Effect of a selective OX1R antagonist on food intake and body weight in two strains of rats that differ in susceptibility to dietary-induced obesity.

An orexin-1 receptor antagonist decreases food intake whereas orexin-A selectively induces hyperphagia to a high-fat diet. In the present study, we evaluated the effect of an orexin antagonist in two strains of rats that differ in their sensitivity to becoming obese while eating a high-fat diet. Male Osborne-Mendel (OM) and S5B/Pl (S5B) rats were treated acutely with an orexin-1 receptor antagonist (SB-334867), after adaptation to either a high-fat (56% fat energy) diet or a low-fat (10% fat energy) diet that were equicaloric for protein (24% energy). Ad libitum fed rats were injected intraperitoneally with SB-334867 at doses of 3, 10 or 30 mg/kg, or vehicle at the beginning of the dark cycle, and food intake and body weight were measured. Hypothalamic prepro-orexin and orexin-1 receptor mRNA expression were analyzed in OM and S5B rats fed at a high-fat or low-fat diet for two weeks. SB-334867 significantly decreased food intake in both strains of rats eating the high-fat diet but only in the OM rats eating the low fat diet. The effect was greatest at 12 and 24 h. Body weight was also reduced in OM rats 1d after injection of SB-334867 but not in the S5B rats. Prepro-orexin and orexin-1 receptor expression levels did not differ between strains or diets. These experiments demonstrate that an orexin antagonist (SB-334867) reduces food intake and has a greater effect in a rat strain that is susceptible to dietary-induced obesity, than in a resistant strain.

Drug treatment of obesity.

At present only two drugs are approved for long-term treatment of obesity. Sibutramine inhibits the reuptake of serotonin and norepinephrine. In clinical trials it produces a dose-dependent 5-10% decrease in body weight. Its side effects include dry mouth, insomnia, asthenia, and constipation. In addition, sibutramine produces a small increase in blood pressure and pulse that is a contraindication to the use of this drug in some individuals with heart disease. Xenical is the other drug approved for long-term use in the treatment of obesity. It works by blocking lipase and thus increasing the fecal loss of triglyceride. One valuable consequence of this mechanism of action is the reduction of serum cholesterol that averages about 5% more than can be accounted for by weight loss alone. In clinical trials it produces a 5-10% loss of weight. Its side effects are entirely due to undigested fat in the intestine that can lead to increased frequency and change in the character of stools. It can also lower fat-soluble vitamins. The ingestion of a vitamin supplement before bedtime is a reasonable treatment strategy. The effect on weight loss during long-term trials with these two drugs is shown in Figs 7 and 8 above. Also in this figure is data on phentermine used in trials of six months or more. Although there were differences in mean weight losses with these drugs, when the placebo effect was taken into account they all had a surprisingly similar magnitude of weight loss.

Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy.

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 microg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.

Differential expression of leptin receptor in high- and low-fat-fed Osborne-Mendel and S5B/Pl rats.

OBJECTIVE: The regulation of body weight and body composition involves input from genes and the environment. This interaction is demonstrated by the different susceptibility of Osborne-Mendel (OM) and S5B/P1 rat strains to obesity when offered a high-fat diet. In animals and humans, diet-induced obesity has been characterized by hyperleptinemia, which has been interpreted as evidence for leptin resistance. This investigation determined if altered expression of leptin receptors (ObR) in the hypothalamus could potentially contribute to altered sensitivity to diet-induced obesity between OM and S5B/P1 rats. RESEARCH METHODS AND PROCEDURES: OM and S5B/P1 rats were fed high-fat (HF) or low-fat (LF) diets for 14 days. Ribonuclease protection assays and Western blotting were used to assay the levels of mRNA and protein, respectively, for short (ObR-S) and long (ObR-L) forms of the leptin receptor in the hypothalamus. RESULTS: The mRNA encoding ObR-L, the predominant signaling form of the receptor, was higher in OM rats than in S5B/P1 rats (p < 0.01) both on HF and LF diets. No changes in ObR-L mRNA expression were observed in OM rats with diet, but, S5B/P1 rats showed a slight increase in the ObR-L on the LF diet. On the contrary, there were no changes in ObR-S mRNA expression due to diet or strain. Western blots showed that both the short and long forms of the receptor were increased on the LF diet, but there were no strain differences. OM and SSB/P1 rats had comparable leptin levels after maintenance on a LF diet (6.20 +/- 0.63 and 4.81 +/- 0.82 ng/mL, respectively). Serum leptin levels in OM rats were increased by the HF diet and were elevated 2-fold over those of their S5B/P1 counterparts. DISCUSSION: These results suggest that a decrease in the levels of both the long form and short form of the receptor may contribute to the leptin resistance seen in HF-fed rats. These effects appear to be post-transcriptional, because equivalent changes were not observed in the expression of ObR-L and ObR-S mRNAs. They may be related to the increase in circulating leptin levels, suggesting that high serum leptin levels contribute to increased leptin resistance and subsequently lead to obesity. We conclude that down-regulation of receptor protein levels is associated with hypothalamic leptin resistance of HF-fed rats.

