Larry L. Bellinger

The dorsomedial hypothalamic nucleus and its role in ingestive behavior and body weight regulation: Lessons learned from lesioning studies

This review article discusses the well-established role of the dorsomedial hypothalamic nucleus (DMN) in feeding, drinking and body weight (BW) regulation. DMN lesions (L) in both weanling and mature rats of both sexes produce hypophagia, hypodipsia and reduced ponderal and linear growth in the presence of normal body composition. The growth reduction is not due to a deficient secretion of growth hormone, insulin-like growth factor-1, thyroxine, triiodothyronine or insulin. DMNL rats actively defend their lower BW (BW settling point) by becoming either hyper- or hypophagic, depending on the experimental manipulation, thereby defending both lean and fat mass. They also regulate their 24-h caloric intake, but they may overeat during the first hour of refeeding following a fast, possibly due to a reduced ability to monitor blood glucose or to respond to cholecystokinin (CCK). 2-Deoxy-D-glucose (2DG) increases c-fos expression in orexin-A neurons in the DMN, and DMNL eliminated the orexigenic effect of 2DG. DMNL rats on high-fat diets do not get as obese as controls, which may be due to a reduction of DMN neuropeptide Y (NPY). Rats lacking DMN CCK-A receptors are obese and have increased expression of NPY in the DMN, supporting earlier data that CCK may act at the DMN to suppress food intake. Excitotoxin studies showed that loss of DMN cell somata, and not fibers of passage, is important in the development of the DMNL syndrome. The DMN is a site where opioids increase food intake and knife-cut studies have shown that fibers traveling to/from the DMN are important in this response. An interaction of glucose and opioids in DMN may also be involved in the control of food intake. DMN knife cuts interrupting fibers in the posterior and ventral directions additively produce the hypophagia and reduced linear and ponderal growth observed after DMNL. Ventral cuts may interrupt important connections with the arcuate nucleus. Lateral and posterior DMN cuts additively produce the hypodipsic effect seen after DMNL, but DMNL rats respond normally to all water-regulatory challenges, i.e., the hypophagia is not due to a primary hypodipsia. The DMN has been shown to be involved in the rats feeding response to an imbalanced amino acid diet. These data show the DMN has an important role in many processes that control both food intake and BW regulation.

THE DORSOMEDIAL HYPOTHALAMIC NUCLEUS REVISITED : 1998 UPDATE

Abstract This article reviews data that have accumulated since the early 1970s on the role of the dorsomedial hypothalamic nucleus (DMN) in neuroendocrine and autonomic homeostasis. Both the ventromedial hypothalamic nucleus (VMN) and the lateral hypothalamic area (LHA) project to the DMN, which in turn projects to the paraventricular nucleus of the hypothalamus (PVN), thus placing the DMN at an important nodal point of neuroendocrine/autonomic circuitries. The DMN is composed of cells and fibers containing neuropeptide Y (NPY), and the nutritional status (starvation-refeeding) is reflected in NPY levels of both VMN and DMN in Sprague-Dawley, Zucker (fa/fa), and corpulent rats (cp/cp JCR:LA). The DMN is involved in the final common pathway of corticotrophin-releasing hormone (CRH) secretion by the PVN, sympathetic nervous system outflow to the adrenal gland, and brown adipose tissue (BAT) thermogenesis. The DMN is also part of a “fear circuitry” regulating cardiovascular responses to stress such as myocardial blood flow and the tachycardia associated with the defense reaction. This appears to be mediated by a gamma amino butyric acid (GABA) mechanism. Although exhibiting reduced ponderal and linear growth and hypophagia and hypodipsia, the rat with DMN lesions (DMNL rat) has normal body composition, anabolic hormone levels, and intermediary metabolism, and it responds normally to numerous endocrine, nutritional, intra- and extracellular thirst and body weight-regulatory challenges. The DMNL rat shows normal efficiency of food utilization, but shows an attenuated response to the feeding-stimulatory effect of insulin. The only other lesion-induced abnormalities are hyperprolactinemia and a disrupted circadian corticosterone rhythm. The hyperprolactinemia in DMNL rats appears to be related to an attenuation of dopamine (DA). Rats with DMNL are capable of mating and can bear offspring, but there is a dramatic effect on litter size and other litter parameters that only improves when one parent is a DMNL rat. Antiaging effects produced by DMNL are evident in the prevention of age-associated microalbuminuria and kidney lesions, as well as, in prevention of the age-related decline in circulating insulin-like growth factor I (IGF-I). Recent evidence suggests that DMN, together with the VMN and the arcuate nucleus (ARC) of the hypothalamus, may be part of the circuitry that is responsive to the feedback signal from adipose tissue by the hormone leptin. The above findings and others suggest that the DMN plays a diverse role in physiological regulatory processes.

