Neuronal activity in hypothalamic nuclei of obese and lean Zucker rats

Central neural activity was assessed by measuring relative cytochrome oxidase (CO) activity in the ventromedial nucleus (VMN; thermogenesis regulation), the parvocellular paraventricular nucleus (PVN; feeding regulation), and the magnocellular PVN (secretion of vasopressin and oxytocin) in 10 age-matched pairs of 39- to 42-day-old Zucker rats. When obese (fa/fa) were compared to lean (Fa/Fa) rats, relative CO activity was significantly lower (approximately 10 percent) in the VMN and parvocellular PVN, but not in the magnocellular PVN. Cell diameters did not differ. To determine if there were corresponding differences in levels or release of hypothalamic monoamines, we compared 7 pairs of 90- to 94-day-old lean (Fa/?) and obese (fa/fa) rats at rest and after 2 h of 9 degrees C. Tissue punches from frozen PVN, VMN, and preoptic area (the latter being a site of thermosensitive units modulating VMN output) were assayed. In obese vs. lean noncold-exposed rats, we observed lower concentrations of: 5-hydroxyindoleacetic acid (5HIAA; metabolite of serotonin, 5HT) in the VMN; 3-methoxy-4-hydroxyphenylglycol (MHPG; metabolite of norepinephrine, NE) and NE + MHPG (index of total NE) in the preoptic area; and 3,4-dihydroxyphenylacetic acid (DOPAC; metabolite of dopamine, DA) in the PVN. Additionally, in the VMN, cold exposure resulted in: elevated concentrations of MHPG and MHPG + NE in both lean and obese rats; elevated concentrations of 5HT, 5HIAA, and 5HT + 5HIAA in obese rats, with no significant changes in these variables in lean animals; decreased ratio of 5HIAA/5HT in obese rats and increased ratio in leans. In the preoptic region, cold exposure led to increased concentrations of MHPG, NE + MHPG, 5HT, and 5HT + 5HIAA in obese but not lean rats. In the PVN, 5HT concentrations were increased in cold-exposed obese but not lean rats. Our data support the hypothesis that neuronal activity in obese rats differs from that of lean rats at rest and during cold exposure and suggest that several monoamine systems play a role in such differences.     

The glucocorticoid antagonist mifepristone reveals abnormal regulation of the adrenocortical system in obese Zucker rats.

The effects of the potent glucocorticoid type-II receptor (GR) antagonist, mifepristone, on corticosterone secretion and on expression of preprocorticotrophin-releasing factor (preproCRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and of pro-opiomelanocortin (POMC) mRNA in the pituitary gland were investigated in lean and obese Zucker rats. Treatment with mifepristone for 4 days (10 mg/kg orally twice daily) significantly (P less than 0.05) stimulated corticosterone secretion in lean but not in obese rats. In lean rats the enhanced corticosterone secretion was associated with non-significant increments in the expression of preproCRF mRNA in the PVN and of POMC mRNA in the pituitary gland, while mifepristone significantly (P less than 0.05) reduced the expression of preproCRF mRNA in the PVN of obese Zucker rats. It is concluded that antagonism of GR by mifepristone results in persistent activation of the adrenocortical axis in lean Zucker rats due to blockade of feedback inhibition by circulating corticosterone. In obese animals the abnormal response to mifepristone suggests that the neuroendocrine control of the HPA axis is altered in genetically determined obesity.     

