Differential effects on body weight of central 6-hydroxydopamine lesions in obese (ob/ob) and diabetes (db/db) mice.

Obese (ob/ob) and diabetes (db/db) mice are genetic mutants that have been shown to have altered levels of central catecholamines (CAs) as well as syndromes of obesity, hyperphagia, and hyperglycemia. Because the CAs, and particularly norepinephrine (NE), are implicated in the control of feeding, levels of central CAs were experimentally reduced in ob/ob and db/db mice to investigate the role of CAs in these cases of spontaneously occurring obesity. Lesions produced by 6-hydroxydopamine (6-OHDA) were used to produce large depletions of NE and dopamine (DA) in both ob/ob and db/db mice and in lean control Ss of the same background strains. In the db/db but not the ob/ob, central CA depletion was accompanied by a significant and persistent weight loss and by a reduction in plasma glucose levels when compared with vehicle-infused controls. Treatment with the NE uptake blocker desipramine (DI) prior to 6-OHDA infusions attenuated NE but not DA depletion. Diabetes Ss that received DI pretreatment showed a weight loss and decrease in plasma glucose proportional to the amount of NE depletion. Lean Ss that received the 6-OHDA treatments showed only a transient weight loss and no significant change in blood glucose. Abnormalities in central noradrenergic systems may account for part of the obesity syndrome in the diabetes mouse. (29 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of intracisternal 6-hydroxydopamine treatment on acquisition and performance of rats in a double T-maze.

136 male Sprague-Dawley rats in 4 experiments were subjected to various treatments with 6-hydroxydopamine (6-OHDA) to produce decrements in brain catecholamine content either before or after learning to respond in an appetitively motivated double –T maze task. Intracisternal injections of 6-OHDA not only impaired acquisition of the required behavioral response but also decreased performance of Ss which had previously acquired the task. Although reduced food consumption found in 6-OHDA-treated Ss may contribute to the observed deficits in –T maze responding, the behavioral deficit produced by 6-OHDA injection did not seem to be due only to a simple decrease in food intake. The decrements in acquisition and performance were clearly related to amount of central catecholamine depletion produced by 6-OHDA treatment. Further analysis suggested that the behavioral deficits were more related to the reductions in dopamine than they were to the depletion of brain norepinephrine. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Variation of food intake and body weight with estrous cycle, ovariectomy, and estradiol benzoate treatment in hamsters (Mesocricetus auratus).

In 3 experiments with 46 female hamsters, food intake and body weight fluctuated systematically with the estrous cycle. Food intake and body weight were lowest when elevated endogenous estrogen levels were expected. Ovariectomized Ss gained a significant amount of body weight compared with sham-operated Ss. Replacement therapy with estradiol benzoate reduced the body weight and food intake of ovariectomized Ss relative to oil-injected, ovariectomized controls. Results are compared with similar data from rats; they support the concept that in females of both species estradiol operates to regulate food intake and body weight. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Development of obesity in diabetic mice pair-fed with lean siblings.

Investigated the role of hyperphagia in the obesity of the diabetic mouse, C57BL/6J/db/db. Ingestion patterns and the amount of food for 25 diabetic mice were controlled by yoking their food intake to that of 16 nonobese siblings obtaining their food by barpressing. Over a period of 6 wks, young (initial ages were 28 days) pair-fed diabetic Ss accumulated 42% more body weight and approximately 5 times more extractable carcass lipid than did their siblings. Weight gain and absolute levels of carcass fat were reduced in food-restricted diabetic Ss compared with db Ss on unrestricted food intake. However, carcass fat as percentage of wet carcass weight was virtually identical in the restricted and unrestricted db rats (47.6 vs 49.6%). From these results it is concluded that the heightened adiposity of the diabetic mouse does not require hyperphagia for its expression and thus represents a metabolic obesity. (34 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estrus- and ovariectomy-induced body weight changes: Evidence for two estrogenic mechanisms.

