Long-term efficacy and cognitive effects of voltage-based deep brain stimulation for drug-resistant essential tremor.

OBJECTIVES: To analyze the long-term efficacy and cognitive effects of voltage-based deep brain stimulation (DBS) for drug-resistant essential tremor (ET). PATIENTS AND METHODS: Patients with drug-resistant ET and treated by voltage-based DBS of the ventral intermediate nucleus (VIM-DBS) were continuously enrolled. Seizure outcomes were assessed by blinded observers using the Tremor Rating Scale (TRS). The full-scale intelligence quotient, full-scale memory quotient, Hamilton Depression Scale, Hamilton Anxiety Scale, and Quality of Life in Essential Tremor Questionnaire were assessed as measures of cognitive function. RESULTS: Eleven patients met the inclusion criteria, and two of them were excluded because of loss to follow-up. The patient follow-up times ranged from 48 to 66 months (median 51 months). TRS scores decreased by 60.4% and 46.0% at the 12- and 48-month follow-ups, respectively. Both changes were highly significant. During the follow-up period, the patients' intelligence and memory had not significantly changed; depression, anxiety, and quality of life significantly improved. After long-term follow-up, the stimulation efficacy and quality of life gradually decreased, and the depression and anxiety levels increased. CONCLUSION: For patients with drug-resistant ET, voltage-based DBS can provide acceptable benefits on tremor, cognitive function, and quality of life. However, the efficacy of VIM-DBS decreased over time.

Role of hypothalamic inputs in maintaining pituitary-adrenal responsiveness in repeated restraint.

The role of hypothalamic structures in the regulation of chronic stress responses was studied by lesioning the mediobasal hypothalamus or the paraventricular nucleus of hypothalamus (PVH). Rats were acutely (60 min) and/or repeatedly (for 7 days) restrained. In controls, a single restraint elevated the plasma adrenocorticotropin (ACTH), corticosterone, and prolactin levels. Repeated restraint produced all signs of chronic stress, including decreased body and thymus weights, increased adrenal weight, basal corticosterone levels, and proopiomelanocortin (POMC) mRNA expression in the anterior pituitary. Some adaptation to repeated restraint of the ACTH response, but not of other hormonal responses, was seen. Lesioning of the mediobasal hypothalamus abolished the hormonal response and POMC mRNA activation to acute and/or repeated restraint, suggesting that the hypothalamo-pituitary-adrenal axis activation during repeated restraint is centrally driven. PVH lesion inhibited the ACTH and corticosterone rise to the first restraint by approximately 50%. In repeatedly restrained rats with PVH lesion, the ACTH response to the last restraint was reduced almost to basal control levels, and the elevation of POMC mRNA level was prevented. PVH seems to be important for the repeated restraint-induced ACTH and POMC mRNA stimulation, but it appears to partially mediate other restraint-induced hormonal changes.

Cardiovascular vagosympathetic activity in rats with ventromedial hypothalamic obesity.

OBJECTIVE: Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long-term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes. RESEARCH METHODS AND PROCEDURES: Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart beta-adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test. RESULTS: A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic-acting drugs showed an increase in heart vagal tone and responsiveness to a beta-agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart beta-adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals. DISCUSSION: These results show the following in this model of massively obese rats with sympathetic impairment: 1). adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2). cardiac responsiveness to beta-agonist stimulation is increased; and 3). despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.

Galanin-R1 receptor in anterior and mid-hypothalamus: distribution and regulation.