The effects on feeding of galanin and M40 when injected into the nucleus of the solitary tract, the lateral parabrachial nucleus, and the third ventricle.

Several reports indicate that central injection of galanin stimulates feeding, and that there is macronutrient specificity in this response. In addition, the galanin receptor antagonist, M40, reduces food intake when injected centrally. The nucleus of the solitary tract (NTS) and the lateral parabrachial nucleus (PBN) contain galanin receptors, and are involved in the control of food intake. Hence, we sought to compare the feeding response to galanin injection into these areas with that of third ventricle (3V) galanin injection. The feeding response to injection of galanin was greatest for the 3V. Hindbrain injection of galanin stimulated food intake only at the beginning of the dark period. NTS injection of M40 inhibited intake of a macronutrient diet in food-deprived rats, but was ineffective at reducing dark-onset feeding or deprivation-induced chow intake. 3V injection of M40 did not reduce deprivation-induced intake. PBN injection of galanin at dark onset had no effect in a group of fat-preferring rats. These results suggest that hindbrain galanin may contribute to feeding by inhibiting satiety, and that hypothalamic galanin receptors are involved with stimulation of intake. Furthermore, the absence of a consistent pattern of the stimulation of macronutrient intake suggests that galanin may not be a significant effector of macronutrient selection during individual meals.

Activation of hypothalamic serotonin receptors reduced intake of dietary fat and protein but not carbohydrate.

Systemic treatment with dexfenfluramine (dF), fluoxetine, or serotonin (5-hydroxytryptamine, 5-HT) recently was shown to suppress fat and occasionally protein but not carbohydrate intake in rats when a macronutrient selection paradigm was employed. These reports contrast with the prevailing literature, which for the past decade has described a role for serotonin neurotransmission in the modification of dietary carbohydrate consumption. To test the hypothesis that the suppression of fat selection and/or consumption by systemic serotonin agonists involves stimulation of central 5-HT receptors, a series of experiments was performed in nondeprived rats. In experiment 1, third cerebroventricular (3V) infusion of the nonselective 5-HT antagonist metergoline prevented the reduction in fat but not carbohydrate feeding caused by systemic dF. Furthermore, 3V metergoline alone increased fat intake. In experiments 2 and 3, 3V infusion of 5-HT(1B/2C) receptor agonists D-norfenfluramine (DNF) or quipazine inhibited fat intake exclusively. Next, the infusion of DNF or 5-HT into the region of the paraventricular nucleus (PVN) reduced both fat and protein intake (experiments 4 and 5). Finally, in experiment 6, when rats were grouped by baseline diet preference, 5-HT infused into the PVN led to a dose-related decrease in fat intake in both carbohydrate- and fat-preferring rats. In contrast, there were no dose effects of 5-HT on carbohydrate or protein intake in either preference group. However, in fat-preferring rats, the highest dose of 5-HT reduced intake of all three macronutrient diets. These results demonstrate a selective effect of exogenous serotonergic drugs in the hypothalamus to reduce fat rather than carbohydrate intake and suggest that higher baseline fat intake enhances responsivity to serotonergic drugs.

A dietary approach to prevent hypertension: a review of the Dietary Approaches to Stop Hypertension (DASH) Study.

