Young Lean Rats Research Articles

Cardiovascular Actions of Leptin in the Subfornical Organ are Abolished by Diet‐Induced Obesity

The subfornical organ (SFO), a sensory circumventricular organ lacking the normal blood-brain barrier with well documented roles in cardiovascular regulation, has recently been identified as a potential site at which the adipokine, leptin, may act to influence central autonomic pathways. Systemic and central leptin administration has been shown to increase blood pressure and it has been suggested that selective leptin resistance contributes to obesity-related hypertension. Given the relationship between obesity and hypertension, the present study aimed to investigate the cardiovascular consequences of the direct administration of leptin into the SFO of young lean rats and in the diet-induced obesity (DIO) rat model, which has been shown to be leptin-resistant. Leptin administration (500 fmol) directly into the SFO of young rats resulted in rapid decreases in blood pressure (BP) [mean area under the curve (AUC) = -677.8 ± 167.1 mmHg*s; n = 9], without an effect on heart rate (mean AUC = -21.2 ± 13.4 beats; n = 9), and these effects were found to be dose-related as microinjection of 5 pmol of leptin into the SFO had a larger effect on BP (mean AUC = -972.3 ± 280.1 mmHg*s; n = 4). These BP effects were also shown to be site-specific as microinjection of leptin into non-SFO regions or into the ventricle was without effect on BP (non-SFO: mean AUC = -22.4 ± 55.3 mmHg*s; n = 4; ventricle: mean AUC = 194.0 ± 173.0 mmHg*s; n = 6). By contrast, microinjection of leptin into leptin-resistant DIO rats was without effect on BP (mean AUC = 205.2 ± 75.1 mmHg*s; n = 4). These observations suggest that the SFO may be an important relay centre through which leptin, in normal weight, leptin responsive rats, acts to maintain BP within normal physiological limits through descending autonomic pathways involved in cardiovascular control and that, in obese, leptin-resistant, rats leptin no longer influences SFO neurones, resulting in an elevated BP, thus contributing to obesity-related hypertension.

Differential expression of peroxisomal proliferator activated receptors α and δ in skeletal muscle in response to changes in diet and exercise

Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that control key genes involved in fatty acid metabolism and energy homeostasis. Little is known about PPAR activation in vivo and the existence of overlapping functions between PPARalpha, -delta and -gamma. As skeletal muscle is an important site for insulin action and acts as a significant sensor for life-style-induced influences in whole-body energy metabolism, we investigated the expression of PPARalpha, -delta and -gamma in rat skeletal muscle in response to exercise after four- and twelve-weeks of high-fat feeding, respectively. PPARalpha mRNA expression in skeletal muscle increased in parallel with other signs of developing metabolic syndrome such as increased visceral fat pad volymes, plasma free fatty acids and muscle triglyceride concentrations. PPARalpha mRNA expression was up-regulated 3-fold after four weeks of high-fat feeding (p<0.01). Exercise reversed the high-fat induced increase in PPARalpha expression in young lean rats (p<0.05), but did not change the PPARalpha, -delta and -gamma expression in the skeletal muscle in the normal nutritional state. The increase in PPARalpha expression declined during a longer term of high-fat feeding. In contrast, exercise increased PPARdelta mRNA and protein expression 3- to 6-fold in skeletal muscle after longer-term high-fat feeding (p<0.05). This effect was accompanied by a reduction in skeletal muscle fat content. These findings suggest that parallel activation of PPARalpha and -delta expression in skeletal muscle may be an important adaptive mechanism in response to increased fatty acid loads in young, lean animals, protecting them from insulin resistance, whereas exercise might be needed to mediate the same positive effects in older animals.

Treatment with CL 316,243, a β3-adrenoceptor agonist, reduces serum leptin in rats with diet- or aging-associated obesity, but not in Zucker rats with genetic (fa/fa) obesity

To assess the effect of chronic treatment with a beta 3-adrenoceptor agonist, CL 316,243 (CL) on serum leptin concentration in rats with diet-induced obesity (DIO) or with genetic obesity (fa/fa Zucker). Leptin concentration was measured in serum of young control rats, young rats with DIO and old control or genetically obese fa/fa Zucker rats, that were treated chronically with CL for 2-4 weeks in our previous studies. Treatment with CL reduced elevated leptin concentrations in young rats with DIO and in old mildly obese control rats to the low concentration of young lean rats. It did not alter the grossly elevated concentration in fa/fa rats. This effect of CL correlated well with its effect to reduce white adipocyte size, except in fa/fa rats. In CL-treated fa/fa rats, despite reductions in body fat mass and in white adipocyte size, and despite normalization of both hyperglycemia and hyperinsulinemia, the leptin concentration did not change. The reason for lack of change in leptin concentrations in fa/fa rats, despite shrinking of white adipocytes and partial reversal of the obesity, may be due to another defect. The large increase in white adipocyte number in these animals was not reversed by the treatment and might have contributed to elevated leptin production. In addition, all forms of leptin receptor are known to be defective in fa/fa rats. Since leptin is rapidly excreted in urine and leptin receptors (including a form known to be involved in leptin transport) are expressed in the kidney, we suggest that leptin excretion is impaired in the fa/fa rat. This impairment contributes to maintenance of an elevated concentration of leptin in its blood and prevents treatment with a beta 3-adrenoceptor agonist from reducing this elevated concentration despite reversal of both obesity and diabetes. In addition, we suggest that CL-induced suppression of hyperphagia in fa/fa rats is leptin-independent and due to the large increase in thermogenesis.