Estrogenic modulation of body weight in female rats is usually thought to result indirectly from estrogenic modulation of food intake. However, present data from 5 experiments with 79 female albino rats suggest that estrogens influence body weight by at least 2 mechanisms, 1 of which is independent of changes in food intake. When Ss were ovariectomized (Ovx) and food intake was limited to preoperative levels, Ovx Ss nonetheless gained large amounts of body weight. Although Ovx Ss gained more weight than controls on the same amount of food, during 33 hrs of food deprivation Ovx and control Ss lost weight at the same rate, indicating that the prefasting metabolic rates of the 2 groups were similar. During the 1st 40 days after surgery, the ano-nasal lengths of Ovx Ss increased twice as fast as that of intact Ss, which suggests a mechanism for the gradual increase in weight induced by Ovx. The weights of intact Ss followed a regular 4-day cycle during ad lib feeding, but when the estrus-associated decrease in food intake was prevented, the cyclic weight changes were altered. Thus estrogens appear to regulate body weight by modulation of food intake and modulation of ano-nasal growth or other metabolic processes. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetically obese (ob/ob) mice are predisposed to gastric stress ulcers.

In Exp I, 20 adult male genetically obese (ob/ob) mice and 20 lean littermate controls were food deprived and subsequently physically restrained at normal room temperatures. Obese Ss became hypothermic and developed gastric stress ulcers. Lean Ss maintained normal body temperatures and did not form gastric ulcers. In Exp II, 5 male obese and 4 lean littermates were used to test the effects of noradrenaline (NA) during restraint, and 5 obese and 5 lean mice were used to test the effects of NA alone. It was expected that in lean, but not in obese, Ss that NA would induce an increase in O? consumption beyond that induced by initial restraint. O? consumption was measured during food deprivation and restraint. Obese and lean Ss had parallel metabolic responses, with obese Ss using significantly less O? at all times. The predisposition to formation of gastric ulcers is a new phenotypic expression of the ob/ob genotype. The pathogenesis of this susceptibility appears to be related to a genetic disturbance in heat production. (14 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ventromedial syndrome: The rat's "finickiness" results from the obesity, not from the lesions.

6 obese, finicky female hooded rats with lesions of the hypothalamic ventromedial nucleus (VMH) and 7 sham-lesioned controls progressively lost weight on an unpalatable diet until at a critical basal level they increased their intake to prevent further loss of weight. The critical basal body weight was similar in both groups and showed no change in the controls when they were subsequently lesioned and retested. At weight levels below the critical basal level the feeding behavior of lesioned and unlesioned Ss was similar, and finickiness could be demonstrated only when body weight exceeded it. The basal level bore no relation to the plateau level of body weight reached by Ss on a free diet. Suggestions that the VMH excites as well as inhibits feeding seem untenable in view of the failure of VMH lesions to impair defense of body weight in the nonobese rat. (17 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of leptin adipose tissue lipoprotein lipase in the obese ob/ob mouse

OBJECTIVE: To characterize the adaptations of lipid metabolism, with special emphasis on tissue lipoprotein lipase, to negative energy balance brought by chronic treatment of obese ob/ob mice with leptin. DESIGN: According to a 2 x 2 factorial analysis, lean and obese C57BL/6J mice were subcutaneously infused with leptin (100 micrograms.kg-1.day-1) or vehicle (phosphate-buffered saline) during seven days. RESULTS: Cumulative food intake and final body weight of vehicle-infused obese mice were twofold higher than in lean controls. Leptin decreased cumulative food intake and body weight of obese, but not lean mice. Lipoprotein lipase (LPL) activity in white inguinal and epididymal and brown interscapular adipose tissues of control obese mice was at least twofold higher than in lean mice, but comparable in the vastus lateralis muscle. Leptin treatment of obese mice significantly lowered LPL activity to that of lean mice in all tissues examined. Vehicle-infused obese mice had higher liver triglyceride content and were hypertriglyceridemic compared to lean mice, and triglyceride concentrations in plasma and liver were decreased proportionally after leptin treatment. Leptin lowered glycemia and insulinemia of obese mice to lean levels and decreased plasma corticosterone. Leptin infusion had no notable effect on tissue lipoprotein lipase nor plasma variables of lean mice. CONCLUSIONS: Leptin infusion abolished hyperinsulinemia in the ob/ob mouse, an effect that was probably responsible for the concomitant normalization of adipose LPL activity. This study shows that decreased LPL activity, plasma triglyceride concentrations and hepatic triglyceride production constitute some of the adaptive peripheral adaptations of lipid metabolism, which accompany the reduction in fat mass accretion brought by leptin treatment of the obese ob/ob mouse.     

