Dorsomedial Hypothalamic Nuclei Lesions Research Articles

Lesions of suprachiasmatic nucleus efferents selectively affect rest-activity rhythm

The suprachiasmatic nucleus (SCN) of the hypothalamus controls circadian rhythms in behavioral, neuroendocrine and physiological functions. In this study, we test the hypothesis that caudal SCN efferents to the subparaventricular zone (SPVZ) control the rhythm in rest-activity (R-A) through projections on posterior hypothalamic area arousal systems (PHA). Small electrolytic lesions of the ventral SPVZ cause a selective loss of the circadian R-A rhythm, sparing the core body temperature rhythm. In contrast, large excitotoxic lesions of the posterior hypothalamic area (PHA) that effectively ablate populations of hypocretin and melanin concentrating hormone neurons projecting to cortex and subcortical arousal areas decrease R-A rhythm amplitude but do not disrupt circadian regulation. Since dorsomedial hypothalamic nucleus lesions have effects similar to PHA lesions (Chou, T.C., Scammell, T.E., Gooley, J.J., Gaus, S.E., Saper, C.B., Lu, J., 2003. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J. Neurosci. 23:10691–10702), these data support the view that the SPVZ is the principal relay nucleus for SCN signals to the multiple posterior hypothalamic arousal systems involved in generation of the R-A rhythm.

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 rat's 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.

Effects of dorsomedial hypothalamic nuclei lesions on intake of an imbalanced amino acid diet.

Within 3 h of ingesting an imbalanced amino acid diet (Imb), rats show attenuated intake, which can be ameliorated by prior administration of the serotonin receptor antagonist tropisetron (Trop). Earlier work in which the dorsomedial hypothalamic nucleus (DMN) was electrolytically lesioned (DMNL) determined that this structure plays a role in the early detection of and subsequent adaptation to Imb. However, that study did not address whether cell bodies in the DMN, fibers of passage, or both were involved in the DMNL response to Imb. In the present investigation in experiment 1, rats were given electrolytic DMNL or a sham operation (Sham). The rats were injected with saline (Sal) or Trop just before introduction of Imb. By 3 h Sal-DMNL rats consumed more Imb than did the Sal-Sham rats; intake was normal by 12 h. Trop enhanced Imb intake, with Trop and DMNL being additive. By day 4 the DMNL rats were eating and gaining weight less than were Sham rats. In experiment 2, DMN cell bodies were destroyed by ibotenic acid (Ibo). Sal-injected Ibo-lesioned and Sham rats showed similar food intake depression on Imb; Trop similarly increased Imb intake in both groups. By day 4 both Ibo-L rats were eating and gaining weight less than were Sham rats. In experiment 3, groups of rats were given knife cuts posterior, lateral, ventral, dorsal, or anterior to the DMN. During the first 3 h of consuming Imb, all cuts except posterior enhanced the intake of Imb. Over the next 24 h the anterior cut group continued to eat more Imb than did the Sham rats. In experiment 4 DMNL rats were given novel diets; the DMNL rats did not display a neophilic response. The data suggest that fiber tracts that pass through the DMN may be involved in the early detection of Imb. DMN cell bodies, or fibers of passage, are not involved in the Trop effect. Finally, DMN cell bodies are necessary for proper long-term adaptation to Imb.

The dorsomedial hypothalamic nucleus revisited: 1998 update.

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.

Increased plasma IGF-1 levels but lack of changes in adipocyte glucose transport in weanling rats with dorsomedial hypothalamic nucleus lesions 1 year after lesion production

