Biomedical subjects

J P Montani

Publications and source records attributed to J P Montani.

At least 19 recordsLinked to original sources

PubMed2006

beta-Adrenergic control of stearoyl-CoA desaturase 1 repression in relation to sympathoadrenal regulation of thermogenesis.

Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether beta-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking beta-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking beta-adrenoceptors is not a direct effect of blunted beta-adrenergic signalling, and that beta-adrenergic control of SCD1 repression is unlikely to be a primary effector mechanism in sympathoadrenal regulation of thermogenesis. Whether approaches that target both SCD1 and molecular effectors of thermogenesis under beta-adrenergic control might be more effective than targeting SCD1 alone are potential avenues for future research in obesity management.

Adipose Tissue, White↗

PubMed2005

Corticotropin-releasing hormone directly stimulates thermogenesis in skeletal muscle possibly through substrate cycling between de novo lipogenesis and lipid oxidation.

The mechanisms by which CRH and related peptides (i.e. the CRH/urocortin system) exert their control over thermogenesis and weight regulation have until now focused only upon their effects on brain centers controlling sympathetic outflow. Using a method that involves repeated oxygen uptake determinations in intact mouse skeletal muscle, we report here that CRH can act directly on skeletal muscle to stimulate thermogenesis, an effect that is more pronounced in oxidative than in glycolytic muscles and that can be inhibited by a selective CRH-R2 antagonist or blunted by a nonselective CRH receptor antagonist. This thermogenic effect of CRH can also be blocked by interference along pathways of de novo lipogenesis and lipid oxidation, as well as by inhibitors of phosphatidylinositol 3-kinase or AMP-activated protein kinase. Taken together, these studies demonstrate that CRH can directly stimulate thermogenesis in skeletal muscle, and in addition raise the possibility that this thermogenic effect, which requires both phosphatidylinositol 3-kinase and AMP-activated protein kinase signaling, might occur via substrate cycling between de novo lipogenesis and lipid oxidation. The effect of CRH in directly stimulating thermogenesis in skeletal muscle underscores a potentially important peripheral role for the CRH/urocortin system in the control of thermogenesis in this tissue, in its protection against excessive intramyocellular lipid storage, and hence against skeletal muscle lipotoxicity and insulin resistance.

Adenylate Kinase↗

PubMed2004

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity.

Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely: the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport),the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recentlythe stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes). This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.

CCAAT-Enhancer-Binding Proteins↗

PubMed2003

Skeletal muscle mitochondrial oxidative capacity and uncoupling protein 3 are differently influenced by semistarvation and refeeding.

We investigated, in skeletal muscle mitochondria isolated from semistarved and refed rats, the relation between the protein expression of uncoupling protein 3 (UCP3) and mitochondrial oxidative capacity, assessed as state 4 and state 3 respiration rates in presence of substrates that are either non-lipids (glutamate, succinate) or lipids (palmitoyl CoA, palmitoylcarnitine). During semistarvation, when whole-body thermogenesis is diminished, state 3 respiration was lower than in fed controls by about 30% independently of substrate types, while state 4 respiration was lower by 20% only during succinate oxidation, but UCP3 was unaltered. After 5 days of refeeding, when thermogenesis is still diminished, neither state 4, state 3 nor UCP3 were lower than in controls. Refeeding on a high-fat diet, which exacerbates the suppression of thermogenesis, resulted in a two-fold elevation in UCP3 but no change in state 4 or state 3 respiration. These results during semistarvation and refeeding, in line with those previously reported for fasting, are not in support of the hypothesis that UCP3 is a mediator of adaptive thermogenesis pertaining to weight regulation, and underscore the need for caution in interpreting parallel changes in UCP3 and mitochondrial oxidative capacity as the reflection of mitochondrial uncoupling by UCP3.

Animal Feed↗

PubMed2002

Skeletal muscle heterogeneity in fasting-induced upregulation of genes encoding UCP2, UCP3, PPARgamma and key enzymes of lipid oxidation.