Changes in hypothalamic expression levels of galanin-like peptide in rat and mouse models support that it is a leptin-target peptide

Galanin-like peptide (GALP) is a novel peptide that has been isolated from the porcine hypothalamus. The expression of GALP mRNA is localized to the hypothalamic arcuate nucleus and is thought to be under the regulation of leptin. First, we confirmed by real-time PCR analysis that sc administration of leptin to Wistar rats under food-deprived conditions resulted in a 1.5-fold increase in hypothalamic GALP mRNA levels. Next, GALP mRNA levels were found to be reduced by 50% in 11-wk-old male Zucker obese rats compared with age-matched Zucker lean rats, whereas neuropeptide Y mRNA levels were increased by 55% and proopiomelanocortin mRNA levels were reduced by 53% in Zucker obese rats. Analysis using a two-site enzyme immunoassay revealed a lower level of hypothalamic GALP immunoreactivity in 11-wk-old Zucker obese rats (5.9 fmol/mg protein) than in age-matched Zucker lean rats (19.6 fmol/mg protein). Immunohistochemical studies demonstrated that Zucker obese rats (11 wk old) had a reduced number of GALP immunoreactivity-positive cells (29.4 cells/3 slices) in the arcuate nucleus compared with age-matched Zucker lean rats (115 cells/3 slices). Furthermore, Zucker obese rats showed increased sensitivity to intracerebroventricularly administered GALP compared with Zucker lean rats, in that a lower dose of GALP increased plasma LH levels in male Zucker obese rats, but not in male Zucker lean rats. In addition, a reduction in the level of hypothalamic GALP mRNA was found in db/db and ob/ob mice. The result supports the hypothesis that the hypothalamic GALP gene expression is controlled by leptin signals and suggests possible involvement of GALP in the reproductive abnormalities of the Zucker obese rat.     

Effects of the CRF1 receptor antagonist SSR125543 on energy balance and food deprivation-induced neuronal activation in obese Zucker rats

The corticotropin-releasing factor (CRF) system is involved in numerous physiological and behavioral actions, including the regulation of energy balance. We examined the effects of the CRF(1) receptor antagonist, SSR125543, on energy balance and food deprivation-induced neuronal activation in obese rats. Lean (Fa/?) and obese (fa/fa) Zucker rats were treated orally with SSR125543 at a daily dose of 30 mg/kg for 21 days. Rats were killed either fed ad libitum or food deprived for 6 h in order to induce a mild stress response in obese rats. SSR125543 reduced plasma corticosterone levels in lean rats, prevented corticosterone response to fasting in obese rats, and increased CRF mRNA levels in the paraventricular hypothalamic nucleus (PVN) of both lean and obese rats, further confirming that the antagonist partially blocked CRF(1) receptors. SSR125543 increased protein gain in obese rats. Whole carcass analyses showed reduced energy and fat gains in lean rats. Consistent with reduced fat gain, circulating triglyceride and leptin levels were reduced in SSR125543-treated lean rats. In obese rats, circulating glucose levels and the homeostasis model assessment of insulin resistance index of insulin resistance were reduced by SSR125543 treatment. CRF(1) receptor blockade increased uncoupling protein-1 mRNA levels in interscapular brown adipose tissue of obese rats. The antagonist partly blocked the fasting-induced changes in c-fos mRNA levels in the PVN and arcuate nucleus of obese rats. Overall, these results suggest that although SSR125543 had relatively mild effects on energy balance, CRF(1) receptor blockade attenuated several metabolic effects of short-term fasting and improved plasma variables related to the metabolic syndrome and diabetes.     

Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin

Obese (fa/fa) Zucker rat is a spontaneous genetic obesity model and, by comparison with lean Zucker rat, exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia. The aim of this study was to examine the physiological difference concerning adiponectin between obese (fa/fa) Zucker rats and control lean Zucker rats. We therefore measured plasma adiponectin level and analyzed adiponectin and adiponectin receptor 1 mRNA expression in retroperitoneal white adipose tissue (RT WAT), brown adipose tissue (BAT), liver, and soleus muscle. We also examined the tissue mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR delta, and PPAR gamma, which regulate adiponectin expression sensitivity to a PPAR gamma agonist shown by brown adipocytes from obese (fa/fa) Zucker rats and lean Zucker rats, by measuring adiponectin release from these cells. Plasma adiponectin levels of obese (fa/fa) Zucker rats were significantly higher than those of lean Zucker rats. Adiponectin mRNA expression levels in RT WAT were lower in obese (fa/fa) Zucker rats than in lean Zucker rats, but those in BAT were higher. Adiponectin receptor 1 expression levels in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats were lower than in lean Zucker rats. The expression level of PPAR alpha, PPAR delta, and PPAR gamma in BAT was lower in obese (fa/fa) Zucker rats than in lean Zucker rats. Moreover, the PPAR gamma agonist increased adiponectin release only from the brown adipocytes isolated from lean Zucker rats. It is the conclusive difference between obese (fa/fa) Zucker rats and lean Zucker rats that plasma adiponectin levels of obese (fa/fa) Zucker rats are significantly higher than those of lean Zucker rats. Moreover, we clarified that mRNA expression level of adiponectin receptor 1 in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats is low despite high plasma adiponectin level, and low expression of PPARs in BAT leads to less sensibility of adiponectin release from brown adipocytes to a PPAR gamma agonist in obese (fa/fa) Zucker rats.     