Experimental destruction of the dorsomedial hypothalamic nuclei (DMN) in weanling rats exerts an antiaging effect by preventing microalbuminuria and kidney lesions both 1 month and 1 year after lesion production. In the present study we report further on antiaging effects of DMN lesions (DMNL) by measuring glucose transport into adipocytes and plasma levels of insulin-like growth factors 1 and 2 (IGF-I, IGF-II). Male and female weanling Sprague-Dawley rats received bilateral electrolytic lesions in the DMN; sham-operated animals served as controls (SCON). The rats were maintained for 1 year and food intake was measured 3 weeks after surgery and 3 weeks prior to sacrifice. As expected, DMNL resulted in profound reductions of body weight and food intake, with male DMNL rats showing higher body weights and body weight gains than their female counterparts. The same was true of the respective SCON. In male DMNL rats, carcass fat in absolute terms was significantly reduced vs. SCON, but it was comparable among all groups when expressed in percent. Lean body mass (LBM), although significantly reduced in absolute terms in DMNL rats vs. SCON, was, however, significantly higher in male DMNL vs. SCON when expressed in percent, but not in females. LBM laid down per food energy taken in was higher in DMNL rats of both sexes than in their respective SCON. Efficiency of food utilization was normal in male DMNL vs. male SCON but was higher in female DMNL vs. SCON. Both male and female DMNL rats had significantly higher plasma IGF-1 concentrations than their respective SCON, and male DMNL rats had higher values than female DMNL rats. Plasma concentrations of IGF-II were significantly higher in DMNL vs. SCON, but only in females. Under both basal and insulin-stimulated conditions, DMNL rats had normal 3-0-methylglucose flux in adipocytes from epididymal fat pads vs. SCON. However, DMNL and SCON responded similarly to the stimulating effect of insulin. Although one-year-old rats may not be considered “aged”, we do consider the observed lack of a drop in plasma IGF-1 levels that occurs with aging as an “anti-aging” effect of DMN lesions.

Hormone and somatic changes in rats pair-fed to growth retarded dorsomedial hypothalamic nuclei-lesioned rats

Rats with dorsomedial hypothalamic nuclei lesions (DMNL) are hypophagic and have reduced linear and ponderal growth, but have normal body composition and anabolic hormone concentrations. Previous studies have shown rats pair-fed to levels consumed (70–80% of ad lib) by DMNL rats, using a meal-feeding paradigm, have abnormal body composition and hormone concentrations. Whether the noted changes were due to restriction per se or method of food presentation was uncertain. In the present study, one group of shamoperated rats was pair fed (SHPF) by a computer-operated system that presented 45 mg food pellets in the exact amount and pattern as their DMNL yoked partner; another sham-operated group was ad lib fed (SHAD). At the end of Experiment 1 (11 days) and Experiment 2 (3 weeks) blood was collected for hormone and metabolite analyses; body compositions were also determined. Unlike an earlier report, the DMNL and SHPF groups had normal percentage body fat. Percentage carcass protein was similar in all groups at 11 days, but slightly elevated in DMNL rats at 3 weeks. Also, in contrast to an earlier study, plasma-free fatty acid levels were comparable in DMNL and SHPF rats. Plasma insulin was normal in the DMNL and SHPF rats at 11 days, but was lowered ( p < 0.05) in the SHPF group at 3 weeks. Plasma thyroxine was reduced ( p < 0.01) in the SHPF group at 11 days but returned to normal by 3 weeks. Thyroxine and triiodothyronine levels were normal in the DMNL groups. Plasma corticosterone levels were similar in all groups. The hormonal data suggests that hypophagic DMNL rats do not show the physiological changes that are observed in SHPF rats and that the DMNL rats' lower food consumption may be normal for their lesioned-induced lowered body weight. These data also show that not only food restriction per se, but the pattern of intake during food restriction can have an important influence on resultant hormonal and body composition data.

The effect of dorsomedial hypothalamic nucleus lesions on kidney function and structure after 1 and 12 months

According to the Dillman theory (17), aging results from a deterioration of metabolism that begins with an elevation of hypothalamic receptor thresholds for feedback signals from the periphery. Three hypothalamic areas are known to contain such receptors: the ventromedial and dorsomedial hypothalamic nuclei (DMN) and the lateral hypothalamic area. We have hypothesized that selective destruction of those hypothalamic areas might be followed by physiological changes associated with aging. Electrolytic bilateral DMN lesions were produced in male and female weanling rats. These rats were maintained for up to 13 months of age. Sham-operated rats served as controls. Food intake and body weight were monitored postoperatively and prior to sacrifice. Before sacrifice, tail blood and a 24-h urine samples were obtained. In accordance with previous findings, rats with DMN lesions showed dramatic reductions of ponderal growth and food intake but had normal body composition. Total protein and albumin excretion rates were significantly lower in rats with lesions. The fractional contribution of albumin to total urinary protein was also decreased in rats with lesions. Histological examination of the kidneys showed significnalty less pathology in the kidneys of rats with DMN lesions; the severity of renal pathology was correlated directly with proteinuria. These changes were seen as early as 1 month after production of the lesion. The attenuation of age-related changes in kidney function and structure in rats with lesions could be due to reduced food intake (dietary restriction is known to produce similar results), and/or a direct effect of the lesion. The latter could be related to the demonstrated existence in rats with DMN lesions of an altered organismic set point that produces a scaled-down, but otherwise homeostatic normal animal.