The dorsomedial hypothalamic nucleus revisited: 1986 update

ingestive behavior ...................................................................................................................................... 2.1. Short-term satiety .............................................................................................................................. 2.2. Caloric density manipulation ................................................................................................................ 2.3. Fasting and refeeding .......................................................................................................................... 2.4. Caloric compensation ......................................................................................................................... 2.5. Plasma glucose manipulation-2-deoxy-D-glucose (2-DG), insulin ................................................................ 2.6. Diet texture, consistency, and taste ......................................................................................................... 2.7. Finickiness ....................................................................................................................................... 2.8. Dietary self-selection .......................................................................................................................... 2.9. Response to high-protein diet ................................................................................................................ 2.10. Efficiency of food utilization (EFU) ........................................................................................................ 2.11. Exocrine pancreas and intestinal enzymes ................................................................................................ 2.12. Water intake and thirst mechanisms ........................................................................................................ 2.13. Summary .........................................................................................................................................

Effect of Meal Feeding on Daily Rhythms of Plasma Corticosterone and Growth Hormone in the Rat

After rats had adapted to regular meal feeding in the morning they demonstrated an altered circadian rhythm of plasma corticosterone (B) even under the normal light-dark cycle. The altered daily rhythm of plasma B consisted of two peaks, with one peak at 08.00 h in anticipation of meal feeding and a second peak corresponding to the normal peak of plasma B prior to lights-off seen in ad libitum-fed animals. Neither peak of plasma B in the meal-fed animals achieved the magnitude of the single peak observed in control animals. In spite of some quantitative differences during certain periods of the day, after the animals had adapted to meal feeding there was no difference in the basic profile of the daily rhythm of plasma immunoactive growth hormone (GH).

Effect of ventromedial and dorsomedial hypothalamic lesions on circadian corticosterone rhythms.

Weanling rats received bilateral electrolytic lesions in the dorsomedial (DMH) or ventromedial (VMH) hypothalamic areas destroying primarily the dorsomedial (DMN) or ventromedial (VMN) hypothalamic nuclei. Sham-operated rats served as controls. Lesions in the VMN and DMN, both of which have previously been shown to disrupt normal diurnal feeding rhythms, were also observed to disrupt normal plasma corticosterone rhythms in the present study. The a.m. values of plasma corticosterone in the DMN-lesioned rats were higher than the sham-operated controls. In the p.m., the values of both VMN- and DMN-lesioned rats were lower than those of the controls but unchanged in comparison to their own a.m. concentrations. This disruption of the normal diurnal plasma corticosterone rhythm persisted for at least 9 post-operative weeks.

Meal patterns in male rats during and after intermittent nicotine administration

Previously we observed in male rats that intermittent administration of nicotine (NIC) during the dark phase reduces food intake (FI) by initially decreasing only dark phase meal size. This was followed several days later by an increase in dark phase meal frequency such that FI returned to normal, while body weight remained suppressed. Termination of NIC treatment resulted in a modest dark phase hyperphagia. Since some human females use NIC as a weight control drug, the present study investigated changes in FI and body weight regulation in adult female rats treated for five estrous cycles with saline or a 1.40 mg/kg/day (free base) dose of NIC, which was given in four equal i.p. doses during the dark phase. The rats were followed for 15 days after cessation of NIC. Initially both dark and light phase FI were reduced and this was caused by an immediate decrease in dark and light phase meal size; the attenuation of meal size continued after cessation of NIC. On day 7 of NIC, the rats compensated by significantly increasing the number of dark, but not light, phase meals they took. This resulted in a normal 24-h FI, which was caused by a dark phase increase in FI coupled with a continued decrease in light phase FI. Importantly, these changes in meal patterns persisted for some time after termination of NIC. Upon NIC cessation, the NIC group showed no hyperphagia even though their body weight was significantly decreased. These results document that administration of NIC during the dark phase resulted in a reorganization of the microstructure of FI in females rats that resembles, but does not exactly duplicate, that observed in male rats. Like males, long lasting alterations in the microstructure of FI (e.g., meal size and meal number), were noted in female rats for up to 2 weeks after cessation of NIC. These results differ from studies in which NIC was given continuously 24-h per day and indicate that dark phase NIC administration in rats may represent an appropriate model to study the impact of NIC on meal patterns.

