in blood pressure, and a slight increase in heart rate. On the contrary, younger rats exhibited atrioventricular block followed by ventricular arrest, and decreases in both blood pressure and heart rate. The findings demonstrate the existence of age-related cardiovascular responses to acute myocardial ischaemia in rats, and suggest that 10-15-week-old male Sprague-Dawley rats are suitable experimental animals for producing early ventricular arrhythmias by acute coronary artery ligation.     

Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling

Liver-derived hyperleptinemia induced in normal rats by adenovirus-induced gene transfer causes rapid disappearance of body fat, whereas the endogenous adipocyte-derived hyperleptinemia of obesity does not. Here we induce liver-derived hyperleptinemia in rats with adipocyte-derived hyperleptinemia of acquired obesity caused by ventromedial hypothalamus lesioning (VMH rats) or by feeding 60% fat (DIO rats). Liver-derived hyperleptinemia in obese rats caused only a 5-7% loss of body weight, compared to a 13% loss in normoleptinemic lean animals; but in actual grams of weight lost there was no significant difference between obese and lean groups, suggesting that a subset of cells remain leptin-sensitive in obesity. mRNA and protein of a putative leptin-resistance factor, suppressor of cytokine signaling (SOCS)-1 or -3, were both increased in white adipose tissues (WAT) of VMH and DIO rats. Since transgenic overexpression of SOCS-3 in islets reduced the lipopenic effect of leptin by 75%, we conclude that the increased expression of SOCS-1 and -3 in WAT of rats with acquired obesity could have blocked leptin's lipopenic action in the leptin-resistant WAT population.     

Muscle strength and body composition as determinants of blood pressure in young men

The correlations of blood pressure to various indices of muscularity and fatness were studied in 183 young healthy men (mean age 19.7, SD 2.1 years). Systolic pressure showed significant positive correlations with body fat percentage, isometric strength of trunk extensors, body mass index, lean body mass, strength of leg extensors, heart rate, and the sum of four skinfolds. Diastolic pressure had significant positive correlations with body mass index, lean body mass, body fat percentage, sum of skinfolds, strength of leg extensors, strength of trunk extensors, and age. A stepwise selective multiple regression analysis for systolic pressure resulted in four significantly correlating variables: body fat percentage (p less than 0.001), heart rate (p less than 0.01), lean body mass (p less than 0.05), and strength of trunk extensors per kg body weight (p less than 0.05). For diastolic pressure the analysis resulted in two explaining variables: body mass index (p less than 0.001) and age (p less than 0.05). In a regression equation with 13 variables the strength of trunk flexors was negatively correlated with diastolic pressure. It is concluded that both fatness and muscularity are factors related to blood pressure in young men. The muscularity effect is more clearly associated with trunk and leg extensor strength.     

Decreased [3H]nitrendipine binding in the brainstem of deoxycorticosterone-NaCl hypertensive rats

Binding studies with the 1,4-dihydropyridine calcium channel antagonist [3H]nitrendipine [( 3H]NTD) were performed in uninephrectomized, deoxycorticosterone (DOCA)-NaCl hypertensive rats and vehicle treated normotensive control littermates. After 6 weeks of treatment, hypertensive (199 mmHg, systolic arterial pressure) DOCA rats showed significantly increased heart, left ventricle, and kidney weight in contrast to normotensive (135 mmHg) controls. [3H]NTD binding in the brainstem was significantly reduced (51 +/- 5 fmol/mg protein) in DOCA-NaCl rats, as compared to controls (116 +/- 24 fmol/mg protein). However, no significant differences were found in the [3H]NTD dissociation constants for DOCA-NaCl (0.43 +/- 0.03 nM) or control rats (0.62 +/- 0.06 nM). Cerebral cortical and left ventricular tissue showed no significant alterations in receptor binding density or affinity. Specific [3H]NTD binding was not significantly altered in other selected brain regions or the atria. These data suggest that alterations in the dihydropyridine binding sites associated with calcium channels in the brainstem may be involved in the etiology of DOCA-NaCl-induced hypertension.     