BACKGROUND: Populations eating mainly vegetarian diets have lower blood pressure levels than those eating omnivorous diets. Epidemiologic findings suggest that eating fruits and vegetables lowers blood pressure. HYPOTHESIS: Two hypotheses were tested: (1) that high intake of fruits and vegetables lowers blood pressure, and (2) that an overall dietary pattern (known as the DASH diet, or DASH combination diet) that is high in fruits, vegetables, nuts, and low-fat dairy products, emphasizes fish and chicken rather than red meat, and is low in saturated fat, cholesterol, sugar, and refined carbohydrate lowers blood pressure. METHODS: Participants were 459 adults with untreated systolic blood pressure < 160 mmHg and diastolic blood pressure 80-95 mmHg. After a 3-week run-in on a control diet typical of Americans, they were randomized to 8 weeks receiving either the control diet, or a diet rich in fruits and vegetables, or the DASH diet. The participants were given all of their foods to eat, and body weight and sodium intake were held constant. Blood pressure was measured at the clinic and by 24-h ambulatory monitoring. RESULTS: The DASH diet lowered systolic blood pressure significantly in the total group by 5.5/3.0 mmHg, in African Americans by 6.9/3.7 mmHg, in Caucasians by 3.3/2.4 mmHg, in hypertensives by 11.6/5.3 mmHg, and in nonhypertensives by 3.5/2.2 mmHg. The fruits and vegetables diet also reduced blood pressure in the same subgroups, but to a lesser extent. The DASH diet lowered blood pressure similarly throughout the day and night. CONCLUSIONS: The DASH diet may offer an alternative to drug therapy in hypertensives and, as a population approach, may prevent hypertension, particularly in African Americans.

Nutrition and obesity: prevention and treatment.

The increased risk of morbidity and mortality from obesity, central body fat, and weight gain, and the beneficial effects of weight reduction argue that the cost associated with obesity could be beneficially affected by prevention of weight gain or induction of weight loss. Genetic, metabolic, and demographic predictors of weight gain have been identified that allow selection of high-risk individuals. Among the metabolic predictors are a low metabolic rate, insulin sensitivity, and a high respiratory quotient. Demographic predictors include current smokers, certain dieting behaviors, lower socio-economic class, a low level of education, use of contraceptives, status post-partum, and rapid weight gain in childhood. Several studies suggest that weight gain can be prevented. Targets for such strategies might be high-risk families, current smokers, those who are planning to stop smoking, and those with a low metabolic rate. For those who fail primary prevention, treatment may be appropriate. The greater the degree of excess weight, the greater the risk and the more appropriate treatment becomes to reduce body weight.

Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity.

The Differential Display technique has been used to identify differences in mRNA expression in adipose tissue after the introduction of a high fat diet to two strains of rat (OM and S5B/PI) that differ in their susceptibility to develop obesity on this diet. The insulin receptor tyrosine kinase inhibitor protein (fetuin) was shown to be differentially expressed in OM but not S5B/PI rats. This circulating protein may play a role in the development of peripheral insulin resistance associated with high fat diets.

Does vegetable oil attenuate the beneficial effects of fish oil in reducing risk factors for cardiovascular disease?

Contradictory reports on the protective effect of fish consumption on cardiovascular disease (CVD) risk could be due to variations in the intake of n-3 and n-6 polyunsaturated fatty acids (PUFAs). Metabolic competition between n-3 and n-6 PUFAs suggests that n-6 PUFAs in vegetable oils could attenuate the efficacy of n-3 PUFAs in fish oil to favorably alter endpoints relevant to CVD risk. We determined the effects of varying dietary amounts of fish oil on lipid and thrombotic endpoints relevant to risk factors for CVD and whether these effects were attenuated by vegetable oils. Two randomized, double-blind, placebo-controlled, parallel studies were conducted in human subjects fed varying amounts of n-3 and n-6 PUFAs; n-3 PUFA intake was varied by using fish or placebo oil capsules, and n-6 PUFA intake was modified by incorporating varying amounts of safflower oil into the diet. Endpoints included changes in membrane fatty acid composition, blood lipids, and thrombotic profile. The results indicated that absolute amounts of fish oil, and not the relative amounts of fish and vegetable oil (ratios of n-3 to n-6 PUFAs), determined the magnitude of the reduction of arachidonic acid and increase in eicosapentaenoic acid in phospholipids of plasma and platelets. The suppression of plasma triacylglycerols by fish oil was not affected by varying amounts of dietary n-6 PUFAs. Fibrinogen concentrations decreased with 15 g but not with 9 g fish oil/d fed at the same ratio of n-3 to n-6 PUFAs. The efficacy of fish oil in favorably modifying certain risk factors for CVD was not attenuated by vegetable oil.

Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus.

BACKGROUND: Acarbose delays release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, thereby attenuating postprandial increments in blood glucose and insulin. This multicenter, double-blind, placebo-controlled study compared the efficacy and safety of diet alone, acarbose, tolbutamide, and acarbose-plus-tolbutamide in non-insulin-dependent diabetes mellitus (NIDDM) patients. PATIENTS AND METHODS: A total of 290 patients with NIDDM and fasting plasma glucose levels of at least 140 mg/dL were randomized to receive treatment TID with acarbose 200 mg, tolbutamide 250 to 1,000 mg, a combination of both drugs, or placebo. A 6-week run-in period was followed by double-blind treatment for 24 weeks, then a 6-week follow-up period. RESULTS: All active treatments were superior (P < 0.05) to placebo in reducing postprandial hyperglycemia and HbA1c levels. The ranking in order of efficacy was: acarbose-plus-tolbutamide, tolbutamide, acarbose, and placebo. The postprandial reductions in glucose were approximately 85 mg/dL for acarbose-plus-tolbutamide, 71 mg/dL for tolbutamide, 56 mg/dL for acarbose, and 13 mg/dL for placebo. Tolbutamide was associated with increases in body weight and postprandial insulin levels when taken alone, but these were ameliorated when tolbutamide was taken in combination with acarbose. Acarbose alone or in combination with tolbutamide caused significantly more gastrointestinal adverse events (mainly flatulence and soft stools or diarrhea) than tolbutamide or placebo, but these were generally well tolerated. Clinically significant elevations in hepatic transaminase levels occurred in 3 patients in the acarbose group and 2 in the acarbose-plus-tolbutamide group. Transaminase levels returned to normal when therapy was discontinued. CONCLUSIONS: Acarbose was effective and well tolerated in the treatment of NIDDM. Control of glycemia was significantly better with acarbose compared with diet alone. Acarbose-plus-tolbutamide was superior to tolbutamide alone.

Extracellular hypothalamic monoamines measured by in vivo microdialysis in a rat model of dietary fat-induced obesity.

We tested two hypotheses about monoamine neurotransmitters in two strains of rats that differ in their sensitivity to obesity when eating a high-fat diet; 1) that the concentrations of norepinephrine and serotonin and of their metabolites differ in the extracellular fluid of the ventromedial hypothalamus of conscious, unrestrained Osborne-Mendel and S 5B/Pl rats, and 2) that these monoamines are altered differently between strains by a high-fat diet. The monoamines were measured by HPLC in dialysate collected by in vivo microdialysis in rats eating a semisynthetic low-fat diet (10% of kcal as fat) and again after either two or seven days of eating a high-fat diet (56% of kcal as fat). Norepinephrine, serotonin (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) were lower in Osborne-Mendel rats than in S 5B/Pl rats eating the low-fat diet. Norepinephrine and serotonin both increased in Osborne-Mendel rats with the onset of the high-fat diet so that Osborne-Mendel and S 5B/Pl rats no longer differed in these neurotransmitters. By day 7 of high-fat feeding, the concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-HIAA and the 5-HIAA/5-HT ratio rose in both strains. Ambient extracellular monoamines in the medial hypothalamus are lower in Osborne-Mendel rats than in S 5B/Pl rats and the response of these catecholamines to dietary fat was greater in Osborne-Mendel rats than in S 5B/Pl rats.

Insulin secretion in hypothalamic obesity: diurnal variation and the effect of naloxone.

