Pioglitazone attenuates diet-induced hypertension in rats.

Consumption of diets rich in fats or sugars is correlated with the onset of insulin resistance and hypertension in rats. In the present study, rats were fed diets that induce hypertension; 50% of the rats were also treated with pioglitazone, a thiazolidinedione derivative that sensitizes target tissues to insulin and decreases plasma insulin concentration in insulin-resistant animals. Pioglitazone treatment prevented the development of hypertension and reduced plasma insulin concentration by 70% and 37% in rats fed a high-fat or glucose diet, respectively (P < .05 compared with rats fed the same diet without pioglitazone). In rats fed a control diet, neither insulin nor blood pressure (BP) was affected by pioglitazone treatment. The effect of pioglitazone on insulin and BP could not be attributed to a reduction in body weight, since pioglitazone increased the weight gain of rats fed the high-fat or glucose diet. These findings suggest that in rats fed a diet high in fat or glucose, treatment with pioglitazone maintains plasma insulin concentration and BP at control levels, regardless of body weight.

Hypertensive effect of polyunsaturated dietary fat.

Male Sprague-Dawley rats were fed a diet high in either saturated fat (lard) or polyunsaturated fat (corn oil) beginning at 10 weeks of age. After 10 weeks of diet treatment, blood pressure (BP) was 17% higher in rats fed saturated fat and 8% higher in rats fed polyunsaturated fat than in rats fed a low-fat control diet. Rats fed the lard diet became obese, and their fasting insulin levels were elevated (38% above control). These data demonstrate that both saturated and polyunsaturated dietary fats induce hypertension.

Adrenal medulla as a mediator of diet-induced hypertension.

Male Sprague-Dawley rats fed either a high-fat or glucose-enriched diet for 10 wk developed higher blood pressure (BP) and higher urinary catecholamine excretion than rats fed a control diet. After 10 wk of diet treatment, systolic BP was 164 +/- 3, 156 +/- 2, and 145 +/- 4 mmHg in rats fed the high-fat, glucose, and control diets, respectively (P < 0.02 vs. control). During weeks 7-9 of diet treatment, excretion of epinephrine and norepinephrine was increased in hypertensive rats (those fed the high-fat or glucose diet) when compared with rats fed the control diet (P < 0.001). The purpose of this study was to determine whether the hypertensive response to nutrients could be prevented by prior surgical removal of the adrenal medulla. Adrenal demedullation nearly abolished epinephrine excretion, attenuated norepinephrine excretion, and completely blocked the hypertensive response to dietary fat and glucose. These findings suggest that adrenal medullary catecholamines play a role in the hypertensive response to nutrients.

Diminished epinephrine excretion in genetically obese (ob/ob) mice and monosodium glutamate-treated rats.

While numerous studies have examined sympathetic nervous system activity in experimental obesity, adrenal medullary function in this condition has received less attention. The experiments described herein evaluated adrenal medullary secretion by measurement of urinary epinephrine (Epi) excretion in genetically obese (ob/ob) mice and monosodium glutamate (MSG)-treated rats. In both male and female ob/ob mice Epi excretion was reduced 42% (P less than 0.015) and 47% (P less than 0.025), respectively, despite higher rates of urine output and excretion for other amines in obese compared to lean animals. In a similar fashion, urinary Epi was also lower in MSG-treated adult rats than in untreated controls; this reduction was out of proportion to group differences in body weight or excretion of other catecholamines. Administration of D,L-fenfluramine to mice, or dietary protein supplementation in rats, increased Epi excretion to the same extent in obese and lean animals. These findings indicate that secretion of Epi by the adrenal medulla is diminished, but is normally responsive to stimulation in these two models of animals obesity, and are thus consistent with accumulating evidence of a functional impairment in adrenal medullary secretion in animal and human obesity.

Effects of high fat-feeding to rats on the interrelationship of body weight, plasma insulin, and fatty acyl-coenzyme A esters in liver and skeletal muscle.

