Lee L. Bernardis

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 .........................................................................................................................................

Disruption of diurnal feeding and weight gain cycles in weanling rats by ventromedial and dorsomedial hypothalamic lesions

Abstract At the age of 28 days, male Sprague-Dawley rats received bilateral electrolytic lesions in the ventromedial (VMN) and dorsomedial (DMN) hypothalamic nuclei, repectively. Sham-operated rats served as controls. Food intake and body weight gains were measured for 13 days at the beginning of the light period (0800–2000 hr) and prior to the start of the dark period (2000-0800 hr). Both types of hypothalamic lesions caused a disruption of the naturally occurring diurnal feeding and weight gaining cycles. In accordance with previous data, the VMN rats remained normophagic and made normal weight gains while DMN animals were hypophagic and gained weight subnormally; linear growth was reduced in both types of lesioned animals, but only the VMN rats became obese. The data suggest the existence in the medial hypothalamus of an area that is involved in feeding and weight gaining cycles. From the standpoint of overall-caloric intake, this area consists of two types of neuronal assemblies that differ fuctionally as profoundly as they are anatomically separate.

Prediction of carcass fat, water and lean body mass from Lee's ‘nutritive ratio’ in rats with hypothalamic obesity

Verschiedene Untersuchungen im Zusammenhang mit Fettsucht wurden bei Ratten mit hypothalamischer Fettsucht, erzeugt durch Läsionen im Bereich des ventromedialen Teiles des Hypothalamus durchgeführt. Es konnten wertvolle Korrelationen zwischen Körperfett, Körperwasser und fettfreier Körpermasse errechnet werden.

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.

Effect of Lesion Size in the Ventromedial Hypothalamus on Growth Hormone and Insulin Levels in Weanling Rats

Electrolytic lesions of three different sizes were placed in and around the ventromedial hypothalamic nuclei (VMN) in weanling rats. After three weeks, during which food intake was measured, the rats were killed and the following parameters were measured: plasma growth hormone (GH), insulin and glucose, carcass fat, water and lean body mass, pituitary weight and GH content, and ponderal and linear growth. Progressive decreases in pituitary weight, pituitary and plasma GH, linear growth, and carcass water and lean body mass were produced by increasing lesion size. Concomitant increases occurred in plasma insulin and carcass fat. Ponderal growth and plasma glucose were unaffected by any of the lesions and none of the experimental groups exhibited hyperphagia. The data indicate that the VMN are a control site for GH and insulin secretion. The lack of correlation between parameters of growth and those of obesity suggests that the two hormonal control mechanisms are subserved by independent neuronal assemblies.

Effects of ventromedial hypothalamic destruction in rats: With preexisting streptozotocin-induced diabetes☆

Abstract This report describes the effects of electrolytic destruction of the ventromedial hypothalamic nuclei (VMN) in rats previously made diabetic by injection of streptozotocin. Results were compared to those obtained following VMN destruction in non-diabetic rats. Findings indicate that diabetes does not entirely prevent the obesity or changes in adipose tissue metabolism seen after VMN destruction, whereas it does prevent the development of hyperinsulinemia or significant increase in hypertriglyceridemia. Possible mechanisms are discussed.

Participation of the dorsomedial hypothalamic nucleus in the “feeding center” and water intake circuitry of the weanling rat

Precise electrolytic lesions were placed in the dorsomedial (DMNL) and ventromedial (VMNL) hypothalamic nuclei of weanling rats to study the effect on food and water intake, body weight and length and body composition. Lesions in the DMN consistently resulted in hypophagia, hypodipsia and decreased ponderal and linear growth, both when compared with VMNL rats and with sham-operated controls. The DMNL rats contained more carcass water and lean body mass but less fat than the VMNL rats. The lesion effect persisted in the DMNL rats even after placement of minute lesions of 2.5 mC, while such lesions failed to elicit the changes found with larger lesions in the VMNL rats. The data show that the DMN, at least in the weanling rat, appear to be part of the “feeding center” and water intake circuitry. They also show the minuteness of the area involved and its sharp functional and anatomical delineation from the VMN. Präzise elektrolytische Läsionen wurden in den dorsomedialen (DMNL) und ventromedialen (VMNL) hypothalamischen Kernen von abgesetzten Ratten placiert, um ihren Einfluß auf Futter- und Wasseraufnahme, Körperwachstum und Zusammensetzung zu studieren. Läsionen in den DMN hatten Hypophagie, Hypodipsie und gehemmtes Körperwachstum zur Folge, sowohl im Vergleich zu den Kontrollen als auch den VMNL-Tieren. Die DMNL-Tiere enthielten mehr Körperwasser und fettfreie Körpermasse, aber weniger Fett als die VMNL-Ratten. Der beschriebene Effekt wurde auch in DMNL-Ratten beobachtet, welche Läsionen von nur 2.5 mC erhalten hatten, während die in den VMNL-Tieren beobachteten Veränderungen nach solchen kleinen Läsionen nicht mehr augenscheinlich waren. Die Ergebnisse zeigen, daß die DM-Kerne, wenigstens in der abgesetzten Ratte, an der Regulation von Futter- und Wasseraufnahme teilnehmen und daß dieses neuronale Gebiet scharf begrenzt ist.

Adipose tissue metabolism of weanling rats after destruction of ventromedial hypothalamic nuclei: Effect of hypophysectomy and growth hormone

Abstract This report describes the effects of hypophysectomy and growth hormone treatment on the endocrine-metabolic alterations associated with destruction of the ventromedial hypothalamic nuclei (VMN) in weanling rats. In addition to previously noted characteristics of the syndrome (increased plasma insulin and triglyceride levels without hyperphagia, normal plasma glucose, and decreased plasma growth hormone levels with impaired linear growth), changes in in vitro adipose tissue metabolism of glucose-U-C 14 and palmitate-1-C 14 were observed. Glucose oxidation and incorporation into lipid were markedly elevated, whereas palmitate oxidation was decreased in adipose tissue of VMN rats. Although hypophysectomy and growth hormone treatment alone or in combination produced effects in rats with or without VMN lesions, neither significantly modified the characteristic changes observed in untreated rats with VMN lesions.