Influences of deviations of thyroid functions on the effects of MAOI in rats--changes of 5-HT, 5-HIAA and norepinephrine contents and tyramine uptake by the brain and fluctuation of the rectal temperature]

The drug 6-hydroxydopamine (6-OHDA) has been reported to reduce hypothalamic norepinephrine (NE) content after administration into the lateral ventricle without altering the dopamine content of tubero-infundibular neurons. Serum prolactin levels in male rats injected with 2 X 250 mug 6-OHDA were significantly higher than in untreated control rats. Intraventricular injection of male rats with artificial cerebrospinal fluid resulted in elevated mean prolactin levels similar to those observed in 6-OHDA-treated animals. Further experimentation on animals decapitated at different times after removal from the animal quarters, indicates that prolcatin levels in 6-OHDA-treated rats are continuously elevated whereas they rise from basal levels to extremely high levels in CSF-treated rats, thus resulting in similar mean values. The CSF-treated controls ate hypersensitive to the stress of being removed from their normal environment. Such an effect was not observed in 6-OHDA-treated nor in untreated, and thus stress-inexperienced rats. In a long term study, serum prolactin and luteinizing hormone (LH) levels were followed over a period of 71 days after 6-OHDA treatment. Prolactin levels increased within one day after treatment and stayed at a high level for 15 days. Subnormal prolactin values were measured 37 days after 6-OHDA treatment. Serum LH levels were below normal 3 h and one day and were increased 37 and 71 days after 6-OHDA treatment. These results suggest that NE is important in the transmission of stressful stimuli to hypothalamic prolactin regulating centers. They further suggest functional recovery of LH and prolactin regulating mechanisms after 6-OHDA treatment.     

Effects of diet on feeding and body weight regulation during pregnancy and lactation in the golden hamster (Mesocricetus auratus).

Conducted 3 experiments with 90 female golden hamsters to test the hypothesis that the weight loss shown by lactating hamsters constitutes a regulated weight loss. Results support the hypothesis, showing that prefattened overweight Ss lost more weight from the time of mating to the end of lactation than did unmanipulated controls. However, the weight loss during lactation was reduced by giving Ss access to a high-fat diet, a result indicating that a portion of the lactational weight loss may also be regulated by the diet provided. When lactating Ss were given access to a fractionated diet consisting of pure fat, pure carbohydrate, or 45% protein, they increased their proportional intake of both protein and fat but not of carbohydrate. Studies show that hamsters differ from rats in their pattern of energy regulation during pregnancy, lactation, and the postsuckling period. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Decrease in food intake following cortical spreading depression in static obese rats with ventromedial hypothalamic lesions.

Subjected 19 male and 23 female rats with ventromedial hypothalamic (VMH) lesions or with sham lesions to cortical spreading depression (CSD) 150 days after lesioning. Lesioned Ss showed a significantly lower food intake (as percentage of intake before CSD) than sham-lesioned Ss in the 14 days after CSD, but water intake did not differ between lesioned and sham-lesioned Ss. Both groups showed a slight decline in body weight, but lesioned Ss lost significantly more weight than sham-lesioned Ss. After 14 days, body weight, food intake, and water intake had returned to pre-CSD levels in both groups. Findings indicate that Ss with VMH damage are more sensitive to the effects of CSD than are normals and suggest that CSD acts to increase the activity of the VMH and to inhibit food intake, and this increase in activity is prolonged in VMH-lesioned Ss. (22 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retinal dopamine depletion in young quail mimics some of the effects of ageing on visual function

The hypothesis that retinal dopaminergic (DA) neurones are involved in the visual functions of interest was tested. The retinal DA in young quail was partially depleted by intravitreal injection of 6-hydroxydopamine (6-OHDA). It was found that the refractive state of 6-OHDA-treated birds became more myopic than normal (untreated) young, whereas the pupil diameter was not affected. The contrast sensitivity of 6-OHDA treated quail was significantly lowered (two to three times) at all spatial frequencies studied (0.25-5 c/d), and the peak latency of pattern electro-retinogram (PERG) response was prolonged by 3-4 msec (9%). Furthermore, the visual acuity and maximal amplitude of PERG response of the 6-OHDA-treated young quail were lower than those of normals. From histochemical studies, it was revealed that the morphology of the DA cells of 6-OHDA-treated young appeared similar to those of the old quail; the DA cells of 6-OHDA-treated retinae were less fluorescent and 2.5-5 times less numerous than respective controls. Combining the PERG and the morphological results, it would seem that the retinal DA plays an important role in the visual functions studied, and that loss of retinal DA could underlie some of the visual changes which occur during ageing.     