Hypophagic rats with dorsomedial hypothalamic lesions produce lighter and smaller pups with a lower survival rate at weaning than offspring of sham-operated controls

Weanling and mature rats with dorsomedial hypothalamic nucleus lesions (DMNL rats) show reduced ponderal and linear growth and hypophagia and hypodipsia in the presence of normal body composition and anabolic hormone levels. The present study was conducted to assess their reproductive/parenting capacity and some offspring parameters. Four groups were used: DMNL mothers and fathers, DMNL mothers and control (SCON) fathers, SCON mothers and DMNL fathers, and SCON mothers and SCON fathers. The constituent rats of each group were bred to yield between 14 and 22 litters. The smallest litter size, litter weight, mean pup weight, percent of live-born and percent of weaned pups and greatest percentage of still-born pups were recorded when both parents were DMNL rats. The latter parents also cannibalized the majority of litters. The above parameters improved when only one parent was a DMNL rat, but this was still significantly below the offspring of SCON × SCON parents. The DMN is not part of the classical hypophysiotropic area (HTA), but earlier findings indicate hyperprolactinemia in DMNL rats. Therefore, the lesion-induced hypophagia during gestation and the postpartum neuroendocrine profile of the DMNL mothers may be the cause of the observed litter deficiencies and poor survival.

Brown (BAT) and white (WAT) adipose tissue in high-fat junk food (HFJF) and chow-fed rats with dorsomedial hypothalamic lesions (DMNL rats)

Male weanling rats received dorsomedial hypothalamic nucleus lesions (DMNL) or sham operations and were fed for 173 postoperative days a high-fat diet and given a 32% sucrose solution as drinking fluid. This was supplemented with chocolate chip cookies, potato chips and marshmallows. Other DMNL and sham-operated controls were fed lab chow instead of the above high-fat junk food diet (HFJF) and given tap water instead of 32% sucrose solution. All animals were killed on postoperative day 174. Caloric intake per 100 g body weight was similar in all groups; however, the HFJF fed control and DMNL rats had significantly elevated carcass fat. Since HFJF-DMNL rats were not nearly as obese as the HFJF control animals, it appears that the DMNL offered some protection against the HFJF-diet-produced obesity. When their smaller body size is considered. DMN lesions had no effect on brown adipose tissue (BAT) mass in chow-fed or HFJF fed rats, whereas BAT size was significantly enlarged in HFJF-fed control animals. This suggests but does not prove that HFJF-fed controls, but not DMNL rats, may be using dietary-induced thermogenesis (DIT) to attenuate their obesity. We hypothesize that the HFJF-fed DMNL may not be enhancing DIT as reflected in normal BAT size, because they had not attained a degree of fatness to activate this system, or the DMN lesions impaired its activation. Both HFJF-fed groups showed reduced linear growth compared to their counterparts. The reason for stunting is uncertain, but may be related to their low plasma insulin concentrations.

Somatic, endocrine and metabolic changes in controls pair-fed for six weeks to rats with dorsomedial hypothalamic nucleus lesions (DMNL rats)

One group of weanling male Sprague-Dawley rats received lesions in the dorsomedial hypothalamic nuclei (DMNL rats), whereas two additional groups of rats were sham-operated (CON). One of these CON groups was allowed to feed ad lib (CON-ADLIB) while the other CON group was pair-fed for 6 weeks to the DMNL rats (CON-PF). Despite eating the same amount of food as DMNL rats, CON-PF animals had consistently lower body weights and also utilized food energy more poorly than DMNL rats. The CON-PF group also had smaller kidneys and less percent liver protein but more epididymal fat pad percent protein than DMNL rats. Whereas plasma glucose concentrations were comparable among the three groups, insulin levels were significantly higher, and free fatty acid levels lower in CON-PF than in DMNL rats. The CON-PF group incorporated less glucose-U-C 14 carbon into liver glycogen but more of the tracer into liver lipid than the DMNL group. Glucose carbon was also incorporated more avidly into epididymal fat pad lipid by CON-PF than by DMNL rats. The data not only confirm previous findings in DMNL rats but in addition show that the neurologically intact rats fed the same amount of food that is eaten spontaneously by DMNL rats show somatic and metabolic alterations that suggest that they cannot cope with this low amount of substrate. The normalcy of the DMNL rats, compared to ad lib-fed sham-operated controls, in all metabolic parameters suggests that the low food intake is indeed “normal” for this preparation and may be the reflection of an “organismic” set point.