Parenteral lipid emulsion-induced atherosclerosis in the obese Zucker rat and its lean littermate.

We have shown previously that parenterally-administered lipid emulsions can be utilized to induce early atherosclerosis in the aortas of Sprague-Dawley rats. In order to evaluate the effect of obesity on lipid-induced atherogenesis, we have utilized this same approach in the present study to demonstrate that i.v. infusions of the parenteral lipid emulsion, Lipofundin-S, will induce in the genetically obese Zucker rat and its lean littermate aortic endothelial and myofibroelastic changes indicative of early atherogenesis. Four groups of rats were used: 1) obese controls, 2) obese lipid-infused, 3) lean littermate controls, and 4) lean littermate lipid-infused. Observations were made with light and transmission electron microscopy (TEM), using qualitative morphological criteria to evaluate the results. Based on the fact that both untreated control and Lipofundin-S-induced atherosclerosis was more frequent and generally more advanced in the obese animals than in their respective lean counterparts, it appears that the obese Zucker rat is more susceptible to both spontaneous and hyperlipidemia-induced atherosclerosis than its respective lean littermate. Thus, obesity in these animals, as might be the case in humans, could potentiate an atherogenic process already enhanced by hyperlipidemia.     

Lipoprotein and apolipoprotein distribution in Zucker rats following an endurance running program

We examined the response to 12 weeks of endurance running of the obese Zucker rat and its lean littermate with regard to changes in serum lipids, lipoproteins and apoproteins. The obese Zucker rat is hyperlipoproteinemic, characterized by elevated serum triglyceride and cholesterol levels primarily associated with the very low density lipoprotein (VLDL) fraction. In lean Zucker rats, training did not affect the concentrations of serum lipids or apolipoproteins. In marked contrast, obese Zucker rats that were trained had significant decreases in serum concentrations of triglycerides, free and esterified cholesterol, and apolipoprotein B compared to their sedentary counterparts. Training obese rats caused an increase in the serum concentration of apolipoprotein E (HDL fraction). In contrast, training did not affect the concentration of Apo E in lean rats. The VLDL fraction was most affected by training obese rats showing marked 50-65% decreases in VLDL triglyceride and VLDL cholesterol. HDL cholesterol was unchanged in lean rats whereas training prompted a 29% increase in obese rats. These data show that exercise training altered the metabolic abnormalities of obese Zucker rats which are responsible for the accumulation in serum of VLDL, lipids and apolipoproteins.     

VMN dopaminergic graft and feeding pattern in obese Zucker rats

OBJECTIVE: To study the role of dopamine in the ventromedial hypothalamus (VMN) in the regulation of meal size and meal number during obesity. METHODS: Embryonic mesencephalic cells rich in dopaminergic neurons from lean rats were grafted into the VMN of obese Zucker rats. Since food intake is the product of meal size and number, these variables were measured using a rat 'eater meter'. Dopamine and serotonin concentrations in the VMN were assayed in grafted and control rats via in vivo microdialysis and HPLC two months after transplantation. RESULTS: Food intake increased in grafted rats due to an increase of both meal size and meal number 2 weeks after implantation and to an increase of meal size with insufficient compensatory decrease of meal number 2 months after transplantation. Grafted rats showed higher absolute dopamine and lower serotonin concentrations in the VMN. CONCLUSION: It would appear that an increase of dopamine and a decrease of serotonin in the VMN of grafted obese rats may correlate with increase in meal number and meal size, respectively. Since obese Zucker rats usually display an enlarged meal size, we deduce from the data that chronically elevated VMN dopamine and low serotonin are involved in producing the large meal size observed during obesity.     