The uncoupling protein homologs UCP2 and UCP3 have been proposed as candidate genes for the regulation of lipid metabolism. Within the context of this hypothesis, we have compared, from fed and fasted rats, changes in gene expression of skeletal muscle UCP2 and UCP3 with those of carnitine palmitoyltransferase I and medium-chain acyl-CoA dehydrogenase, two key enzymes regulating lipid flux across the mitochondrial beta-oxidation pathway. In addition, changes in gene expression of peroxisome proliferator-activated receptor gamma, a nuclear transcription factor implicated in lipid metabolism, were also investigated. The results indicate that in response to fasting, the mRNA levels of UCP2, UCP3, carnitine palmitoyltransferase I and medium-chain acyl-CoA dehydrogenase are markedly increased, by three- to sevenfold, in the gastrocnemius and tibialis anterior (fast-twitch muscles, predominantly glycolytic or oxidative-glycolytic), but only mildly increased, by less than twofold, in the soleus (slow-twitch muscle, predominantly oxidative). Furthermore, such muscle-type dependency in fasting-induced transcriptional changes in UCP2, UCP3, carnitine palmitoyltransferase and medium-chain acyl-CoA dehydrogenase persists when the increase in circulating levels of free fatty acids during fasting is abolished by the anti-lipolytic agent nicotinic acid - with blunted responses only in the slow-twitch muscle contrasting with unabated increases in fast-twitch muscles. Independently of muscle type, however, the mRNA levels of peroxisome proliferator-activated receptor gamma are not altered during fasting. Taken together, these studies indicate a close association between fasting-induced changes in UCP2 and UCP3 gene expression with those of key regulators of lipid oxidation, and are hence consistent with the hypothesis that these UCP homologs may be involved in the regulation of lipid metabolism. Furthermore, they suggest that in response to fasting, neither the surge of free fatty acids in the circulation nor induction of the peroxisome proliferator-activated receptor gamma gene may be required for the marked upregulation of genes encoding the UCP homologs and key enzymes regulating lipid oxidation in fast-twitch muscles.

Animals↗

PubMed2001

Loss of nocturnal dipping of blood pressure and heart rate in obesity-induced hypertension in rabbits.

We have investigated in rabbits whether overfeeding and weight gain, which lead to hypertension, are associated with changes in circadian rhythm of blood pressure (BP) and heart rate, and whether the sympathetic nervous system is involved in these changes. In adult male rabbits, mean arterial pressure (MAP) and heart rate (HR) were monitored by telemetry 22 h a day. Daily MAP and HR records were divided into four equal intervals and used to calculate day-night differences. After a 1-week control period, animals were switched to a high-fat (HFD) ad libitum diet for 8 weeks. HFD increased whole day MAP and HR, and rapidly abolished the normal diurnal rhythm of MAP and HR. Since HFD abolished the nocturnal dip in MAP, but had little effect on daytime values, the loss of dipping appears to account for most of the hypertension in this model of obesity. In a separate set of rabbits, alpha- and beta-adrenergic blockade (terazosin + propranolol) prevented HFD-induced hypertension and attenuated the increase in HR by more than half. Adrenergic blockade alone abolished the diurnal rhythm of MAP, chiefly by preventing daytime elevation of MAP. The addition of HFD ad libitum did not further modify daily MAP or its circadian pattern. The diurnal rhythm of HR was relatively unaffected by alpha + beta blockade alone, but was abolished after switching to HFD. In conclusion, rabbits fed an HFD ad libitum develop hypertension and tachycardia associated with a loss of the normal diurnal rhythm of MAP and HR. The hypertension appears to be sympathetically mediated.

Adrenergic alpha-Antagonists↗

PubMed2000

Role of the sympathetic nervous system during the development of obesity-induced hypertension in rabbits.

We have previously reported that weight gain induced by high-fat diet (HFD) leads to an increase in mean arterial pressure (MAP, +14%) and heart rate (HR, +31%) in the adult rabbit. In the present study, we tested the hypothesis that an increased activity of the sympathetic nervous system may contribute to the development of obesity-induced hypertension. A combination of alpha- and beta-adrenergic blockers (terazosin + propranolol) was chronically administered to rabbits housed in metabolic cages for continuous monitoring of arterial pressure by telemetry, 24 h a day. After 2 weeks of adrenergic blockade under control diet, animals were switched to HFD for the next 6 weeks. HFD induced a progressive increase in body weight, but no increase in mean arterial pressure (+0.2+/-2.5%) and a slight increase in heart rate (+14+/-3%). Time-control animals fed normal diet showed no changes in MAP or HR with long-term alpha- and beta-adrenergic blockade. Our results indicate that the activation of the sympathetic nervous system may play an important role in the pathogenesis of obesity-induced hypertension.

Adrenergic alpha-Antagonists↗

PubMed2000

Influence of angiotensin on the early progression of heart failure.