Production of Generalized Learning Deficit and Permanent Growth Stunting by Bilateral Brain Stem Lesions

Bilateral lesions of the globus pallidus, ventrolateral thalamus, substantia nigra, or the median raphe produce a generalized learning deficit in rats. Bilateral lesions of the dorsomedial hypothalamic nuclei stunt growth in rats without significantly disturbing endocrine functions and without producing a generalized learning deficit. Globus pallidus, ventrolateral thalamus, substantia nigra, median raphe, and dorsomedial hypothalamic nuclei lesions were produced in weanling Sprague-Dawley rats to compare their effect on physical growth. At approximately 72 d of age, all lesions had resulted in reduced body wt, tail length, and tibial length. The differences lacked significance only in body wt after median raphe lesions and tail length after ventrolateral thalamus lesions. In rats with the generalized learning deficit, body size was most stunted after substantia nigra lesions. Tibial epiphyseal width was modestly increased in rats with the generalized learning deficit. Food intake/average body wt ratio in substantia nigra and dorsomedial hypothalamic nuclei rats did not differ significantly from control values. Decreases in brain, heart, liver, kidney, and testes tended to occur after all the lesions, but brain and testis organ wt/body wt ratios were either increased or unchanged. We conclude that brain lesions producing a generalized learning deficit in rats result in impaired physical growth. The results indicated that the stunted animals maintain adequate food intake and have normal growth hormone function. The anatomical substrate for generalized learning impairment may overlap with that of a set point for body size.

Recovery of rats with dorsomedial hypothalamic nucleus lesions (DMNL rats) from body weight restriction: Effect of duration of postoperative prerestriction period

The present study was performed to see whether somatic and underlying metabolic-adaptive responses of DMNL rats and sham-operated controls (CON) to body weight restriction and subsequent refeeding could be influenced by the duration of ad lib feeding between lesion production and start of restriction. In contrast to previous studies (42 and 55 days, respectively) this time was reduced to 25 days. Restriction was similar, i.e., 27 days. DMNL rats show the same adaptive capacity in most parameters as do restricted CON. However, this response was at a lower level of absolute body weight, appropriate, so it appears, for their DMNL-induced lower body weight. In some parameters different responses were noted, however, suggesting that the time of ad lib feeding following the DMNL does indeed affect adaptive responses. Notably, this is the case in both DMNL and CON commensurately. Linear growth was reduced by restriction in the present but not in the two previous studies. Food intake showed a pronounced “overshoot” on refeeding but did not previously. Efficiency of food utilization was normal in the present study but depressed previously. A rise in plasma free fatty acids was not evident but was so in previous experiments. We concluded that, although DMNL rats respond to food restriction and recovery like similarly-treated CON, the duration of the ad lib feeding before restriction and/or the absolute age of the animals at that time, do indeed affect some parameters. This may be related to the fact that different aspects of the DMNL syndrome declare themselves in a sequential rather than a simultaneous manner.

Further evidence for the existence of an “organismic” set point in rats with dorsomedial hypothalamic nucleus lesions (DMNL rats): Normal catch-up growth

The present study was performed to assess the capacity of rats with dorsomedial hypothalamic nucleus lesions (DMNL rats) and sham-operated controls (CON) for catch-up growth following body weight (b.wt.) reduction prior to DMNL (and sham-lesion) production. Male SD rats (45 days, 157±1.3 g) were maintained for 11 days ad lib (ADLIB) after arrival and then divided into two groups. One group continued to feed ADLIB, the other group was fed half of the ration eaten by ADLIB rats for 32 days. At this point each group was divided into two subgroups. One subgroup received DMNL, the other subgroup consisted of CON. From then on all rats were fed ADLIB [except for one group of CON that was pair-fed to the ADLIB DMNL rats (PF-CON) for 37 days (69th day of experiment) and then killed. DMNL rats lesioned at normal b.wt. (ADLIB DMNL) showed a precipitous drop in food intake, b.wt. and efficiency of food utilization (EFU). In striking contrast, rats that had received DMNL after b.wt. restriction (REST DMNL) and were then refed ADLIB showed a dramatic rise in food intake, b.wt., change in b.wt. and EFU, the latter being almost twice that of the ADLIB DMNL. Notably, the PF-CON weighed less than the ADLIB CON and utilized food poorer than ADLIB CON, REST CON and ADLIB DMNL. Liver weight (both absolute and relative (per kg 3 4 b.wt.) was reduced in DMNL irrespective of dietary treatment. In contrast, testes weights were higher in ADLIB DMNL than in ADLIB CON in both absolute and relative terms; this difference was not evident in REST DMNL vs. REST CON. However, the testes of the PF-CON were heavier than those of the ADLIB. Weights of kidneys and epididymal fat pads were reduced in REST DMNL vs. REST CON but not in ADLIB DMNL vs. ADLIB CON. Relative weights were normal among the groups, as was carcass protein. Notably, the PF-CON group had less carcass fat than the REST CON, all other group values being comparable. Restriction of b.wt. prior to DMNL evidently promotes rapid adjustments that are almost identical in magnitude to those in CON. Despite reduced food intake and ponderal and linear growth, the DMNL rat is competent to regulate its new body weight and to adjust it after severe b.wt. reduction prior to lesion production. In conjunction with previous data this suggests the existence of an “organismic” set point.