Rats with hypothalamic obesity are insensitive to central leptin injections.

Genetically determined obesities, involving leptin- and melanocortin-signaling pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four medial cell groups contain leptin receptors. To determine which of these cell groups normally mediates the effects of leptin on food intake and body weight gain, we injected colchicine bilaterally into each nucleus and determined the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in sham-lesioned rats decreased food intake during the dark period, but not during the light period. Lesions of the arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivity; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivity to leptin on feeding and body weight gain. Although rats with ARC and PVN lesions were obese, they were still capable of reducing caloric efficiency over the 5 days of study and increasing uncoupling protein content in interscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathways. We conclude that the medial hypothalamic cell groups, each with a different role in energy balance, are all necessary for normal leptin responsiveness.     

Functional characterization of alpha-adrenoceptors on pancreatic islets of fa/fa Zucker rats.

Recently, a defect in pertussis toxin-independent actions of epinephrine on pancreatic B-cells of fa/fa Zucker rats was reported (Cawthorn and Chan (1991) Mol. Cell. Endocrinol. 75, 197-204). We now report studies of islet alpha 2-adrenoceptor function of fa/fa rats. Insulin and cAMP production by islets of obese rats were both inhibited by the alpha 2-adrenoceptor agonist clonidine. Calculated pD2 values for clonidine were 9.57 +/- 0.59 and 9.43 +/- 0.33 for lean and fa/fa rat islets, respectively. Yohimbine reversed clonidine effects equipotently in lean and obese rat islets (pA2 values of 7.48 +/- 0.57 vs 7.43 +/- 0.58). Unexpectedly, the alpha 1-antagonist prazosin stimulated insulin secretion from islets of obese but not lean rats. Functional characteristics of the alpha-adrenoceptors on fa/fa islets are thus similar to those recently designated alpha 2B. Altered expression of alpha-adrenoceptors on pancreatic islets of fa/fa rats may contribute to changes in the pertussis toxin-independent pathway of epinephrine action previously observed.     

Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats

Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in obese humans and animals may be associated with obesity and the metabolic syndrome. We investigated the effect of inhibition of 11beta-HSD with glycyrrhetinic acid (GE), an effective 11beta-HSD inhibitor, on body weight regulation in obese Zucker rats, which have a defect in the leptin receptor gene. GE (280 mg/kg/d) was administered in drinking water to 8-week-old male Zucker rats for 14 weeks. GE had no effect on food intake or weight gain, and did not affect hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels in obese rats. In contrast, average daily food intake and body weight on week 14 were significantly reduced by GE in lean rats (both P <.0001). Hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels were also significantly decreased by GE in lean rats (both P <.05). GE had no significant effect on plasma corticosterone levels in obese rats but lowered them in lean rats (P <.05). Plasma leptin levels declined in both GE-treated obese and lean rats (both P <.01). In conclusion, long-term GE treatment decreased weight gain in lean Zucker rats but not in obese Zucker rats. These findings suggest that the differing responses of 11beta-HSD1 to GE in obese and lean Zucker rats are closely associated with the different weight-gain responses. Furthermore, the weight-lowering effect of GE may require intact leptin receptors.     

Adrenalectomy in the Zucker fatty rat: effect on m-RNA for malic enzyme and glyceraldehyde 3-phosphate dehydrogenase.