The distribution and regulation of galanin-R1 receptor (GAL-R1-R) mRNA has been studied in the anterior and mid-diencephalon by using in situ hybridization. Moreover, possible colocalization of GAL-R1-R mRNA and prepro-galanin or vasopressin mRNAs has been analyzed at the cellular level using double in situ hybridization methodology. Many nuclei in the hypothalamus expressed GAL-R1-R mRNA, including the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). Strong expression was also seen in the same sections in various areas outside of the diencephalon. The distribution patterns are similar to those described in earlier studies. Double labeling experiments showed GAL-R1-R mRNA in vasopressin neurons in the PVN and SON. Moreover, GAL-R1-R mRNA and prepro-galanin mRNA were colocalized in several hypothalamic nuclei. GAL-R1-R mRNA levels showed a high degree of plasticity. Thus, salt loading resulted in a marked increase in GAL-R1-R mRNA levels in the PVN and SON and a moderate decrease was seen during lactation. In contrast, hypophysectomy caused a decrease in GAL-R1-R mRNA levels. Differential effects of colchicine were recorded with a decrease of GAL-R1-R mRNA in the magnocellular hypothalamic neurons. After salt loading or during lactation, GAL-R1-R mRNA and prepro-galanin mRNA were regulated in parallel, whereas their levels changed in opposite directions after hypophysectomy and colchicine injection. In conclusion, GAL-R1-Rs are present in several hypothalamic nuclei, partly in neurons synthesizing galanin. The receptors are regulated in a specific fashion in the various nuclei, depending on the stimulus applied. The results suggest that the effect of galanin in the hypothalamus partly depends on the state of receptor expression.

Dorsomedial hypothalamic lesions alter intake of an imbalanced amino acid diet in rats.

Within 3 h of ingesting an imbalanced amino acid diet (IAAD), rats show attenuated intake. The associated conditioned taste aversion can be ameliorated by giving the serotonin3 receptor blocker, tropisetron (TROP). A recent c-fos study indicated that the dorsomedial hypothalamic nucleus (DMN) may be activated 2-3 h after ingestion of IAAD. In Experiment 1, DMN-lesioned rats (DMNL) or sham-operated (SHAM) rats were injected with saline (SAL) or TROP just before introduction of IAAD. By 3 h, SAL-DMNL rats consumed more (P < 0.01) of the IAAD than did the SAL-SHAM rats. Thereafter, over the next 21 h, the intake of the SAL-DMNL group returned to control levels. TROP treatment enhanced the intake of the treated groups; the TROP and the lesion effect were additive (P < 0.01). By d 4 of receiving the IAAD, the DMNL groups were eating less than SHAM rats (P < 0.05). The data suggest that the DMN may be involved in the early detection of the amino acid deficiency induced by IAAD, is not involved in the TROP effect and is necessary for proper long-term adaptation to an IAAD.

Visceral fat accumulation and vascular complications associated with VMH lesioning of spontaneously non-insulin-dependent diabetic GK rat.

OBJECTIVE: We have reported that ventromedial hypothalamic (VMH) lesions induced marked hyperglycemia and a distinct reduction in pancreatic insulin content during short-term observation in male Goto-Kakizaki (GK) rats, an animal model for non-insulin-dependent diabetes mellitus (NIDDM) (Metabolism 43: 32-37, 1994). We investigated the long-term effect of VMH lesions on glucose metabolism, pancreatic insulin content, abdominal fat distribution and vascular complications in male GK rats. DESIGN: Metabolic and histological examinations in male GK rats during 16 weeks after making VMH lesions were compared to those in sham operated GK or Wistar rats. SUBJECTS: Eleven 9-week-old male GK rats and 4 male Wistar rats. VMH-lesions were made in 6 GK rats and sham operation were performed on 5 GK rats and 4 Wistar rats as controls. MEASUREMENTS: Food intake, body weight, and plasma glucose, insulin and lipid levels at 2 weeks interval after operation. Urinary protein and albumin levels at 15 weeks after operation. Measurement of pancreatic insulin content, mesenteric fat and abdominal subcutaneous fat weights, and histological examinations of kidney and aorta were performed after 16 weeks. RESULTS: Although food intake increased in VMH-lesioned GK (GK-VMH) rats compared with that in sham-operated GK (GK-sham) rats, the body weight of GK-VMH rats was significantly less than that of GK-sham rats. Plasma glucose was markedly elevated in GK-VMH rats from 2 through 16 weeks after operation, while it was only mildly increased in GK-sham rats. Plasma insulin levels were higher in GK-VMH rats one week after operation and thereafter tended to be lower compared to those in GK-sham rats. Plasma triglyceride levels were significantly increased in GK-VMH rats. The insulin content of pancreas at 16 weeks after operation was markedly decreased in GK-VMH rats. VMH lesions caused a significant 1.2-fold increase in mesenteric fat weight and a 1.3-fold higher ratio of mesenteric fat weight to subcutaneous fat weight in GK rats compared with sham-operated rats at 16 weeks after operation. The urinary excretions of protein and albumin in GK-VMH rats were greater than those in GK-sham rats. Histological examinations of the kidneys in GK-VMH rats revealed that the glomerular basement membranes were thicker than those of GK-sham rats. The descending aorta in GK-VMH rats also showed morphologic changes in the intima characteristic of an early stage of atherosclerosis. CONCLUSION: Male GK-VMH rats may be a useful animal model for non-obese NIDDM with visceral fat accumulation, which develops typical diabetic complications, including both microangiopathy and macroangiopathy.

