Clifton A. Baile

Evidence for the role of insulin-like growth factor II (IGF-II) in the control of food intake.

Highly purified insulin-like growth factors I and II and insulin (100 ng peptide/animal) were injected intracerebroventricularly in rats and the effect on 24 hour food consumption examined. IGF-II injections resulted in a 21% decrease in food intake and 4% body weight loss over the 24 hour period following peptide administration whereas IGF-I and insulin had no effect on either parameter. Increasing the amount of IGF-II injected also increased these responses with depressions of 22, 33 and 44% occurring in rats given 33, 100 and 300 ng IGF-II respectively. In addition, tissue concentrations of IGF-II were detected and found to be differentially distributed, via radioimmunoassay, in specific regions of the brain implicated in the regulation of food intake. IGF-I was not found in these same tissue punches despite radioimmunoassay sensitivity of 6 pg.

Differential distributions of cholecystokinin in hamster and rat forebrain

Rats and golden hamsters show a differential feeding response to intracranial injections of cholecystokinin (CCK). Rats, but not hamsters reduce food intake after CCK injections into the hypothalamic paraventricular nucleus. In view of this species difference, we undertook an immunohistochemical study of the distribution of CCK-immunoreactivity in the hamster hypothalamus and remaining forebrain. CCK-immunoreactive perikarya were abundant in the neocortex, claustrum, hippocampal formation, amygdaloid complex, bed nucleus of the stria terminalis, nucleus of the lateral olfactory tract and in the magnocellular basal nucleus. CCK-immunoreactive neurons had a more restricted distribution in the diencephalon and were relatively rare in the preoptic area-hypothalamus. The only exception was the suprachiasmatic nucleus and adjacent medial anterior hypothalamus, in which CCK-immunoreactive neurons were numerous. CCK-containing perikarya were not observed in the hamster hypothalamic paraventricular and supraoptic nuclei, where they have been reported to occur in the rat. Groups of CCK-positive perikarya were also noted in the hamster thalamic paratenial and parafascicular nuclei. CCK-immunoreactive fibers/terminals were localized in the caudate and putamen, periventricular zones, dorsolateral geniculate, thalamic reticular nucleus and the superficial layer of the optic tectum. Fiber/terminal labeling was also present in those regions associated with CCK-immunoreactive perikarya. Our results indicate that the telencephalic distribution of CCK-containing neurons in the hamster appears to be similar to that reported in the rat. However, several differences occur in the diencephalon. Perhaps the most striking is that the hamster differs from the rat in having a large group of CCK-containing neurons in the suprachiasmatic nucleus, and in lacking the CCK-containing perikarya observed in the rat paraventricular and supraoptic nuclei. These differences may underly species differences in feeding responses to intracranial CCK injections and gonadal responses to short photoperiods. Our data further suggest that the distribution of neuropeptides and other neuroactive substances may not always be conserved during evolution.

Feeding behavior responses of Zucker rats to naloxone

The effects of naloxone on feeding patterns were studied in both obese and lean Zucker rats during both light and dark phases of the diurnal cycle. Eight female obese (471 +/- 9 g) and lean (225 +/- 6 g) Zucker rats were trained to bar press for food. They were administered 0, 0.5, 1.0 or 2.0 mg/kg naloxone at the initiation of the light or dark phase of the diurnal cycle and feeding behavior was recorded for the subsequent 12 hr using an automated real-time data collection system. First meal size and duration were decreased and first postmeal interval was increased by naloxone and responses did not vary with phenotype or phase of the diurnal cycle. Naloxone decreased food intake during the 12-hr period by decreasing average meal size but meal frequency was not affected. Overall, the feeding behavior responses of obese rats to naloxone were greater than those of lean rats, supporting the hypothesis of an association between opioid peptides and obesity. Opioid involvement in diurnal control of food intake is also supported by the greater responses generally demonstrated in the light compared with dark phases.

Immunohistochemical distribution of cholecystokinin, dynorphin A and Met-enkephalin neurons in sheep hypothalamus

The distribution of cholecystokinin (CCK)-, Met-enkephalin (M-ENK)- and dynorphin (DYN)-like immunoreactive perikarya were examined in the sheep hypothalamus using the peroxidase-anti-peroxidase technique. CCK- and DYN-containing neurons were found primarily in the suprachiasmatic nucleus (SCH) and supraoptic nucleus (SO). No CCK- or DYN-containing neurons were found in the paraventricular nucleus (PVN). M-ENK-containing neurons were found mainly in the PVN of the hypothalamus. In addition, M-ENK neurons were found in the dorsomedial (DMH), lateral (LH), anterior (AH) and periventricular hypothalamic areas. The distribution of these neuropeptides may provide a basis for understanding differences in responsiveness to centrally administered peptides.