Magnetic resonance imaging of brain death

The db/db mutant mouse is a rodent model of genetic diabetes that develops renal glomerular lesions with striking mesangial matrix accumulation by the age of 16 weeks, after 8-10 weeks of sustained hyperglycemia. However, abnormalities in renal function that antedate or accompany the appearance of these pathologic changes, which resemble those found in human diabetes, have not been delineated. We therefore examined renal function in young db/ db mice and their nondiabetic db/m littermates from the age of 8 through 15 weeks. Serum creatinine and blood urea nitrogen concentrations at the onset of diabetes in db/db mice did not differ significantly from mean concentrations in db/m controls. An elevated creatinine clearance, due in large part to increased body weight, and increased urinary albumin excretion were observed in db/db compared with db/m mice soon after establishment of sustained hyperglycemia. A relative reduction in creatinine clearance was demonstrable in db/db mice at the age of 15 weeks, coincident with the appearance of overt compromise in renal function manifested by frank increases in the serum creatinine and blood urea nitrogen. The findings indicate that the well-documented glomerular pathology in db/db mice is accompanied by definable alterations in renal function, which are similar in chronology and nature to those found in human diabetes.     

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice

Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.     

Central noradrenergic neurons: Differential effects on body weight of electrolytic and 6-hydroxydopamine lesions in rats.

Compared the effects of bilateral electrolytic and 6-hydroxydopamine (6-OHDA) lesions of the ventral noradrenergic bundle (VB) in 2 experiments with a total of 67 female albino rats. When Ss were fed only a standard laboratory diet, no significant differences were found between groups. When a high-fat diet supplement was introduced, the group with electrolytic lesions became significantly heavier than the control group; however, the 6-OHDA group did not differ from the controls. Norepinephrine depletion was significantly greater following the 6-OHDA than the electrolytic lesions. Both lesions reduced telencephalic dopamine and serotonin only slightly. Exp II, in which both types of lesions were placed at a rostral ventromedial hypothalamic site, yielded the same pattern of results. Diet-dependent increased in body weight were attributed to the destruction of a non-noradrenergic system, which was spared by the relatively selective 6-OHDA lesion but damaged by the nonselective electrolytic lesion. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The development of overt diabetes in young Zucker Diabetic Fatty (ZDF) rats and the effects of chronic MCC-555 treatment

1. Young (6-week-old) pre-diabetic Zucker Diabetic Fatty (ZDF) rats displaying impaired glucose tolerance (IGT), moderate hyperglycaemia and hyperinsulinaemia were treated with the novel thiazolidinedione, MCC-555, for 28 days, during which time beta-cell failure and progression to overt diabetes occurs. 2. Treated ZDF rats exhibited consistently lower blood glucose levels than vehicle-treated diabetic controls, with a delayed rise and lower plateau levels. MCC-555 maintained plasma insulin levels throughout the treatment period, whereas these fell by 40% in untreated ZDF rats. 3. The rise in body weight was maintained in MCC-555-treated rats, whereas vehicle-treated rats exhibited blunted body weight gain after 8 weeks of age. Daily food intake was higher in diabetic, as compared to non-diabetic rats, but treatment did not modify food intake in diabetic rats. Water intake was lower in treated ZDF rats, concomitant with lowering of blood glucose. 4. The hyperinsulinaemic-euglycaemic clamp technique was applied to all rats after treatment to examine the effects of MCC-555 on insulin sensitivity. The glucose infusion rate to maintain normoglycaemia was lower in diabetic than in non-diabetic rats, demonstrating reduced glucose entry into insulin-sensitive tissues in diabetic rats. Increased glucose infusion rates were required to maintain euglycaemia in treated diabetic rats, demonstrating increased insulin sensitivity in these animals. 5. In conclusion, chronic MCC-555 treatment of young ZDF rats displaying IGT attenuates the development of overt diabetes through improved insulin sensitivity and maintenance of beta-cell function. MCC-555 may thus be beneficial in humans with IGT, to prevent or delay the progression of diabetes.     