This paper has tested the hypothesis that patients with hypothalamic obesity have altered mechanisms controlling insulin secretion when compared to obese patients without hypothalamic injury. Fasting glucose and insulin values were significantly higher in the morning than in the afternoon in the six control obese patients, but there was no diurnal difference in the six patients with hypothalamic obesity (n=6). The control obese subjects showed a diurnal variation in glucose-stimulated insulin secretion, whereas the patients with hypothalamic obesity did not, suggesting that hypothalamic injury had destroyed diurnal rhythms. Naloxone, an opioid antagonist, acutely suppressed fasting insulin in the six patients with essential obesity but had little effect on fasting insulin in the three patients with hypothalamic obesity or in five normal-weight controls. Naloxone increased insulin sensitivity in the obese control patients, but did not affect either insulin secretion or insulin sensitivity in patients with hypothalamic obesity or in normal weight subjects. Our results support the conclusion that hypothalamic obesity disrupts diurnal rhythms, with the suggestion that opioid peptides affect insulin secretion differently in patients with essential obesity as compared to normal weight subjects or those with hypothalamic obesity.

d-fenfluramine in a rat model of dietary fat-induced obesity.

d-Fenfluramine is an appetite suppressant drug that acts by releasing serotonin from axon terminals and inhibiting its reuptake. S 5B/P1 rats, which are resistant to dietary-fat induced obesity, and Osborne-Mendel rats, which are sensitive, were adapted to ad lib feeding of either a low- or high-fat diet. d-Fenfluramine (10 mg/kg, IP) was injected daily for 12 days. Other than a slightly greater suppression of food intake in Osborne-Mendel rats, there was little difference in response to d-fenfluramine between S 5B/P1 and Osborne-Mendel rats eating the low-fat diet. However, in Osborne-Mendel rats d-fenfluramine completely abolished the excess food intake and weight gain associated with the high-fat diet. Purine nucleotide (GDP) binding on day 13 was higher in S 5B/P1 rats than in Osborne-Mendel rats and was increased by d-fenfluramine in animals of both strains eating the low-fat diet. The high-fat diet increased GDP binding only in S 5B/P1 rats and blocked the fenfluramine-induced increase in GDP binding in both strains. We speculate that d-fenfluramine blocks a feeding reward system stimulated by the high-fat diet.

The nutrient balance hypothesis: peptides, sympathetic activity, and food intake.

Food intake can be increased or decreased after either central or peripheral administration of peptides. Galanin, neuropeptide Y, opioid peptides, growth hormone releasing hormone and desacetyl-MSH increase food intake whereas insulin, glucagon, cholecystokinin, anorectin, corticotropin releasing hormone, neurotensin, bombesin, enterostatin, cyclo-his-pro and thyrotropin-releasing hormone reduce food intake. A number of these peptides also affect the activity of the sympathetic nervous system. The peptides which have been tested have a reciprocal effect on food intake and sympathetic activity. Opioids, NPY and GHRH, which increase food intake, decrease sympathetic activity. Conversely, peptides which reduce food intake, increase sympathetic activity, with glucagon, cholecystokinin, corticotropin releasing hormone, calcitonin, neurotensin and bombesin being examples, Several of these peptides also affect the intake of specific nutrients. Insulin reduces food intake in animals fed a high carbohydrate diet, but not when fed a high fat diet. Neuropeptide Y increases carbohydrate intake. Galanin and opioid peptides increase fat intake. Enterostatin and cyclo-His-Pro, on the other hand reduce fat intake. Glucagon decreases protein intake. The effect of peptides on the intake of specific nutrients suggests that peptides may work in part by modulating basic feeding mechanisms to lead to the selection of specific nutrients from the diet. This hypothesis might be called a nutrient specific model of peptide-induced food intake.

Sympathetic nerve activity after discrete hypothalamic injections of L-glutamate.