The effects of adrenalectomy with or without replacement doses of corticosterone were examined on the levels of messenger RNA for malic enzyme (ME) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in adipose tissue and liver from Zucker fatty (fa/fa) and littermate lean rats. The levels of both GAPDH and ME mRNAs were increased in the obese rats. Adrenalectomy markedly reduced the m-RNA for GAPDH and ME in Zucker fatty rats to the low levels observed in adrenalectomized lean rats. Corticosterone treatment induced a greater and earlier increase in mRNA levels in adrenalectomized obese rats than in adrenalectomized lean rats. Since the fatty rat represents an autosomal recessive trait, these results are consistent with the hypothesis that the genetic defect is a loss of a modulator of steroid action which normally restricts the response of genes to glucorticoid hormones.     

Insulin attenuation of vasoconstrictor responses to phenylephrine in Zucker lean and obese rats

Recent data from this laboratory indicate that insulin resistant obese Zucker rats exhibit hypertension associated with exaggerated in vitro vascular reactivity to phenylephrine, serotonin, and KCl, and we have found insulin to attenuate vascular reactivity responses to these agonists. Accordingly, in the present study we evaluated the possibility that exaggerated vascular reactivity responses in obese Zucker rats may result from insulin resistance and a consequent failure of insulin to attenuate vasoactive responses. Thoracic aortae were isolated from male 16 week old lean and obese Zucker rats, and replicate helical strips from each animal were suspended in a muscle bath under a resting tension of 1.4 g in the presence or absence of insulin (0.1 mU/mL) for 1 h. The insulin was then washed out, and vascular reactivity responses to phenylephrine were determined. The obese rats exhibited greater reactivity to phenylephrine (ED50:1.10 +/- 90 X 10(-8) v 7.57 +/- 0.88 X 10(-10) mol/L in lean and obese rats, respectively, P less than .025). Insulin caused a significant attenuation of the contractile response in both the lean and obese aortae. However, lean rats exhibited a markedly greater attenuation than the obese rats (46.0 +/- 17.0 v 17.8 +/- 7.5% attenuation in the lean and obese rats, respectively, P less than .01). These data suggest that increased vascular reactivity responses in obese Zucker rats may result from their insulin resistant state and, consequently, a diminished ability of insulin to attenuate vasoconstrictor responses.     

Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation

Neuropeptide Y (NPY) is a potent orexigenic agent capable of producing hyperphagia and obesity. NPY-containing neurons project from the hypothalmic arcuate nucleus to the paraventricular nucleus, an area known to be sensitive to the orexigenic effects of NPY. In this study we investigated the possibility that preproNPY messenger RNA (mRNA) content may be altered in obese Zucker rats compared to that of their lean littermates. Total RNA was isolated from hypothalamic dissections from male and female, obese and lean Zucker rats. RNA was also isolated from dissections of: olfactory bulb, entorhinal cortex, hippocampus, and striatum of female obese and lean rats. PreproNPY mRNA content was determined by solution hybridization-RNase protection analysis. The results revealed a 2- to 3-fold increase in preproNPY mRNA levels in the hypothalamus of obese animals compared to lean. The increase was observed in both sexes and was specific to the hypothalamus. In situ hybridization localized this increase to the arcuate nucleus. An additional RNase protection study was pursued to investigate the effects of 72 h food deprivation on hypothalamic preproNPY mRNA levels in lean and obese animals. Lean animals displayed an approximate 2-fold increase in preproNPY mRNA content, whereas obese animals showed no significant increase after food deprivation. These data are consistent with the hypothesis that NPY projections within the hypothalamus are involved in regulating feeding behavior and weight gain, and that disturbed regulation of hypothalamic NPY expression may play a role in the etiology of obesity in the genetically obese Zucker rat.     

Effect of diazoxide on brain capillary insulin receptor binding and food intake in hyperphagic obese Zucker rats.