Rats fed a high-saturated fat diet consumed more energy, gained more weight, and displayed hyperinsulinemia (P less than .05) without an elevation in the fasting plasma glucose level, compared with animals on two different high-carbohydrate diets. The total fatty acyl-coenzyme A (CoA) concentration was 18% (P less than .0001) and 46% (P less than .0001) higher in liver and skeletal muscle, respectively, from rats fed the high-fat diet compared with each of the other diet groups. Major long-chain fatty acyl-CoA molecular species of both tissues in high fat-fed rats reflected the fatty acid profile of the diet. Approximately 29%, 21%, and 16% of total liver and skeletal muscle fatty acyl-CoAs were comprised of oleoyl-CoA, palmitoyl-CoA, and stearoyl-CoA, respectively. The amounts of these three fatty acyl-CoA esters were significantly higher in liver and skeletal muscle after high-fat feeding than with the other diet treatments (P less than .0001). In contrast, the concentration of linoleoyl-CoA was lower in both tissues after high-fat feeding (P less than .0001). In rats fed the high-fat diet, plasma insulin levels were significantly correlated with gain in body weight or body weight (r = .80, P less than .001 for insulin and gain in body weight; r = .73, P less than .001 for insulin and body weight). Total fatty acyl-CoA ester content in liver and skeletal muscle was also strongly correlated with the plasma insulin concentration in high fat-fed rats (r = .80, P less than .001 for liver; r = .78, P less than .001 for skeletal muscle).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension and sympathetic hyperactivity induced in rats by high-fat or glucose diets.

Male Sprague-Dawley rats fed either a high-fat diet or a glucose-enriched diet developed higher blood pressure (BP) than rats fed a control diet. After 8 wk of diet treatment systolic BP was 11% higher (P less than 0.01) in fat-fed rats and 7% higher (P less than 0.05) in glucose-fed rats when compared with rats fed the control diet. Rats fed the high-fat diet developed hypertension only when they were allowed to overeat and become obese and hyperinsulinemic. But when their feeding was restricted to prevent obesity and hyperinsulinemia, they remained normotensive. In contrast, elevated BP developed in rats consuming the glucose diet in the absence of obesity or hyperinsulinemia. After 7 wk of diet treatment, urinary norepinephrine excretion was 1.9 +/- 0.1, 1.9 +/- 0.1, and 1.5 +/- 0.1 micrograms/day in rats fed the high-fat, glucose, and control diets, respectively (P less than 0.05 vs. control). Higher norepinephrine excretion in hypertensive rats suggests that increased sympathetic nervous system (SNS) activity might participate in mediating the effects of dietary fat or glucose on BP. In addition, insulin may contribute to raising BP in rats fed the high-fat diet, either directly or indirectly through its stimulatory effect on the SNS. We conclude that chronic feeding of diets high in fat or glucose increases BP and enhances SNS activity in rats.

Differential catecholamine responses to dietary intake: effects of macronutrients on dopamine and epinephrine excretion in the rat.

Sympathetic nervous system (SNS) function responds to changes in diet in animals and humans; whether alterations in peripheral dopaminergic activity or in adrenal medullary secretion also occur with dietary manipulation is unclear. The present studies in rats demonstrate that casein supplementation of a lab chow diet raised urinary excretion of dopamine (DA) and epinephrine (E); both sucrose and lard feeding suppressed urinary DA, though only lard appeared to exert any effect on E excretion (reduction). Addition of tyrosine to the chow diet in an amount equivalent to the tyrosine content of casein increased DA output comparably to that seen in casein-fed rats, but did not reproduce the effects of casein on E excretion. Oral administration of carbidopa, an inhibitor of 3,4-dihydroxyphenylalanine (DOPA) decarboxylation in kidney reduced the DA response to casein, but chemical sympathectomy, which lowered urinary norepinephrine (NE), and adrenal denervation, which diminished E excretion, did not. Thus, the patterns of response of the peripheral dopaminergic system in kidney and of the adrenal medulla to short-term nutrient and tyrosine ingestion are distinct from those observed for the SNS and for each other, suggesting that all three peripheral catecholamine systems may be governed by separate regulatory mechanisms.

Thermogenesis after lateral hypothalamic lesions: contributions of brown adipose tissue.