Developmental aspects of the Adipose tissue renin‐angiotensin system: Therapeutic implications

AbstractAdipose tissue possesses considerable growth potential, and excess adipose tissue mass is associated with noninsulin dependent diabetes mellitus (NIDDM). Adipose tissue is a significant source of angiotensinogen, the precursor of angiotensin II (All), a vasoactive peptide with in vitro mitogenic effects. The renin‐angiotensin system remains only partially identified in adipose tissue, however, and knowledge of whether All has a physiologic role in this tissue is dependent in part upon other components of the system being characterized. We have chosen to further investigate aspects of the renin‐angiotensin system in separate adipose tissue depots of rats during growth and development of the tissue. Either epididymal or retroperitoneal adipose tissue was examined in young lean, or adult obese male Sprague‐Dawley rats. Adipose tissue was subjected to collagenase digestion, yielding separate vascular and fat cell fractions. Each fraction was analyzed for angiotensin converting enzyme (ACE) activity and All receptor binding capacity. ACE activity was significantly greater when expressed per gram of adipose tissue in the young lean rats. Vascular and fat cell fractions exhibited All receptors of high affinity, with a greater density of receptors observed in the epididymal adipose tissue fractions. Incubation of adipocytes with exogenous All was associated with the release of prostaglandin into the medium, and analyses of adipocyte cytosol indicated the presence of angiotensinogen. Growing rats given oral losartan, an All receptor antagonist, once daily (15 mg/kg) for 2 weeks exhibited reductions in body weight gain, fat mass, fat cell volume, and All receptor number. These data further document the presence of a peripheral renin‐angiotensin system in anatomically distinct adipose tissue depots at different stages of growth. While the characterization of the effects of All upon adipose tissue development remains incomplete, future investigations with agents affecting the adipocyte renin‐angiotensin system could provide additional information on the role of this system in adipose tissue growth.

Exercise training increases glucose transporter content in skeletal muscles more efficiently from aged obese rats than young lean rats.

Glucose uptake in rat skeletal muscles decreases with age and obesity, but increases with chronic exercise training. The purpose of our study was to determine whether the GLUT4 content in several skeletal muscles from 1-mo-old young, lean rats and 12-mo-old aged, obese rats alters with exercise training. For exercise, a treadmill run of approximately 1 km/day was made for 4 wk by both groups of rats. The concentration of GLUT4 per protein in membrane fraction from several skeletal muscles was measured by immunoblotting. The amount of GLUT4 in the gastrocnemius and white quadriceps from aged rats slightly but significantly decreased to 73% and 78% of that from young rats, respectively. However, no significant difference in GLUT4 amount in the soleus, plantaris, and red quadriceps was observed between young and aged rats. The exercise training resulted in a larger increase in the amount of GLUT4 in each muscle from aged rats than in muscles from young rats. In aged rats, GLUT4 amount increased significantly with exercise training by 30, 33, 41, and 27% in the soleus, plantaris, gastrocnemius, and red quadriceps, respectively, compared with the sedentary controls. However, in young rats, exercise-induced increase of GLUT4 amount was significant only in the plantaris, and the increase was 17%. In exercised aged, obese rats, decreases of body weight, plasma triglyceride levels, and plasma free fatty acid were also observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise training increases glucose transporter content in skeletal muscles more efficiently from aged obese rats than young lean rats

Exercise training increases glucose transporter content in skeletal muscles more efficiently from aged obese rats than young lean rats