Insulin is believed to act as a central adiposity signal by binding to hypothalamic and other brain insulin receptors. Entry of circulating insulin into the brain is accomplished by a saturable receptor-mediated transendothelial transport system and is believed to be impaired in hyperinsulinemic, insulin-resistant, and hyperphagic obese Zucker rats. Theoretically, if hyperinsulinemia is decreased simultaneously while brain capillary insulin binding is increased, uptake of insulin into the brain can be enhanced leading to reduced food intake. To test this hypothesis, we administered diazoxide (DZ, 150 mg/kg/day), an inhibitor of glucose-mediated insulin secretion, or vehicle (control) to 7-week-old female obese and lean Zucker rats for 4 weeks (n = 24-28/subgroup-strain). Animals were assigned to either fasted (FD) or free-fed (FF) protocol for determination of plasma and cerebrospinal fluid (CSF) insulin and brain capillary insulin binding at the end of 4 weeks. DZ obese consumed fewer calories (P<0.01) and gained less weight than control obese (P<0.01), whereas DZ lean had similar amounts of caloric intake and weight gain compared with lean controls. DZ obese had lower fasting and random plasma glucose than control obese (P<0.05). FD and FF DZ-treated obese and lean rats had lower plasma insulin than their respective obese (P<0.01) and lean (P<0.01) controls. FD and FF DZ-treated obese rats demonstrated higher CSF insulin (P<0.05) and CSF/ plasma insulin ratio (P<0.01) than their controls, while only FF DZ lean animals showed higher CSF/plasma insulin ratio (P<0.01) than their controls (P<0.05). This was associated with enhanced brain capillary insulin binding in FD and FF DZ-treated obese (P<0.01) and lean (P<0.05) animals compared with their respective controls. It was concluded that DZ treatment in obese Zucker rats caused a decrease in insulin secretion and partially reversed impaired insulin binding to brain capillaries, leading to enhanced brain insulin uptake, and resulted in reduced food intake and weight gain observed in these animals.     

Involvement of endogeneous glutamate in the stimulatory effect of norepinephrine and serotonin on the hypothalamo-pituitary-adrenocortical axis

The effects of ionotropic glutamate receptor antagonists on the pituitary adrenal responses following injections of norepinephrine (NE) and serotonin (5-HT) receptor agonists into the hypothalamic paraventricular nucleus (PVN) or electrical stimulation of central NE and 5-HT pathways were studied in anesthetized male rats. PVN injections of an alpha(1)-adrenergic receptor agonist or a serotonergic 5-HT(1A) receptor agonist markedly increased both adrenocorticotropin (ACTH) and corticosterone (CS) serum levels. These responses were significantly inhibited by separate pre-injection of the selective non-NMDA and NMDA glutamate receptor subtype antagonists into the PVN in a dose-dependent manner. Electrical stimulation of either the ventral noradrenergic bundle or the dorsal raphe nucleus markedly increased serum ACTH and CS. These responses were also significantly attenuated by pre-injection of the above glutamate ionotropic receptor antagonists in a dose-dependent manner. These results suggest that glutamatergic interneurons in the PVN, acting via non-NMDA and NMDA receptors, may act as an excitatory mechanism in the NE and 5-HT control of hypothalamic ACTH secretagogues.     

Influence of clenbuterol on energy balance, thermogenesis and body composition in lean and genetically obese Zucker rats

Daily injection of lean Zucker rats with a beta 2-adrenergic agonist (clenbuterol, 1 mg/kg) for 22 day increased weight gained by 38 per cent; there were significant increases in carcass protein and water, but fat content was unaltered. Clenbuterol did not affect energy intake or expenditure, the acute thermogenic response to food, or brown adipose tissue (BAT) activity (assessed from mitochondrial purine nucleotide (GDP) binding). In obese Zucker rats, clenbuterol significantly depressed energetic efficiency and increased the thermogenic response to food and BAT activity in these mutants. Body weight gain was not significantly affected by clenbuterol in obese Zucker rats but this was because of a 19 per cent reduction in fat content accompanied by a simultaneous 13 per cent increase in protein content. The ratio of protein/fat gained during the study was increased by 50 and 173 per cent by clenbuterol in lean and obese rats, respectively. Thus, clenbuterol exhibits potent anabolic effects on lean body mass in genetically obese as well as lean rats, but also increases thermogenesis and reduces body fat content in the obese mutants.     

