VMH-lesioned Obese Rats Research Articles

Enhanced responses of the chorda tympani nerve to sugars in the ventromedial hypothalamic obese rat.

Sweet taste sensitivity in obese rats with lesions of the ventromedial hypothalamus (VMH) was studied by examining chorda tympani nerve responses to various taste stimuli including sugars. In the early progressive phase of obesity (2 wk after creating VMH lesions), there was no significant difference in the nerve responses to any taste stimulus between sham-operated and VMH-lesioned rats. In contrast, in the late phase of obesity (15-18 wk after VMH lesions), the magnitude of responses to sugars (except for fructose) was prominently greater than that in age-matched controls. High-fat diet-induced obese rats and streptozotocin-diabetic rats also showed greater chorda tympani nerve responses to sugars as was observed in VMH-lesioned obese rats, indicating that VMH lesions might not be specifically related to the enhanced gustatory neural responses to sugars. Although it has been demonstrated that the enhanced responses of the chorda tympani nerve to sugars in genetically diabetic db/db mice is largely attributable to the lack of the direct suppressive effect of leptin on the taste receptor cells, plasma leptin levels were not correlated with the changes in chorda tympani responsiveness to sugars in these models of obesity and diabetes. Accordingly, our results suggest that some chronic factors, including high blood glucose, inefficiency of insulin action, or leptin resistance may be related to the enhancement of chorda tympani nerve responses to sugars.

Different origin of hypertriglyceridemia induced by a high-fat and a high-sucrose diet in ventromedial hypothalamic-lesioned obese and normal rats.

To clarify the mechanism by which plasma triacylglycerol is affected by a high fat or a sucrose diet. Two sets of six groups each having six rats were prepared-(1) ventromedial hypothalamic (VMH)-lesioned rats fed a standard diet; (2) sham VMH-lesioned rats fed a standard diet; (3) VMH-lesioned rats fed a high-fat diet; (4) sham VMH-lesioned rats fed a high-fat diet; (5) VMH-lesioned rats fed a high-sucrose diet; and (6) sham VMH-lesioned rats fed a high-sucrose diet. After VMH lesions and sham operations, the rats were provided standard, high-fat and high sucrose diets for 2 weeks. Two weeks later, blood samples were collected after overnight fast to determine plasma triacylglycerol (TAG), hepatic triacylglycerol secretion rate (TGSR), fractional catabolic rate (FCR) of triacylglycerol and postheparin plasma lipoprotein lipase (LPL), plasma glucose, insulin and leptin. Values of TAG, TGSR, FCR and LPL in VMH-lesioned obese rats were all greater than those in sham-operated rats, regardless of the diet fed. In sham-operated rats, high-fat diet fed rats showed higher TAG with similar TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed significantly higher TAG with higher TGSR, higher LPL and lower FCR than those of standard diet fed rats. Moreover, high-sucrose diet fed rats showed higher TAG with higher TGSR, lower LPL and higher FCR than those of high-fat diet fed rats. In VMH-lesioned rats, high-fat diet fed rats showed higher TAG with similar TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed markedly higher TAG with notably higher TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed still higher TAG with markedly higher TGSR, similar LPL and higher FCR than those of high-fat diet fed rats. The mechanism by which TAG metabolism is affected by a high-fat or a high-sucrose diet differed; a high-fat diet increased plasma TAG level by lowering removal of TAG without increase in hepatic TAG secretion in sham-operated (normal) rats. A high-sucrose diet, in contrast, induced much higher plasma TAG levels by both increased hepatic TAG secretion and decreased removal of TAG. The effects of a high-fat or a high-sucrose diet were similar but exaggerated in VMH lesioned animals.

JTT-501, a new oral hypoglycemic agent, reverses hypertriglyceridemia in zucker fatty and ventromedial hypothalamus-lesioned obese rats

JTT-501 is a new oral hypoglycemic agent that is reported to be effective in insulin-resistant diabetic animal models by improving insulin resistance. It also improves hypertriglyceridemia. We investigated the mechanism of the reversal of hypertriglyceridemia in two types of obese animals using JTT-501. In Zucker fatty obese rats, an animal model of genetic obesity, fasting plasma triglyceride and glucose significantly decreased after a single daily oral dose of JTT-501 (100 mg/kg) for 7 days. In ventromedial hypothalamus (VMH)-lesioned obese rats, an animal model of nongenetic obesity, fasting plasma triglycerides significantly decreased but fasting plasma glucose levels remained unchanged after treatment with this agent. In Sprague-Dawley (SD) rats, fasting plasma triglyceride and glucose levels remained unchanged. The JTT-501-treated Zucker fatty and VMH-lesioned obese rats showed a decrease in insulin, but it was not significant, while the treated SD rats showed a significant decrease in insulin. Postheparin plasma lipoprotein lipase (LPL) increased significantly in treated Zucker fatty obese and SD rats, but did not change in VMH-lesioned obese rats. The hepatic triglyceride secretion rate (TGSR) did not change in any species treated with JTT-501. There was a negative correlation between postheparin plasma LPL and plasma triglyceride levels in Zucker fatty obese rats, while no such correlation was observed in VMH-lesioned obese or SD rats. The fractional catabolic rate (FCR) for plasma triglyceride was increased significantly by JTT-501 in both Zucker fatty and VMH-lesioned obese rats. These results suggest that JTT-501 decreases plasma triglycerides mainly by increasing postheparin plasma LPL in Zucker fatty obese rats, while it ameliorates an impairment in the ability of adipose tissue to remove triglyceride from the circulation in VMH-lesioned obese rats.

Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats.

To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production.

Plasma leptin levels and triglyceride secretion rates in VMH-lesioned obese rats: a role of adiposity.

To explore the role of adiposity on hypertriglyceridemia associated with obesity, we examined the relation between triglyceride secretion rate (TGSR) and plasma leptin, insulin, or insulin resistance in ventromedial hypothalamus (VMH)-lesioned rats in the dynamic and static phases (2 and 14 wk after lesions, respectively). VMH-lesioned rats gained body weight (BW) at fivefold higher rates in the dynamic phase compared with sham-operated control (sham) rats, and BW gain reached a plateau in the static phase. Parametrial fat pad mass was increased 2.5-fold in VMH-lesioned rats compared with sham rats in both phases. Leptin levels were sixfold higher in VMH-lesioned rats of the dynamic phase and even higher in the static phase. Insulin levels were twofold higher in VMH-lesioned rats than in sham rats in both phases. In the dynamic phase, VMH-lesioned rats had 2-fold higher plasma triglyceride (TG) levels and 2.6-fold higher TGSRs, whereas steady-state plasma glucose (SSPG) values, an indicator of insulin resistance, were lower. SSPG values became significantly higher in VMH-lesioned rats in the static phase, but TGSR was not further accelerated. TGSR was significantly associated with leptin, independent of insulin. Leptin was highly correlated with BW, fat mass, and nonesterified fatty acids (NEFA). These results suggest that adiposity itself plays a critical role in TGSR probably through increased NEFA flux from enlarged adipose tissues. Insulin resistance is not associated with the overproduction of TG in this animal model for obesity.

Decrease of norepinephrine and preservation of acetylcholine in the hypothalamus of VMH obese rats

We investigated to find which types of neuronal disturbance in the hypothalamus are responsible for ventromedial hypothalamic nucleus (VMH) lesion-induced development of obesity. We found that in VMH-lesioned obese rats, the contents of norepinephrine (NE) and dopamine in the hypothalamus were selectively decreased, but that the serotonin and acetylcholine levels were unchanged from those in sham controls. Also, the content of NE in the lateral portion of the hypothalamus was decreased. Our results show that disturbance of the hypothalamic noradrenergic and dopaminergic neurons, but not of the serotonergic or cholinergic neurons, contributes to the development of VMH lesion-induced obesity.

Increased level of apolipoprotein B mRNA in the liver of ventromedial hypothalamus lesioned obese rats

The mRNA level of apolipoprotein B (apoB), which is a principal protein component of nascent very low density lipoprotein (VLDL), was determined in parallel with the measurement of acetyl-coenzyme A (Ac-CoA) carboxylase activity in the liver of ventromedial hypothalamus (VMH) lesioned obese rats. Eight weeks after the electrolysis of the bilateral VMH, the level of apoB mRNA in the VMH-lesioned rats was about 1.5-fold higher than that in the sham-operated rats, indicating increased apoB synthesis in the liver of the VMH-lesioned obese rats. The activity of Ac-CoA carboxylase, which is a rate-limiting enzyme for the fatty acid biosynthesis, was about 1.8-fold higher in the VMH-lesioned rats. These observations indicated that VLDL synthesis is increased in the liver of VMH-lesioned obese rats.

Effects of intraventricular infusion of corticotropin-releasing factor on VMH-lesioned obese rats.

Corticotropin-releasing factor (CRF) has been administered into the third ventricle of sham-operated and ventromedial hypothalamic (VMH)-lesioned rats in acute and chronic experiments. After a single 5-microgram injection of CRF, there was an acute reduction of food intake in both sham-operated and VMH-lesioned rats that persisted for 3 h. The effect was still present in the VMH-lesioned rats between 3 and 6 h but had dissipated in the sham-operated controls. Guanosine 5'-diphosphate (GDP) binding to mitochondria from interscapular brown adipose tissue was used as an index of thermogenic activity in this tissue. In 21-h food-deprived rats, GDP binding was significantly lower in VMH-lesioned than in sham-operated animals. Although the mean increase in sham-operated animals was increased, this was not significantly different from saline-injected controls. In the VMH-lesioned rats, however, CRF acutely increased GDP binding to values not different than those of the sham-operated controls. Serum corticosterone was significantly lower in the VMH-lesioned rats, but both groups showed a significant stimulation by CRF during a 7-day infusion of CRF (4.8 micrograms/day) into the third ventricle. Food intake was significantly depressed in the VMH-lesioned animals that received CRF, from values of 35 g/day to approximately 25 g/day. Body weight showed a slow steady decrease, having fallen by nearly 15 g at the end of the 7-day infusion period. In contrast the mean value in the VMH-lesioned controls had significantly higher in CRF-infused animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphological changes of pancreatic B cells in ventromedial hypothalamic (VMH)-lesioned obese rats

Morphological changes of pancreatic B cells were investigated in ventromedial hypothalamic (VMH)-lesioned obese rats. An increase in body weight, a decrease in body length, and a marked increase in fat-pad were observed in VMH-lesioned obese rats. The volume density of pancreatic islets and that of B cells in VMH-lesioned obese rats were more increased than those in sham-operated control rats. The B cells of VMH-lesioned obese rats often showed a slight reaction for aldehyde fuchsin or anti-pig insulin serum. By the electron microscopy, the degranulated B cells were found to contain well developed Golgi apparatus and rough endoplasmic reticulum. These observations indicate increased activities of synthesis and release of insulin. We concluded that VMH-lesioned obesity was caused by accelerated lipogenesis with hypersecretion of insulin.