The role of thermogenesis in the regulation of energy balance

Our knowledge of mammalian energetics has improved considerably during the last decade. Some twelve years ago energetics, which was a low priority research area (except perhaps for the agricultural nutritionists), started to revive with the publication of major contributions emphasizing the role of thermogenesis in the regulation of energy balance. Trayhum et al. (1979) observed that obesity in genetically obese mice was associated with a reduced energy expenditure for thermoregulatory thermogenesis. Meanwhile, Rothwell and Stock (1979) published results suggesting that the ability of young leanrats to resist obesity when made hyperphagic by palatable food was due to an increase in a facultative form of thermogenesis. Brown adipose tissue, which was recognized in the meantime as the main site of nonshivering thermogenesis in cold-adapted, cold-exposed rats (Foster and Frydman 1979), was also proposed as the major thermogenic effector in diet-induced thermogenesis. These studies attracted several researchers interested in understanding the etiology of obesity, an energy balance disorder that tends to be too often seen as merely the result of overfeeding. As a consequence, a tremendous amount of literature has emerged from a wide spectrum of disciplines. Although this literature supports the role of thermogenesis in energy balance of experimental animals, it does not provide all the mechanistic bases underlying this action. Besides, the role of thermogenesis in energy balance in man remains to be more firmly established. The present issue of the Canadian Journal of Physiology and Pharmacology contains a series of articles on the role of thermogenesis in energy balance. The following topics are reviewed: the role of thermogenesis in the regulation of energy balance in relation to obesity; the regulation of energy metabolism in diabetes; the role of brown adipose tissue in diet-induced thermogenesis; the role of exercise training in energy balance; and the role of thermogenesis in the energetics of pregnancy and lactation. These articles summarize the current views of some Canadian researchers who have actively contributed to the development of our knowledge on nutritional energetics during recent years.

Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase.

Fatty-acid synthase has been purified to homogeneity from human liver by a 3-step procedure including protamine sulfate/ammonium sulfate fractionation, affinity chromatography on 2',5'-ADP-Sepharose 4B and gel filtration on Sephacryl S-300. Both the human and rat fatty-acid synthase had similar characteristics regarding molecular mass, subunit structure, amino-acid composition, and substrate affinities. In order to measure the fatty-acid synthase activities in small tissue samples it was necessary to improve the sensitivity of an isotopic assay using [14C]malonyl-CoA as tracer. Special attention was paid to the dual role of free CoASH as an activator and inhibitor of the enzyme. Considerable differences existed between the specific activities of the fatty-acid synthase complex measured in human and rat lipogenic organs. Only negligible values of about 1 mU/mg protein were found in human liver and adipose tissue, while the corresponding activities were 10- to 50-fold higher in young lean rats. Less pronounced but still remarkable differences were determined for the activity of the acetyltransferase which catalyses the initial primer reaction of the fatty-acid synthase complex. In some selected cases under long-term fat-free diet (alcoholism, parenteral nutrition) elevated values of fatty-acid synthase activities were detected in human tissues. Under usual diet, with a relatively high fat content of up to 40 percent, and even after a carbohydrate-rich diet for three days, fatty-acid synthase activity remained low. It is concluded that under the dietary conditions, common for the industrialized world, de novo lipogenesis in man is negligible.

Specific binding of growth hormone by rat adipocytes.

Human GH (hGH) binding by isolated epididymal fat cells was studied in nonhypophysectomized Wistar rats. Total binding of [125I]hGH was temperature and time dependent; nonspecific binding was maximal within 30 min of incubation at both 24 and 37 C. Equilibrium binding of [125I]hGH by small adipocytes (mean volume, 40–70 pl) from young lean rats (150– 220 g BW) at 24 C was reached at 90 min and remained stable for at least 3 h. At 2 h, nonspecific binding was 30% of the total radioactivity bound. Specific binding was demonstrable and directly related (r = 0.998; P < 0.001) to the number of cells present in the flasks from 0.2 to 2.4 × 106 fat cells/ml. The amounts of hGH specifically bound to small fat cells increased as the hGH concentration in the medium increased from 10 to 100 ng/ml, and remained at a constant level with further increments in medium hGH concentration. Several nonprimate GH preparations suppressed [125I]hGH binding to adipocytes, but did so to a lesser extent than biologically equivalen...

Variations in glucose metabolism and sensitivity to insulin of the rat's adipose tissue, in relation to age and body weight.

The epididymal adipose tissue’s in vitro pattern of glucose metabolism and sensitivity to insulin were compared in 3 groups of rats; Group A) young lean rats (130–160 g, 6–8 weeks old), fed ad lib.; Group B) older heavier rats (500–600 g,>l yr old), fed ad lib.; Group C) rats of Group B after body weight had been reduced 21% through underfeeding, and during subsequent weight regain through resumption of ad lib. feeding. In addition, glucose conversion to CO2 and the insulin effect on this process were compared at monthly intervals during the first 10 months of life, in rats either fed 10 g of chow/day or fed ad lib. The data show that, during the first year of life of the ad lib. fed rat, the pattern of the adipose tissue’s glucose metabolism changes to one where conversion of glucose to glyceride-glycerol becomes the major pathway and conversion of glucose to glyceride-fatty acid virtually disappears, and that simultaneously the responsiveness of the tissue’s glucose metabolism to insulin declines markedly. These changes can be completely reversed by reducing the 1 yr old ad lib. fed rat’s body weight 21% by underfeeding and can be prevented by limiting the rat’s food intake to 10 g chow daily from the time of weaning. (Endocrinology82: 1133, 1968)