The role of brown adipose tissue in the thermogenic response to lateral hypothalamic (LH) lesions was investigated. Interscapular brown adipose tissue (IBAT) temperatures were measured during the hours following bilateral electrolytic LH lesions in male rats sedated with pentobarbital sodium. Local temperature changes were also recorded from skin and colonic sites. Consistent with the view that brown adipose tissue plays a primary role in the hyperthermia produced by LH lesions, IBAT depot temperature rose before, at a faster rate, and to a higher level than the other sites. In two subsequent experiments, oxygen consumption, activity, and core temperature were monitored in freely moving male rats with LH lesions, both in warm (25 degrees C) and cold (5 degrees C) environments. The results of these experiments provide some support for the view that LH lesions produce an increase in the regulated level of body temperature. This hyperthermic and hypermetabolic state seems to be mediated, in part, by brown fat thermogenesis and may represent a general increase in sympathetic nervous activity induced by the lesion.

The effects of various carbohydrates on sympathetic activity in heart and interscapular brown adipose tissue of the rat.

The present studies were undertaken to determine the effect of various carbohydrates on sympathetic nervous system (SNS) activity. Tritiated-norepinephrine (3H-NE) turnover was measured in heart and interscapular brown adipose tissue (IBAT) of rats fed either chow or chow plus 50% caloric supplements of fructose, sucrose, dextrose, or corn starch. Additional studies were performed to examine whether absorption of carbohydrate plays a role in the SNS response, and to determine whether sweet taste in the form of artificial sweeteners may influence SNS activity. After five to ten days on the respective diets, 3H-NE turnover was increased to a similar extent by all carbohydrates tested (from 38% to 160% greater than controls in different studies). Addition of acarbose (which impairs sucrose absorption) to a sucrose-supplemented diet abolished the SNS stimulatory response, whereas cholestyramine (a drug that blocks fat absorption) had no effect. Finally, the addition of saccharin or aspartame to a chow diet failed to alter SNS activity. Thus, caloric supplementation with several carbohydrates, in addition to sucrose, stimulates both cardiac and IBAT SNS activity, absorption of carbohydrate is required for this effect, and noncaloric sugar substitutes do not alter SNS function.

Relationship of thyroid hormones and norepinephrine to the lateral hypothalamic syndrome.

The role of thyroid hormones and norepinephrine in the elevated thermogenesis seen following lateral hypothalamic (LH) lesions was investigated by measuring serum thyroid hormone levels and urinary norepinephrine excretion during the 24 hours following placement of LH lesions and again one month later when body weight had stabilized at a reduced level. During the first 24 hours following LH lesions, serum thyroxine (T4) and triiodothyronine (T3) were significantly depressed. By one month postlesion, both T4 and T3 had returned to normal. In contrast, urinary excretion of norepinephrine (NE) was increased 100% during the 24 hours following LH lesions. By one month postlesion, NE had returned to normal levels. These results indicate that the elevated thermogenesis seen shortly following LH lesions does not reflect enhanced thyroid activity, but is probably a consequence of sympathetic nervous system stimulation. The return of NE to normal levels after one month is consistent with the observation that LH-lesioned rats are by one month postlesion no longer hypermetabolic, but display levels of heat production appropriate to the reduced body weight they then maintain.

Effect of protein on sympathetic nervous system activity in the rat. Evidence for nutrient-specific responses.

Increased energy intake activates the sympathetic nervous system (SNS) in animals and man. While dietary carbohydrate and fat stimulate, the impact of dietary protein on the SNS is not well defined. The present studies examine the effect of protein ingestion on sympathetic function based upon the measurement of [3H]norepinephrine (NE) turnover in heart and interscapular brown adipose tissue (IBAT) as the index of SNS activity. In these experiments, animals were pair-fed mixtures of laboratory chow and refined preparations of casein, sucrose, and lard to permit comparisons among nutrients with total energy intake held constant or with additional energy provided in the form of a single nutrient. After 5 d of eating a 2:1 mixture of chow and either casein or sucrose cardiac, [3H]NE turnover was less (P less than 0.005) in casein-fed rats (6.4%/h and 28.9 ng NE/h) than in animals given sucrose (11.2%/h and 46.5 ng NE/h). Similar results were obtained in IBAT and in experiments using 1:1 mixtures of chow and casein/sucrose. Casein-fed animals also displayed slower rates of NE turnover than lard-fed rats in both heart (7.8%/h vs. 13.2, P less than 0.001) and IBAT (7.0%/h vs. 12.8, P less than 0.01). Addition of casein (50% increase in energy intake) to a fixed chow ration raised NE turnover slightly, but not significantly, in heart (an average increase of 15% in six experiments). Thus, in distinction to SNS activation seen with dietary carbohydrate or fat, the SNS response to dietary protein is minimal in both heart and IBAT, indicating that the effect of increased energy intake on the SNS is dependent upon diet composition.