The purpose of this study was to elucidate the role of circulating ANG II in mediating changes in systemic and renal hemodynamics, salt and water balance, and neurohormonal activation during the early progression of heart failure. This objective was achieved by subjecting six dogs to 14 days of rapid ventricular pacing (240 beats/min) while fixing plasma ANG II concentration (by infusion of captopril + ANG II) either at approximately normal (days 1-8, 13-14) or at high physiological (days 9-12) levels. Salt and water retention occurred during the initial days of pacing before sodium and fluid balance was achieved by day 8. At this time, cardiac output and mean arterial pressure were reduced to approximately 55 and 75% of control, respectively; compared with cardiac output, reductions in renal blood flow were less pronounced. Although plasma ANG II concentration was maintained at approximately normal levels, there were sustained elevations in total peripheral resistance (to approximately 135% of control), filtration fraction (to approximately 118% of control), and plasma norepinephrine concentration (to 2-3 times control). During the subsequent high rate of ANG II infusion on days 9-12, there were no additional sustained long-term changes in either systemic or renal hemodynamics other than a further rise in right atrial pressure. However, high plasma levels of ANG II induced sustained antinatriuretic, sympathoexcitatory, and dipsogenic responses. Because these same long-term changes occur in association with activation of the renin-angiotensin system during the natural evolution of this disease, these results suggest that increased plasma levels of ANG II play a critical role in the spontaneous transition from compensated to decompensated heart failure.

Angiotensin II↗

PubMed1999

Contribution of baroreceptors and chemoreceptors to ventricular hypertrophy produced by sino-aortic denervation in rats.

1. To test whether sino-aortic denervation (SAD)-induced right ventricular hypertrophy (RVH) is a consequence of baroreceptor or chemoreceptor denervation, we compared the effects of aortic denervation (AD), carotid denervation (CD), SAD and a SAD procedure modified to spare the carotid chemoreceptors (mSAD), 6 weeks after denervation surgery in rats. A sham surgery group served as the control. 2. The blood pressure (BP) level was unaffected by AD, CD or SAD, but increased (9 %) following mSAD. The mean heart rate level was not affected. Short-term BP variability was elevated following AD (81 %), SAD (144 %) and mSAD (146 %), but not after CD. Baroreflex heart rate responses to phenylephrine were attenuated in all denervation groups. 3. Significant RVH occurred only following CD and SAD. These procedures also produced high mortality (CD and SAD) and significant increases in right ventricular pressures and haematocrit (CD). 4. Significant left ventricular hypertrophy occurred following CD, SAD and mSAD. Normalized left ventricular weight was significantly correlated with indices of BP variability. 5. These results suggest that SAD-induced RVH is a consequence of chemoreceptor, not baroreceptor, denervation. Our results also demonstrate that a mSAD procedure designed to spare the carotid chemoreceptors produced profound baroreflex dysfunction and significant left, but not right, ventricular hypertrophy.

Adrenergic alpha-Agonists↗

PubMed1999

Serial changes in cardiovascular and renal function of rabbits ingesting a high-fat, high-calorie diet.

To explore the mechanisms of obesity-induced hypertension we analyzed the sequential changes in cardiovascular and renal function in adult rabbits switched to high-fat diet (HFD) for 8 weeks. Animals were housed in metabolic cages for continuous 24-h recording of arterial pressure by telemetry and daily urine collection. High-fat diet induced a progressive increase in body weight (+47%) and a rapid rise in mean arterial pressure, heart rate, and glomerular filtration rate that stabilized, respectively, at 14%, 31% and 68% greater than control values. Time-course analysis of changes in blood pressure may reveal two components of obesity-induced hypertension, an early phase related to HFD itself and a later phase related to weight gain.

Animals↗

PubMed1999

Regulation of blood pressure during long-term ouabain infusion in Long-Evans rats.

We tested whether ouabain, an inhibitor of the sodium pump, can lead to chronic hypertension in Long-Evans rats using sensitive 24-h measurements of blood pressure. After a control week of vehicle isotonic saline infusion (14.4 mL/day), ouabain was infused intravenously at 30 microg/kg/day in intact (2K) and uninephrectomized (1K) Long-Evans rats for a total of 4 weeks. Although plasma ouabain concentration rose to 0.97 +/- 0.15 nmol/L with ouabain infusion, mean arterial pressure did not change in either 2K (delta = -0.6 +/- 1.3 mm Hg) or 1K (delta = -1.2 +/- 0.7 mm Hg) rats. These data suggest that Long-Evans rats are insensitive to the hypertensive effects of ouabain.

Animals↗

PubMed1999

Baroreflex stabilization of the double product.