Effects of selective vagotomy on circadian rhythms of plasma glucose, insulin and food intake in control and ventromedial hypothalamic (VMH) lesioned rats.

Effects of hepatic and celiac vagotomy on circadian rhythms of plasma glucose, insulin, and food intake were examined in sham-operated (control) and ventromedial hypothalamic (VMH) lesioned rats. Rats were acclimated to the condition with a 12-hour light-dark cycle for 1 week before surgery. One week after VMH lesions, control and VMH lesioned rats were divided into three groups: sham vagotomy, hepatic vagotomy, and celiac vagotomy. Three days after vagotomy, food intake was measured at 6-hour intervals. Seven days after vagotomy, plasma glucose and insulin were measured at the midpoint of each feeding period. In control rats, hepatic vagotomy destroyed circadian rhythms of plasma glucose and insulin probably due to removal of afferent function. In VMH lesioned rats, celiac vagotomy destroyed circadian rhythm of food intake due to the reduction of plasma insulin by removal of efferent function without affecting the loss of circadian rhythms of plasma glucose and insulin.

Angiotensin II pressor activity depends on medial and lateral anterior hypothalamic pathways.

The preoptic region of hypothalamus was disconnected from caudal structures with two different-size knife cuts in rats to investigate the pathway responsible for the effects of intracerebroventricular (ICV) and intravenous (IV) angiotensin II (ang II) on blood pressure and arginine vasopressin (AVP) release. Seven days after surgery ICV ang II (125 ng) in sham-operated (sham) rats increased mean arterial pressure (MAP) (+23 +/- 3 mmHg) and decreased heart rate (HR) (-58 +/- 5 beats/minute). However, ICV ang II had no effect on MAP or HR of rats with a large (preoptic-hypothalamic disconnection) cut. Both the pressor response (+12 +/- 2 mmHg) and the bradycardia (-39 +/- 6 beats/minute) were significantly reduced by a small (medial preoptic-hypothalamic disconnection) cut. The increased plasma AVP to ICV ang II in sham rats (9.8 +/- 3.6 pg/mL) was abolished in large-cut rats and attenuated in small-cut rats (3.2 +/- 0.7 pg/mL). IV bolus injection of ang II (125 ng) in sham rats increased MAP by 43 mmHg, whereas large-cut rats showed a blunted (25%) pressor response. The pressor response to IV infusion of ang II (8 ng/20 microL/minute for 15 minutes) was diminished in large-cut rats (+4 +/- 1 mmHg) as compared with that in sham rats (+19 +/- 2 mmHg). Both cuts transected the projection between the periventricular tissue surrounding the anteroventral third ventricle and supraoptic nucleus, but the supraoptic-neurohypophyseal pathway was severed only by the large cut.(ABSTRACT TRUNCATED AT 250 WORDS)

Caloric intake stimulates growth hormone secretion in food-deprived rats with anterolateral deafferentation of the medial basal hypothalamus or administered antiserum to somatostatin.