Trigeminal deafferentation and feeding behavior patterns in the pigeon (Columba livia).

Data from a study with 11 White Carneaux pigeons show that after an aphagic period, trigeminally deafferented Ss regulated body weight at reduced levels. The deficit involved was characterized by comparing feeding patterns of deafferented and food-deprived birds with equivalent weight losses. Deafferented Ss showed disproportionate increases in meal size during the early portion of the feeding period but abnormally rapid attenuation of feeding activity in the course of the day, which led to a reduced overall level of food intake. Trigeminal input appears to influence both the size of bouts and the frequency of bout initiation. Findings are discussed in relation to the homeostatic model of intake control and within the framework of food conditioning. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Depletion of dopamine in the nucleus accumbens prevents the generation of locomotion by metabotropic glutamate receptor activation

The contribution of dopamine (DA) to the locomotion elicited by activation of nucleus accumbens (NAcc) metabotropic glutamate receptors (mGluRs) was investigated in the rat. Different groups of rats were pretreated with bilateral microinjections of either 6-hydroxydopamine (6-OHDA) or its vehicle into the NAcc and, on separate tests starting 10 days later, were tested for locomotion following microinjections (into the same site) of saline, the mGluR agonist, 1-aminocyclopentane-trans-1,3-dicarboxylic acid [(1S, 3R)-ACPD, 0.5 nmol/side] and amphetamine (AMPH, 6.8 nmol/side). DA levels at the microinjection sites were significantly depleted in 6-OHDA-treated rats (42-99% depletions compared to control values obtained in vehicle-treated rats). In contrast to the increased locomotion observed in non-lesioned animals, rats pretreated with 6-OHDA showed no increase in locomotor activity in response to (1S, 3R)-ACPD or AMPH when these were microinjected into the NAcc. The two groups of rats were indistinguishable when tested following NAcc saline. These findings suggest that, as with AMPH, enhanced locomotion produced by NAcc mGluR activation is dependent on intact DA neurotransmission in this site.     

Weight regulation with palatable food and liquids in rats with lateral hypothalamic lesions.

Maintained 25 female Carworth CFE albino rats with 4- or 7-sec 1-ma bilateral lesions of the lateral hypothalamus (LH) for 87 days on a high-fat diet and a sequence of fluids (water, 6% sucrose, and 1 or .2% saccharin). Lesioned Ss reached a greater weight than 9 sham-lesioned Ss offered the same diet and fluids, and maintained greater weight regardless of the fluid offered. These data do not support the hypothesis that LH lesions lower the set point for weight. Rather, the finickiness of LH Ss results in smaller intake of unpalatable foods and water which, in turn, results in stablization of weight below that of controls. If sufficiently hydrated, LH Ss eat greater quantities of highly palatable foods than do controls, resulting in greater body weight. (24 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Insulin and glucagon as determinants of body weight set point and microregulation in rats.

Seven adult male Long-Evans rats were observed for body weight and microregulation (feeding, drinking, and running patterns) after manipulation of insulin and glucagon levels. They received 3 injections/day for 3 days/wk of 3 U of protamine zinc insulin, .25 mg of zinc glucagon, 50 μg of protamine zinc somatostatin (SRIF), or protamine zinc vehicle. Diabetes was then induced with an iv injection of streptozotocin (65 mg/kg), and the injection schedule was repeated after the full diabetic syndrome emerged. In all Ss whose insulin levels were increased relative to glucagon levels, body weight increased; in those whose glucagon levels were increased relative to insulin levels, body weight decreased. All injections except vehicle reduced meal sizes in both normal and diabetic rats, but only insulin increased the frequency of feeding. These effects could be predicted by the glucostatic theory of food intake regulation and are thus interpreted as supporting this theory. Results also support the hypothesis that the relative concentration of insulin to glucagon is a regulator of body weight set point. (PsycINFO Database Record (c) 2010 APA, all rights reserved)