Natriuretic peptide system: a link between fat mass and cardiac hypertrophy and hypertension in fat-fed female rats

The present study was designed to develop an animal model of hypertension and cardiac hypertrophy associated with obesity in female rats. Furthermore, we studied the involvement of the natriuretic peptide system in the mechanisms of these conditions. Obesity was induced in Wistar rats by a high fat diet and ovariectomy. The rats were divided into four groups: ovariectomized or sham-operated with high-fat diet and ovariectomized or sham-operated with control diet. After 24 weeks of diet, rats were killed, and their tissues were removed. Cardiac atrial natriuretic peptide (ANP), clearance receptor (NPr-C) gene expression was determined by PCR. ANP concentrations were measured in plasma. Ovariectomized fat-fed rats (OF) showed increased body weight, visceral fat depot and blood pressure and decreased sodium excretion compared to other groups. Also, these rats showed higher heart-to-body weight and cell diameters of ventricular cardiomyocytes and lower cardiac ANP mRNA and plasma ANP than the control group. The adipocyte and renal NPr-C mRNA of OF rats were higher than the control group. These data showed that combined ovariectomy and high fat diet elicited obesity, hypertension and cardiac hypertrophy. These results suggest that the impairment of the natriuretic peptide system may be one of the mechanisms involved not only in development of hypertension but also in cardiac hypertrophy associated with obesity in ovariectomized rats.     

Induction of blood plasma carboxycathepsin (angiotensin I-converting enzyme) in normo- and hypertensive rats in response to a single administration of captopril

The experiments were carried out to elucidate the effect of carboxycathepsin (CC) activity inhibition by a specific inhibitor--captopril--on plasma enzyme concentration in normotensive rats and rats with renovascular hypertension. A single oral administration of captopril (10 mg/kg body weight) produced an increase in CC concentration in both hypertensive and sodium-depleted normotensive rats with a parallel decrease in arterial pressure, but had no effect on sodium-repleted normotensive rats. It is suggested that the increase in plasma CC concentration is a compensatory response to the inhibition of CC activity by captopril; it is also possible that the increase observed reflects the state of renin-angiotensin system.     

Fat Intake Affects Adiposity,Comorbidity Factors,and Energy Metabolism of Sprague‐Dawley Rats

Objective: Childhood obesity is an emerging health problem. This study assesses the effects of three levels of dietary fat (10%, 32%, and 45% measured by kilocalories) on weight gain, body composition, energy metabolism, and comorbidity factors in rats from weaning through maturation. Research Methods and Procedures: The role of dietary fat on the susceptibility to obesity was assessed by feeding diets containing three levels of dietary fat to rats from weaning through 7 months of age. Body composition was analyzed by DXA after 6 and 12 weeks of dietary treatment. Energy metabolism was measured by indirect calorimetry. Results: Energy intake, weight gain, fat mass, and plasma glucose, cholesterol, triglyceride, free fatty acid, leptin, and insulin levels increased dose‐dependently with increased dietary fat. No difference in absolute lean mass among the three groups was observed. Therefore, the differences in weight gain are accounted for primarily by increased fat accretion. Compared with rats that were relatively resistant to obesity when on a 45% fat diet, diet‐induced obesity‐prone rats were in positive energy balance and had an elevated respiratory quotient, indicating a switch in energy substrate use from fat to carbohydrate, which promotes body‐fat accretion. Discussion: Our data support the hypothesis that administration of increasing amount of dietary fat to very young rats enhances susceptibility to diet‐induced obesity and its comorbidities.     

Regulation of lean mass, bone mass, and exercise tolerance by the central melanocortin system

Signaling via the type 4-melanocortin receptor (MC4R) is an important determinant of body weight in mice and humans, where loss of function mutations lead to significant obesity. Humans with mutations in the MC4R experience an increase in lean mass. However, the simultaneous accrual of fat mass in such individuals may contribute to this effect via mechanical loading. We therefore examined the relationship of fat mass and lean mass in mice lacking the type-4 melanocortin receptor (MC4RKO). We demonstrate that MC4RKO mice display increased lean body mass. Further, this is not dependent on changes in adipose mass, as MC4RKO mice possess more lean body mass than diet-induced obese (DIO) wild type mice with equivalent fat mass. To examine potential sources of the increased lean mass in MC4RKO mice, bone mass and strength were examined in MC4RKO mice. Both parameters increase with age in MC4RKO mice, which likely contributes to increases in lean body mass. We functionally characterized the increased lean mass in MC4RKO mice by examining their capacity for treadmill running. MC4R deficiency results in a decrease in exercise performance. No changes in the ratio of oxidative to glycolytic fibers were seen, however MC4RKO mice demonstrate a significantly reduced heart rate, which may underlie their impaired exercise performance. The reduced exercise capacity we report in the MC4RKO mouse has potential clinical ramifications, as efforts to control body weight in humans with melanocortin deficiency may be ineffective due to poor tolerance for physical activity.