In rats, food deprivation inhibits episodic growth hormone (GH) secretion. On the basis of previous studies, we hypothesized that during a recovery from prolonged fasting, caloric intake stimulates the release of GH-releasing factor (GRF) and this process does not depend on the specific macronutrients in the meal, while protein in the meal acts to restore characteristic ultradian rhythmicity of GH secretion. To test this hypothesis, the effect of caloric intake on GH secretion was examined in fasted adult male Wistar rats devoid of somatostatin (SS) influence on GH secretion either by anterolateral deafferentation (ALC) of the medial basal hypothalamus (MBH) or administration of anti-SS goat serum (ASS). Rats were provided with an indwelling right atrial cannula and were deprived of food for 72 h. ALC was performed 2 weeks prior to the study. ASS was given i.v. 8 h and 7 h prior to refeeding, respectively. Serial blood specimens were collected every 10 min. In rats with ALC (ALC rats) or rats given ASS (ASS rats), the blood GH level revealed irregularly occurring small fluctuations, instead of the usual high bursts and low trough level. The baseline GH level and the mean GH level of fasted ALC rats or fasted ASS rats were significantly lower than those of fed ALC rats or fed ASS rats. Feeding the isocaloric mixed meal, the protein meal or the protein-deficient meal increased the GH pulse frequency, the pulse amplitude, the baseline GH level and the mean GH level in 72-h fasted ALC rats. These changes in GH secretory pattern persisted during the period of observation and were independent of the type of meal ingested. Following feeding the mixed meal, similar changes in the GH secretory pattern demonstrated in 72-h fasted ALC rats were also observed in 72-h fasted ASS rats, suggesting that the stimulation of GH secretion following caloric intake is not limited to ALC rats. Since the influence of SS on GH secretion has been largely eliminated in ALC or ASS rats, it is highly unlikely that the augmentation of GH secretion following feeding after prolonged food deprivation was the consequence of inhibition of SS secretion. Although GRF measurement was not performed, it is conceivable that the signal of caloric intake is conveyed to the MBH and acts to stimulate GRF release.

Plasma CRH response to water immersion-restraint stress in rats bearing a hypothalamic knife cut.

We reported earlier that the plasma level of corticotropin-releasing hormone (CRH) remained high 120 min after the onset of such strong sustained stress as ether-laparotomy or water immersion-restraint, which reflected the persistent secretion of CRH from the hypothalamic median eminence (ME). We investigated the change in plasma CRH during water immersion-restraint stress in rats bearing an anterolateral cut around the medial basal hypothalamus (MBH) which cuts the CRH neurons from the PVN to the ME. Concentrations of CRH in the hypothalamus, extrahypothalamic tissues and peripheral blood were measured by radioimmunoassay. Plasma ACTH was measured with an immunoradiometric assay kit. Plasma baseline ACTH and CRH concentrations did not differ significantly in the sham vs. cut groups. At 120 min after the onset of stress, plasma ACTH concentrations were definitely higher in both groups. In the cut group, plasma CRH at 120 min after stress did not differ significantly from the baseline level, whereas plasma CRH at 120 min was definitely higher in the sham group. Baseline CRH concentrations in the ME did not differ greatly in the two groups. CRH concentrations in the ME of both groups had decreased appreciably 120 min after the onset of stress as compared with baseline CRH, and the CRH decrease was greater in the cut group than in the sham group. CRH in the neurointermediate lobe (NIL) and adrenal gland of both groups showed no significant change at 120 min, compared with the control. These findings confirm that the continuous CRH increase in plasma during sustained stress is derived mainly from the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the hypothalamic paraventricular nucleus upon the activity of thyroid and adrenal glands and their relation with body defense function.

Lesion of the PVH or its isolation--either alone or together with the medial hypothalamus, at fronto-lateral or complete level, induces a significant decrease in plasma thyroxine and a negligible modification of triiodothyronine. Variations recorded with various groups, having the medial hypothalamus deconnected, suggest that the main thyroliberin secreting (TRH) region is located at the level of PVH. Immunization of animals restores the thyroid function in the animals with damaged PVH, under the action of thyrotropin (TSH) of lymphocyte origin. Although the main CRH source occurs at the level of PVH, the results obtained after lesions or isolations of the hypophysotropic region demonstrate the extended distribution of CRH within various nervous areas, and its possible involvement in maintaining the adrenal gland function.

Improved yield of obese rats using a double coordinate system to locate the ventromedial or paraventricular nucleus.