Increased sympathetic nervous system activity in rats fed a low-protein diet.

To examine the state of sympathetic nervous system (SNS) function in animals fed a protein-restricted diet, [3H] norepinephrine ([3H]-NE) turnover was measured in heart and interscapular brown adipose tissue (IBAT) of rats fed synthetic diets of equal caloric density containing 22% protein (as casein) or 7% protein (the difference being made up by sucrose). Because dietary availability of tyrosine is a potential mediator of SNS responses to protein ingestion, a third diet (7% protein supplemented with tyrosine) was also tested. After 12 days dietary preparation [3H]-NE turnover was increased 35-70% in heart by 7% protein feeding and 93-103% in IBAT. When smaller animals were fed the synthetic diets for 4-5 wk, sympathetic stimulation in those given the protein-restricted formula was also apparent, although demonstration of this response was complicated by comparative problems due to the marked differences in body size between normal and protein-restricted groups. Addition of tyrosine (sufficient to normalize plasma and brain tyrosine levels) was without effect on the stimulation of NE turnover induced by the protein-deficient diet. Similarly, augmented urinary NE excretion observed in animals consuming the 7% protein diet was unaffected by supplemental tyrosine. Urinary dopamine excretion, however, was uniquely and strikingly elevated with restoration of dietary tyrosine to animals fed the low-protein diet. Thus isocaloric substitution of sucrose for casein in the diet activates the SNS in heart and IBAT, a response unrelated to limitation of dietary tyrosine.

Heat production and body weight changes following lateral hypothalamic lesions.

Factors causing rats with lateral hypothalamic (LH) aphagia to lose weight at a faster rate than food deprived controls were investigated in two experiments. In Experiment 1, the heat production of LH-lesioned and control rats was measured by indirect calorimetry for four days following surgery. A higher rate of energy expenditure was shown to account for the greater weight loss of the LH-lesioned rats. In Experiment 2, the heat production of rats receiving LH lesions either at normal or reduced body weights was measured continuously for 24 hours following surgery. Reducing body weight prior to lesioning attenuated postlesion heat production. It was also found that, though the heat production of LH-lesioned rats was consistently higher than that of nonlesioned rats of similar body weight, the fundamental relationship between body weight and heat production was unchanged by the lesion. These findings of higher rates of energy expenditure when at the same weight as nonlesioned animals, accompanied by normal adjustments in expenditure in response to weight change, are consistent with the view that LH-lesioned rats, both behaviorally and metabolically, regulate body weight at a reduced level. Their elevated rate of heat production following lesioning can be seen as an adaptive metabolic adjustment which, coupled with LH aphagia, leads to the rapid decline in body weight to a lower maintenance level.

Effects of beta-adrenergic blockade on lateral hypothalamic lesion-induced thermogenesis.

Oxygen consumption is markedly elevated in rats with lesions of the lateral hypothalamus (LH), a response typically associated with hyperactivity. To test for involvement of adrenergic systems in this hypermetabolic state, propranolol was administered before and immediately after LH lesions. Propranolol attenuated both the lesion-induced rise in oxygen consumption and activity in the 12 h after surgery. A second experiment evaluated the contribution of activity to this thermic response by lesioning rats immobilized by a continuous barbiturate infusion. The persistence of lesion-induced increases in oxygen consumption in the absence of activity and the attenuation of this response by propranolol demonstrated that 1) LH lesions directly alter metabolic heat production, and 2) this effect is at least partly mediated by beta-adrenergic systems. The functional significance of increased energy expenditure after LH lesions is discussed in light of the known effects of this lesion on the level of regulated body weight.