Medial hypothalamic lesions in Syrian hamsters: Characterization of hyperphagia and weight gain ☆

Syrian golden hamsters (Mesocricetus auratus) received bilateral lesions aimed at the ventromedial hypothalamus (VMH) or a sham lesion. In the first study, some of the animals in each surgical group were housed in standard sedentary conditions while others had free access to running wheels. The lesions produced a 30% increase in the daily intake of chow, and this was accomplished exclusively by increased meal sizes. As a result, lesioned hamsters gained body weight relative to controls both on the chow diet and in a subsequent high fat diet phase. The effects were comparable in both sedentary and exercising groups. The lesions produced increases in body length and fat content. In the second study, lesions were made in the VMH or in adjacent nuclei and, after an initial period on chow, the hamsters were then given a choice between chow and high fat diet. The lesioned hamsters showed no unusual preference for the high fat diet but, as before, those with damage to the VMH or paraventricular nucleus (PVN) showed exaggerated body weight gain. Hamsters with these lesions were hyperinsulinemic in both fed and fasted conditions at the end of the study.

Role of glucagon in the control of food intake in zucker obese and lean rats

Although there is strong evidence for glucagons role in the control of food intake, the essentiality of this role remains in question. In several experiments the feeding responses to glucagon and glucagon antisera were investigated in both Zucker and Sprague-Dawley rats. Intraperitoneal injection of 400 micrograms/kg glucagon decreased 30-min food intake 18% (p less than 0.01) in Zucker lean rats and increased 30-min food intake 16% (NS) in Zucker obese rats, suggesting obese rats are less sensitive. In Sprague-Dawley rats the same dose decreased first meal size 28% (p less than 0.01), indicating that they were more sensitive than Zucker lean rats. Intraperitoneal injection of 400 micrograms/kg glucagon increased plasma glucagon concentrations in the vena cava and the tail vein 150-fold and 10-fold, thus, superphysiological doses may be required to elicit satiety. In contrast, administration of a glucagon antisera increased food intake of Zucker rats for up to 6 hr and increased meal size for 5 hr. The findings suggest that glucagons role in control of food intake in Zucker obese and lean rats is similar, but the superphysiological glucagon changes which occur with exogenous administration indicate that glucagon may only indirectly elicit satiety.

Intestinal infusion of a liquid diet alters CCK and NPY concentrations in specific brain areas of rats.

Cholecystokinin (CCK) and neuropeptide Y (NPY) have been implicated in the control of food intake in a number of species. This study was carried out to determine 1) whether nutrient-related stimulation of the upper small intestine could activate central CCK and NPY neuronal systems, resulting in changes in concentration of these peptides in specific brain areas, and 2) the influence of the circadian cycle on nutrient-related effects. Four groups of rats received treatments of either 1.0 ml saline (S) or Ensure liquid diet (E) infused into the duodenum either during the dark (D) or light (L) phase of the circadian cycle. CCK and NPY concentrations in extracts of specific brain areas were measured by RIAs. CCK concentration in the supraoptic n. (SON) was higher in D than in L, regardless of infusion treatment, and in the dorsal parabrachial n. area (DPN), CCK concentration was higher in E than S infused rats, regardless of circadian phase. CCK concentration in the dorsal motor vagal n. area (DMV) was higher in E, but only during L. NPY concentration was higher in DPN and paraventricular n. areas (PVN) and lower in the suprachiasmatic n. area (SC) after E, regardless of circadian phase. The changes in concentration of CCK and NPY in specific brain areas in response to food in the upper intestine suggest that nutrient-related signals from the intestine can activate specific CNS CCK and NPY-containing neural pathways.

Clonidine has a bidirectional effect on operant responding for food.

Clonidine, an alpha-noradrenergic agonist, has had inconsistent effects when administered peripherally in previous studies of feeding behavior. The present experiment was undertaken to evaluate clonidine using an operant feeding paradigm (continuous reinforcement schedule) to provide detailed data on the time course of its effects. Over an entire four-hour session, all doses of clonidine tested (25, 50, or 100 micrograms/kg) increased bar-pressing. The 50 micrograms/kg dose was most effective. An examination of the time course of responding revealed that the initial effect of clonidine was to decrease responses with the duration and magnitude of the decrease directly proportional to dose. However, clonidine also prolonged a phase of steady responding for food once the animals resumed bar-pressing, resulting in a net increase of food intake. Future investigations of clonidine should take into account the effects of increasing dose on delayed onset of feeding.

Weight gain and food intake in corticotropin releasing factor immunized zucker rats

In Zucker obese rats (fa/fa) there are disturbances in the regulation of ACTH and corticosterone. In addition, beta-endorphin concentrations are higher in the pituitary and hypothalamus in obese than in lean rats. Since ACTH and beta-endorphin are thought to be controlled by corticotropin releasing factor (CRF), these effects may be due to abnormalities in CRF regulation. This possibility was investigated by immunizing rats against CRF. Obese rats immunized against CRF developed higher titer antibodies than lean rats. Hypothalamic CRF concentrations were higher in CRF-immunized obese but not lean rats compared with those of control rats, suggesting that compensation for sequestration of peripheral CRF developed in obese rats. In obese, but not lean rats, immunization against CRF decreased weight gains during weeks 1-4 and increased gains during weeks 9-12 and food intakes were decreased during weeks 5-8 compared with those for obese rats immunized against bovine serum albumin (BSA). Adrenal glands weighed 30% less in both obese and lean rats immunized against CRF compared with those immunized against BSA. These responses to immunization against CRF occurred even though plasma, hypothalamic and pituitary concentrations of ACTH and beta-endorphin were unaffected at the end of the study.