This article describes a highly efficient method for making VMH and PVN-lesioned obese rats by using a newly developed coordinate system. In previous methods, the coordinates for creating VMH and PVN lesions were determined from single point, either the interaural line or the bregma. Because skull size varies, the use of two reference points resulted in greater consistency. We therefore developed a system for making VMH- and PVN-lesioned obese rats using both the interaural line and the bregma. With this new double coordinate system the success rate for producing obese rats varied from 52% to 92% for VMH lesions and from 36% to 61% for PVN lesions.

Possible role of cingulate cortex in regulating sexual behavior in male rats: effects of lesions and cuts.

The role of the cingulate cortex in regulating male sexual behavior was studied in testosterone propionate-treated castrated male rats. Males with lesions in the anterior part of the cingulate cortex showed lower levels of mount, intromission and ejaculation activities than sham-operated control males and males with lesions in the posterior part of the cingulate cortex or the frontal cortex. In male rats in which lateral connections of the anterior cingulate cortex were bilaterally interrupted by sagittal cuts, the sexual activity was much lower than in the control rats, being comparable to that of the anterior cingulate cortex lesion group, but transection of the anterior connections by a transverse cut made in the anterior part of the anterior cingulate had no effect. These results suggest that the anterior cingulate cortex and its lateral connections are critical in regulating male sexual behavior in male rats.

Restoration of circadian corticosterone rhythm in ventromedial hypothalamic lesioned rats.

The effects of ventromedial hypothalamic (VMH) lesions on the circadian periodicity of blood corticosterone were studied in female rats. The rats were kept on a 12-hour light/12-hour dark illumination regimen and fed ad libitum. Three, 10 and 12 weeks after the VMH lesions, the concentrations of blood corticosterone were measured every 4 h for 48 h in the same unanesthetized rats. Three weeks after the operation, the circadian rhythm in VMH-lesioned rats was disturbed and disappeared. The corticosterone levels at 03:00, 07:00, and 11:00 were significantly higher than those in sham-operated rats. 10 and 12 weeks after the operation, the circadian rhythm, however, was notable (p less than 0.05, p less than 0.05). The elevated mean corticosterone levels over 48 h at 3 weeks after the operation decreased at 10 and 12 weeks. The sham-operated rats showed a significant circadian rhythm at 3, 10 and 12 weeks after the operation (p less than 0.001 in each period) with a peak concentration at 19:00 and through at 07:00. These findings show that the corticosterone circadian rhythms which were disturbed in the dynamic phase after VMH lesions recovered in the static phase of obesity, suggesting that the ventromedial hypothalamus is not an essential biological clock of circadian corticosterone rhythm.

Prolactin response to immobilization stress and hemorrhage: the effect of hypothalamic deafferentations and posterior pituitary denervation.

The roles of posterior and anterolateral connections to the mediobasal hypothalamus (MBH) as well as innervation of the posterior pituitary in the PRL response to immobilization (IMO) and hemorrhage (HEM) were studied by means of surgical isolation, performed 6-9 days before stress exposure. Male rats bearing indwelling tail artery cannulae subjected to 120-min IMO reached peak PRL secretion in 5-20 min. HEM of 25% elicited a significant rise of PRL levels. A posterior cut in the MBH, performed without damaging the serotonergic fibers from the brain stem, attenuated the PRL response to 25% HEM, whereas the PRL elevation due to IMO remained unaffected. An anterolateral cut around the MBH eliminated both the IMO- and HEM-induced stimulation of PRL. Posterior lobe denervation reduced by about 27% the PRL response to IMO and eliminated the response to HEM. These results suggest the following conclusions. The neural structures located posteriorly to the MBH are involved in the transfer of signals triggering PRL secretion due to hypovolemia. Intact anterolateral pathways to the MBH and stalk-median eminence region are essential for the PRL-releasing activity under both stimuli. The posterior lobe may be an important link in the PRL stress response in male rats.

Hypothalamic control of the generation of mature natural killer lymphocytes in bone marrow and spleen of the mouse.