We investigated whether the baroreflex control of heart rate (HR) stabilizes the product of arterial pressure (P(A)) and HR, called the double product (DP), an indirect indicator of left ventricular oxygen consumption. During pharmacological increases and decreases of P(A) in conscious rabbits, the mean (+/-SE) rate of change of the DP with respect to P(A) (dDP/dP(A)) was -88 +/- 36 and -20 +/- 36 DP units/mmHg, respectively. Regression analysis of all peak responses obtained in individual rats produced a dDP/dP(A) value of 15 +/- 16 DP units/mmHg. These estimates were significantly less than the dDP/dP(A) value predicted if HR were constant (184 +/- 7 DP units/mmHg) and were not significantly different from zero. We also compared values of baroreflex sensitivity (BRS) from the literature with those calculated to provide ideal stabilization of the DP. BRS values were significantly correlated with the calculated ideal values (R = 0.95; n = 14). BRS averaged 128 +/- 24% of the ideal value in all species and 148 +/- 28% in mammals and birds. Our results suggest that stabilization of the DP is a common consequence of the baroreflex control of heart rate.

Animals↗

PubMed1999

Diastolic compliance is reduced in obese rabbits.

Obesity often leads to symptoms of cardiopulmonary congestion associated with normal systolic but abnormal diastolic function. This study analyzed alterations in passive diastolic compliance in obesity using the rabbit model. New Zealand White rabbits were fed a normal (n=8) or 10% added fat diet (n=8). After 12 weeks, rabbits fed the high fat diet developed obesity (5.34+/-0.11 versus 3.68+/-0. 04 kg, P</=0.05) and left ventricular hypertrophy (1.37+/-0.07 versus 0.98+/-0.03 g dry weight, P</=0.05). Compliance was assessed with the isolated heart preparation by analyzing the passive end-diastolic left ventricular pressure-volume relationship. The pressure-volume relation was fit to an exponential function by regression analysis; results showed that the modulus of stiffness was greater in obese than in lean rabbits (1.21+/-0.16 versus 0. 83+/-0.05, P</=0.05), indicating that diastolic compliance was reduced. Computer simulation analyses suggested that an isolated reduction in diastolic compliance may contribute to elevated cardiac filling pressures and exercise intolerance. These data suggest that diastolic compliance is reduced early in the development of obesity and may be an important component in the reduction of cardiac reserve in obesity.

Animals↗

PubMed1997

Theoretical analysis of the mechanisms of chronic hyperinsulinemia.

Steady-state insulin resistance results in a fasting hyperinsulinemia and is a common feature of type II diabetes mellitus and obesity. In this study, a systems analysis approach was used to study glucose homeostasis which is considered as the dynamic balance between glucose release by the liver and its uptake by the peripheral tissues as regulated by insulin and glucagon. A series of computer simulation studies were performed utilizing a mathematical model of glucose homeostasis. The purpose of the study was to better understand the factors which control glucose balance and to ascertain their relative importance in the development of steady state, fasting hyperinsulinemia. When peripheral cellular insulin receptors which regulate glucose uptake were reduced to 25% of normal, the steady state plasma insulin concentration showed little change from the basal level of 8 microU/ml. When insulin receptors in the liver were also reduced to 25% of normal, the steady state insulin concentration increased from the basal levels to 32 microU/ml. Reducing pancreatic alpha cell insulin receptors to 25% of normal further increased the hyperinsulinemia to 80 microU/ml. Hence, this study suggests that the liver and its release of glucose, as controlled by insulin and glucagon, plays a central role in the development of a steady-state insulin resistance and hyperinsulinemia.

Adult↗

PubMed1996

Hypertension, cardiac hypertrophy, and neurohumoral activity in a new animal model of obesity.

Although obesity is a major risk factor for morbidity and mortality, the mechanisms mediating cardiovascular abnormalities in response to weight gain are unclear. One reason for the paucity of information in this area is the lack of appropriate animal models for the study of human obesity. Therefore, the goal of the present study was to develop a small animal model of dietary-induced obesity that mimics many of the characteristics of human obesity. We studied female New Zealand White rabbits fed either a normal (n = 17) or high-fat diet (n = 15) and examined the cardiovascular consequences of obesity, including changes in blood pressure, humoral activation, and end-organ effects such as cardiac hypertrophy. After 12 wk, rabbits on the high-fat diet were 46% heavier than their lean counterparts (5.49 +/- 0.09 vs. 3.77 +/- 0.06 kg, respectively; P = 0.0001). Obese rabbits had higher resting heart rates than lean rabbits (220 +/- 7 vs. 177 +/- 6 beats/min; P = 0.0001) and developed hypertension (96 +/- 2 vs. 85 +/- 1 mmHg; P = 0.0001), hyperinsulinemia (32.5 +/- 3.4 vs. 15.5 +/- 1.0 microU/ml; P = 0.0001), hyperglycemia (162.4 +/- 2.9 vs. 141.9 +/- 2.7 mg/dl; P = 0.0001), and elevated triglycerides (102.3 +/- 9.1 vs. 48.5 +/- 4.0 mg/dl; P = 0.0001). Obese rabbits also developed cardiac hypertrophy, as evidenced by left ventricular (LV) dry weights that were 52% greater in obese than in lean rabbits (P = 0.0003). In addition, LV total protein was increased in proportion to the increase in LV weight. The results of this study suggest that rabbits fed a high-fat diet for a period of 12 wk develop many of the characteristics of human obesity. The obese rabbit should provide a small and relatively inexpensive animal model to investigate mechanisms of obesity-related cardiovascular abnormalities.