Acute effects of fat and carbohydrate on metabolic rate in normal, cold-acclimated and lean and obese (fa/fa) Zucker rats

The rise in metabolic rate after intragastric feeding with fat and carbohydrate was enhanced in cold-acclimated (5 degrees C) rats and diminished in warm-acclimated (30 degrees C) rats compared to controls (24 degrees C), but the response was largest in cold-acclimated animals intubated with fat. These acute effects of nutrients were almost completely abolished by beta-adrenergic blockade with propranolol in all groups, while the parasympathetic antagonist atropine sulphate enhanced the responses in control rats, but had little effect in cold-acclimated animals. Feeding carbohydrate produced similar increases in interscapular brown adipose tissue (BAT) temperature in control and cold-acclimated rats, but fat caused a much greater rise in the latter group. The thermic effects of both nutrients were lower in genetically obese Zucker rats than in their lean littermates. Atropine slightly increased the thermic responses to fat and carbohydrate in the lean Zucker rats and caused marked potentiation in obese rats intubated with fat, but did not alter the effect of carbohydrate in the obese animals These data suggest that the size of the acute rise in metabolic rate after fat and carbohydrate is dependent on the thermogenic capacity of the animal. The response to fat was particularly large in cold-acclimated rats, where BAT activity is high, possibly due to a direct action of fat on the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine fails to inhibit Na,H-exchanger in proximal tubules of obese Zucker rats.

Dopamine via the activation of D1-like receptors inhibits Na,K-ATPase and Na,H-exchanger and subsequently increases sodium excretion. We have previously reported that dopamine failed to inhibit Na,K-ATPase in the proximal tubules (PTs) of obese Zucker rats. The present study was designed to determine the effect of dopamine on Na,H-exchanger in PTs of lean and obese Zucker rats, and examine D1-like receptor-coupled signal transduction pathway mediating the inhibition of Na,H-exchanger. We found that dopamine inhibited Na,H-exchanger in the PTs of lean rats but this response was absent in obese rats. In brush border membranes, [3H]SCH 23390 binding revealed a approximately 45% reduction in D1-like receptor binding sites in obese compared to lean rats. Dopamine stimulated cAMP accumulation in PTs of lean but not in obese rats. Forskolin-mediated stimulation of cAMP was similar in lean and obese rats. Dopamine as well as forskolin and dibutyryl cAMP-mediated stimulation of protein kinase A (PKA) was reduced in PTs of obese compared to lean rats. The data suggest that reduction in D1-like receptor binding sites, defective coupling with signaling pathway and inability of PKA activation may be responsible for the failure of dopamine to inhibit Na,H-exchanger in PTs of obese rats. This phenomenon may contribute to an increase in sodium reabsorption and development of hypertension in obese Zucker rats.     

Testosterone supplementation in male obese Zucker rats reduces body weight and improves insulin sensitivity but increases blood pressure

Androgen levels are lower in obese men as compared with normal weight individuals. However, there are no safety data regarding the chronic use of androgen supplements in middle-aged men. The present study was undertaken to determine the cardiovascular and metabolic effects of chronic (10 weeks) testosterone treatment in male obese Zucker rats, starting at 22 weeks of age, when testosterone levels were significantly decreased. Testosterone supplements increased plasma levels, 10-fold in both obese Zucker rats and lean Zucker rats. In obese Zucker rats, testosterone supplements reduced body weight, plasma insulin, and cholesterol levels and improved the oral glucose tolerance test. None of these parameters were affected in lean Zucker rats. Mean arterial pressure was significantly increased in obese Zucker rats but not lean Zucker rats. Testosterone supplements increased proteinuria and accelerated renal injury in lean Zucker rats only. Thus, treatment of obese men with chronic testosterone supplements should be done with careful monitoring of blood pressure.