Following previous work showing that electrothermocoagulation of the median region of the hypothalamus (MH) caused a marked and permanent decrease in the cytotoxicity of natural killer (NK) cells and in the number of large granular lymphocytes, a study was made of the effect of such lesions on the generation of NK cells in the bone marrow (BM) and spleen of C57BL/6 mice. Fresh spleen and BM cells from MH-lesioned and sham-operated mice were cultured with 40 U of recombinant interleukin-2 (rIL-2). NK activity was significantly higher in BM of lesioned mice, whereas spleen NK activity was greater in the sham-operated controls. NK cells matured by culture with rIL-2 were characterized by assay with fluorescent monoclonal antibodies and found to display the typical NK phenotype. These results show that the number of NK precursors is greater in BM of MH-lesioned mice and that their migration into other organs is probably partially impeded. It can also be concluded that intactness of both BM and the hypothalamus is essential for the physiological generation of NK cells.

Rapid changes in growth hormone regulation and hypothalamic somatostatin after transection of anterolateral pathways to the medial-basal hypothalamus in the rat.

Plasma and pituitary GH content, in-vitro GH release and somatostatin-like immunoreactivity (SLI) in the stalk-median eminence were studied up to 7 days after making an anterolateral cut (ALC) around the medial-basal hypothalamus. Plasma GH concentration increased within 15 min to a very high level, then fell to a high level which was unchanged for several hours. The GH concentration then steadily decreased between days 2 and 7. The SLI content in the stalk-median eminence decreased to 3.5% of the control value within 3 days. The GH content of the anterior pituitary gland was 58.8% of the control value by 1 week after the operation but the in-vitro sensitivity to somatostatin of the GH cells failed to change. Pentobarbitone injection stimulated GH release in the sham-operated controls but decreased it in the rats with an ALC. These findings suggest that transection of somatostatin-containing fibres is followed by a rapid rise and a lasting high concentration of plasma GH which slowly returns towards lower levels in parallel with a marked depletion of pituitary GH content. In rats with transected somatostatin innervation of the median eminence, sodium pentobarbitone probably decreases GH secretion by depressing the secretion of GH-releasing hormone.

Effects of catecholamine agonist and antagonist drugs on acute stomach ulceration induced by medial hypothalamic lesions in rats.

In order to investigate the involvement of catecholamines (CAs) in acute stomach ulceration induced by hypothalamic lesions, rats were given bilateral electrolytic anodal lesions in the medial hypothalamus followed by a single subcutaneous injection of CA agonist or antagonist drugs. As in previous studies, lesioned rats that received no post operative drug treatment showed extensive gastric damage when examined 24 hr after the brain lesion. Chlorpromazine, amphetamine, desipramine and isoproterenol caused significant reductions in the extent (total length) and/or number of erosions induced by the brain lesion. Haloperidol and propranolol did not seem to affect ulcer formation. Clozapine increased the number but not the total length of ulcers. Phentolamine, alone or in combination with propranolol, significantly increased both the number and total length of lesion-induced ulcers. Similarities between these results and those reported for most of these drugs in the context of ulcers induced by various experimental stress procedures suggest a degree of commonality between acute stress ulcers and ulcers induced by hypothalamic lesions. The overall pattern of results obtained is also consistent with evidence indicating a protective role for catecholamines in acute ulcer formation.

Variations in insulin responsiveness in rat fat cells are due to metabolic differences rather than insulin binding.

Insulin resistance was studied by comparing insulin response and insulin binding in four groups of rats. Glucose metabolism in isolated fat cells from male Wistar rats weighing 340 g was less responsive to a supramaximal dose of insulin than glucose metabolism in fat cells from rats weighing 200 g. Induction of streptozotocin-diabetes in rats weighing 200 g resulted in a marked decrease in the insulin responsiveness of fat cells. Ventromedial hypothalamic lesions of 340 g rats had the opposite effect and restored the insulin responsiveness of fat cells. The responsiveness in the four groups was correlated to the rate of glucose conversion to fatty acids in fat cells. The binding of 125I-insulin was the same in both 340 and 200 g rats. The ventromedial hypothalamic lesioned rats and the diabetic rats showed, in spite of their great difference in insulin responsiveness, the highest binding of 125I-insulin to fat cells. Insulin binding was not correlated to the plasma insulin level which however was reflected in the lipoprotein lipase activity in the adipose tissue. In conclusion, these results indicate that variations in insulin responsiveness in fat cells are due to alterations in cellular metabolism rather than in insulin binding.