Cocaine-induced hypophagia and hyperlocomotion in rats are attenuated by prazosin

The present studies examined the effects of antagonizing alpha(1)-adrenoceptors via systemic administration of prazosin on the behavioral actions of cocaine in rats, including induction of locomotion and suppression of eating. In Experiment 1, locomotor activity was monitored in automated chambers for 80 min in adult male rats pretreated with the alpha(1)-adrenoceptor antagonist prazosin (0, 0.5, or 2 mg/kg, i.p.) and then treated (i.p.) with either 0, 10, 20, or 40 mg/kg cocaine hydrochloride. Cocaine dose-dependently increased total distance traveled and the number of stereotypy counts, and significantly decreased rest time. Each dose of prazosin produced a significant attenuation of the locomotor effects of a limited range of cocaine doses (i.e. 10 and/or 20 mg/kg cocaine, but not 40 mg/kg cocaine). Prazosin alone did not alter any measure of locomotion. In Experiment 2, eating and drinking were monitored for 60 min in male rats pretreated with prazosin (0, 1, and 2 mg/kg, i.p.) and then treated with 0, 10, 20, or 40 mg/kg (i.p.) cocaine. Rats pretreated with vehicle exhibited a dose-dependent suppression of eating, but not drinking, to cocaine. The impact of prazosin on cocaine-induced hypophagia paralleled that noted for locomotion in that administration of prazosin significantly attenuated the hypophagic action of 20 mg/kg cocaine, but not that of 40 mg/kg cocaine. These findings confirm earlier studies noting a partial role for alpha(1)-adrenoceptors in the locomotor stimulant actions of cocaine and extend those findings to the feeding-inhibitory actions of cocaine.

Regulation of cell proliferation in rat mandibular condylar cartilage in explant culture by insulin-like growth factor-1 and fibroblast growth factor-2

Insulin-like growth factor-1 (IGF-1) and fibroblast growth factor-2 (FGF-2) regulate the proliferation and differentiation of growth-plate chondrocytes, but surprisingly little is known of the mechanisms underlying growth regulation in secondary cartilages such as the mandibular condylar. The aims here were to investigate whether IGF-1 and FGF-2 receptors are present in mandibular condylar cartilage in vivo from 28-day-old male Sprague-Dawley rats (by immunohistochemistry), how proliferation in that cartilage responds to increasing concentrations of exogenous IGF-1 or FGF-2 in explant culture (by [3H]thymidine incorporation), and whether the expression of these growth factors and their receptors in the cartilage changes during the transition to puberty (quantitative reverse transcriptase-polymerase chain reaction). Immunoreactivity for receptors (R) for IGF-1 and FGF-2 (IGF-1R, FGFR1, and FGFR3) was most pronounced in chondroblasts and hypertrophic chondrocytes, while FGFR2 immunoreactivity was strongest in the articular and prechondroblastic zones. The proliferative response elicited by exogenous IGF-1 was considerably greater than that induced by FGF-2, although the threshold concentration for a significant response was lower for FGF-2. In the transition from prepuberty (31 days) to the beginning of late puberty (42 days), a pronounced trend of increasing IGF-1 and decreasing FGF-2 gene expression was evident. Of the receptors, only FGFR2 and FGFR3 expression increased. These data provide evidence that proliferation in the mandibular condylar cartilage might be regulated in part by IGF-1 and FGF-2, and that expression of these genes changes considerably at puberty. The data also suggest that mechanisms governing proliferation in mandibular condylar cartilage might have as much in common with those regulating cranial sutures as those regulating growth-plate.

Suppression of feeding by cholecystokinin but not bombesin is attenuated in dorsomedial hypothalamic nuclei lesioned rats

Rats with dorsomedial hypothalamic lesions (DMN-L) or sham operations were injected IP with saline or the satiety peptide cholecystokinin (CCK) at 3.0 and 6.0 micrograms/kg at the onset of the dark phase. Food consumption was then measured 15, 30 and 60 min later. Compared to saline baseline intake, CCK suppressed feeding during the first 30 min following injection in the sham operated group but not in the DMN-L group. Bombesin (BBS), another satiety peptide was also injected (4.0 and 8.0 micrograms/kg) into the two groups. BBS produced significant and comparable suppression of feeding in both DMN-L and sham operated rats. In a third trial a large dose of CCK (12.0 micrograms/kg) was injected into the two groups as described above. The CCK suppressed feeding for 60 min in the control group. CCK also attenuated feeding in the DMN-L group, but for only 30 min. However, even this suppression was reduced compared to the control group. The data suggest that the DMN may play a role in CCK induced satiety.

Effect of deprivation and time of refeeding on food intake

The amount of food eaten in a two hour trial by male Sprague Dawley rats was recorded after periods of food deprivation up to 42 hr in length. Rats ate 50-78% more when refed during the dark phase than when refed during the light phase. This occurred even when light fed animals were fasted for longer periods than the dark fed animals. Rats eat in a rhythmic pattern after deprivation. These data are in good agreement with data previously reported and extend it by increasing the number of observations, increasing the length of deprivation, and comparing different age groups.