In these experiments L-glutamate, an amino acid which stimulates neuronal discharge, was microinjected into several hypothalamic nuclei and the resultant changes in electrical firing rate of sympathetic nerves innervating interscapular brown adipose tissue (IBAT) were measured. Three patterns of response were seen. A single large stimulatory response was seen when L-glutamate was microinjected into the ventromedial hypothalamus (VMH). Microinjection of L-glutamate into the paraventricular nucleus (PVN) produced a predominantly stimulatory response which was of smaller magnitude than the VMN. However in three animals L-glutamate in the PVN decreased firing rate and in one animal a biphasic response was observed. The second pattern was a decrease in sympathetic activity to IBAT which was the predominant pattern following injection of L-glutamate into the dorsomedial hypothalamus (DMH). However, a biphasic pattern was also observed. Injection of L-glutamate into the lateral hypothalamic area (LHA) produced 3 patterns of response; an increase, a decrease; or a biphasic response in nearly equal numbers of animals. The predominant response to L-glutamate in the preoptic area (POA) was biphasic. These data are consistent with the hypothesis that the VMH is the predominant stimulatory site for activation of the sympathetic nervous system to IBAT in the rat. The DMH and LHA appear to be the predominant inhibitory areas.

Adrenal sympathetic nerve activity in response to hypothalamic injections of 2-deoxy-D-glucose.

Adrenal sympathetic nerve activity after microinfusion of 2-deoxy-D-glucose (2-DG) into various hypothalamic nuclei was investigated in anesthetized rats. Infusion of 2-DG into the ventrolateral portion of the lateral hypothalamic area (LHA) induced a large and long-lasting increase (greater than 60 min) in adrenal nerve activity. In contrast, infusion into the dorsal or medial portion of the LHA tended to produce a small decrease with a return to baseline within approximately 60 min after the end of the infusion. The direct administration of 2-DG into either the paraventricular nucleus or the dorsomedial hypothalamic nucleus produced a strong inhibition of adrenal nerve activity. Infusions into the ventromedial hypothalamic nucleus induced either a decrease of adrenal nerve activity or were without effect. These findings provide evidence that induction of glucoprivation in the hypothalamus with 2-DG can excite or inhibit adrenal nerve activity, depending on the hypothalamic region. These data also indicate that the ventrolateral portion of the LHA plays an important role in the regulation of adrenal catecholamine secretion in response to glucoprivic conditions in the central nervous system.

GABA-related feeding control in genetically obese rats.

Feeding in response to glucoprivation induced by 2-deoxy-D-glucose (2-DG) is impaired in genetically obese (Zucker) rats. Muscimol, a GABAA-agonist (0.5 nmol/0.5 microliter in each area) increased food intake in lean rats over 3 h but in fatty rats only at 30 min after infusion into the VMH. Injection of muscimol into the DMH and PVN increased feeding of both phenotypes. Picrotoxin, a non-competitive GABAA-antagonist (0.1 nmol/0.5 microliter) increased food intake after infusion into the LH of both phenotypes and decreased food intake over a 3 h period when infused into the VMH. DMH and PVN of fatty rats. In the lean littermates, picrotoxin was only effective in reducing food intake at 30 min after infusion into the VMH and PVN but not the DMH. The present results suggest that the fatty Zucker rat has a disturbance in the GABA-related regulatory mechanism of feeding behavior in the ventromedial hypothalamus, which may be responsible for the impaired response to glucoprivation found in these rats.

Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats.

To investigate the effects of neuropeptide Y (NPY) on sympathetic nerve activity to interscapular brown adipose tissue (IBAT), we injected NPY into the third cerebroventricle (icv), medial preoptic area (MPOA), anterior hypothalamic area (AHA), paraventricular hypothalamic nucleus (PVN), ventromedial hypothalamic nucleus (VMN), and lateral hypothalamic area (LHA) of anesthetized rats. Multiunit discharges from sympathetic nerves to IBAT were recorded electrophysiologically. The icv injection of NPY suppressed sympathetic nerve activity in a dose-dependent manner, followed by a gradual recovery. The microinjection of NPY (25 pmol) unilaterally into the PVN also significantly suppressed the sympathetic nerve activity to IBAT. In contrast, microinjection of NPY into the MPOA significantly increased the sympathetic nerve activity. The injection of saline into either the PVN or MPOA had no significant effect on sympathetic nerve activity. The microinjection of NPY (25 pmol) into the AHA, VMN, or LHA did not change sympathetic nerve activity to IBAT. We conclude that central administration of NPY affects the sympathetic nerve activity to IBAT and that the suppressive effect of NPY, which may act in part through the PVN, is dominant to the stimulatory effect. The result is consistent with the hypothesis that NPY is a neurochemical modulator of the sympathetic nervous system which controls energy expenditure in IBAT.