Animals↗

PubMed1996

Atrial natriuretic peptide and sodium homeostasis in compensated heart failure.

The purpose of this study was to determine whether high plasma levels of atrial natriuretic peptide (ANP) in compensated heart failure are important in the maintenance of sodium balance. This was achieved by subjecting eight dogs to bilateral atrial appendectomy (APX) to blunt the ANP response to pacing-induced heart failure. Five intact dogs served as controls. In controls, 14 days of left ventricular pacing at 240 beats/min produced a sustained fall in cardiac output and mean arterial pressure of approximately 40 and 20%, respectively; compared with cardiac output, reductions in renal blood flow (up to approximately 25%) were less pronounced and even smaller decrements in GFR occurred (up to 9%). Despite these changes and a threefold elevation in plasma norepinephrine concentration, plasma renin activity (PRA) did not increase and sodium balance was achieved during the second week of pacing in association with a six- to eightfold rise in plasma levels of ANP. Similar responses occurred in four dogs in which APX was relatively ineffective in blunting the ANP response to pacing. In marked contrast, there were substantial increments in PRA and in plasma norepinephrine concentration, and marked sodium and water retention during the last week of pacing in four dogs with APX and severely deficient ANP. These results indicate that ANP plays a critical role in promoting sodium excretion in the early stages of cardiac dysfunction.

Adaptation, Physiological↗

PubMed1996

Cardiac hypertrophy and telemetered blood pressure 6 wk after baroreceptor denervation in normotensive rats.

We investigated cardiac morphometry 6 wk after sinoaortic baroreceptor denervation (SAD) in Long-Evans rats. SAD (n = 19) was associated with an 11% increase in the weight of the left ventricle (LV) plus septum (P < 0.001) and a 39% increase in that of the right ventricular (RV) free wall (P < 0.001), relative to sham-operated rats (n = 18). RV wall thickness was significantly increased in SAD animals, but there was no difference in the LV wall thickness and volumes of the RV and LV between groups. Constrictor responses to methoxamine and dilation responses to acetylcholine were assessed in an in vitro perfused mesenteric circulation preparation, but neither response was affected by SAD. Baroreceptor denervation was associated with marked and significant increases in the variability (2.8-fold) and daily peak (39 mmHg) levels of telemetered mean arterial pressure (MAP) and small (5%) but significant increases in the daily mean MAP level. Our results are consistent with an effect of increased MAP variability on ventricular weight but cannot rule out possible contributions from other mechanisms.

Animals↗

PubMed1995

Reduced parasympathetic control of heart rate in obese dogs.

We investigated why resting heart rate is elevated in dogs fed a high saturated fat diet for 12.7 +/- 1.8 wk. Obese dogs exhibited elevated body weight (59%), blood pressure (14%), and heart rate (25%). Differences in resting heart rate (control, 58 +/- 5 beats/min; obese, 83 +/- 7 beats/min) were abolished after hexamethonium, indicating an autonomic mechanism. Hexamethonium also reduced blood pressure in obese (20 +/- 4 mmHg) but not control (9 +/- 6 mmHg) animals. Propranolol did not affect heart rate in either group, excluding a beta-adrenergic mechanism. Subsequent administration of atropine increased heart rate more in control than in obese dogs (110 +/- 9 vs. 57 +/- 11 beats/min). The sensitivity of the cardiac limb of the baroreflex (Oxford method) was reduced by 46% in the obese group, confirming impairment of the parasympathetic control of heart rate. The standard deviation of blood pressure measurements was normal when expressed as a percentage of the mean arterial blood pressure (control, 11.2 +/- 0.4%; obese, 11.2 +/- 0.5%). Our results indicate that the development of obesity in dogs fed a high saturated fat diet is accompanied by an attenuated resting and reflex parasympathetic control of heart rate.

Animals↗