Failure to demonstrate disruption of ultradian growth hormone rhythm and insulin secretion by dorsomedial hypothalamic nucleus lesions that cause reduced body weight, linear growth and food intake.

Weanling male rats received bilateral electrolytic lesions in the dorsomedial hypothalamic nuclei (DMNL rats); sham-operated animals served as controls. At the end of a 39-day postoperative period DMNL rats were lighter and shorter than controls and also exhibited significant hypophagia. Their efficiency of food utilization (weight gained for the amount of food eaten) was normal, however. Subsequent determination of plasma growth hormone (GH) and insulin (IRI) levels every 15 min for 6-h periods from freely moving chronically cannulated rats showed no differences in pulsatile patterns and peaks of GH nor in plasma IRI levels between DMNL rats and controls. There was also no significant difference between mean 6-H GH and IRI concentrations between the two groups. The reduced body weight, length and food intake are apparently unrelated to the normal GH and IRI secretory patterns. In conjunction with previous data indicating normal somatomedin activity and normal responses to various homeostatic challenges, the data make a strong case for the argument that DMNL rats are not "growth-retarded". Rather, they are normal animals that are "scaled-down" to a smaller size with maintenance of normal homeostatic capacity. This has been hypothesized to be due to the existence in these animals of an "organismic" set point.

Meal patterns of rats with dorsomedial hypothalamic nuclei lesions or sham operations

Rats with bilateral dorsomedial hypothalamic electrolytic lesions (DMNL rats) are hypophagic, hypodipsic and have reduced linear and ponderal growth when compared to sham operated controls (SCON). Nevertheless, previous studies have shown that DMNL rats eat and drink adequate amounts for their size and have normal body composition. In the present study we investigated meal parameters: meal size, and frequency (both light and dark period), total intake and meal size per metabolic size (body weight 0.75). Compared to SCON, DMNL rats at twelve days post surgery weighed less, were shorter, but had a normal body composition as determined by the Lee Index, and were hypophagic (grams eaten/day). The animals were placed into individual, self-contained feeding modules and given powdered chow. After familiarization to the modules, meal parameters were recorded continuously by a computer for an eight day period. While dark phase meal frequency did not differ significantly between groups, the lesioned rats took more meals during the light period. Over the eight-day measurement period DMNL rats were hypophagic compared to SCON in absolute terms. However, when total intake and meal size were normalized to metabolic size, these two parameters did not differ significantly between groups. Upon refeeding, after a one-day fast, the initial meal size of the normally hypophagic DMNL rats exceeded that of SCON. Rats with DMNL have previously been shown to have deficits in some hypothesized short-term food intake control mechanism (e.g., cholecystokinin, glucose sensing). Thus overeating by the lesioned rats after a fast could possibly result from a specific short term control deficit. Nevertheless, under ad lib conditions, except for a slight diurnal disruption in meal frequency, meal parameters were normal in the DMNL rats.

Body energy balance and food intake: a neuroendocrine regulatory mechanism.

Body energy balance and food intake: a neuroendocrine regulatory mechanism.

Water regulation in weanling hypodipsic dorsomedial hypothalamic-lesioned rats.

Weanling rats with dorsomedial hypothalamic nuclei lesions (DMN-L) are hypodipsic and hypophagic when compared to sham-operated rats. When tested for interdependence of food and water intake (WI) the DMN-L rats drank in the absence of food and ate in the absence of water. The data suggest DMN-L rats are not prandial drinkers. On testing for intracellular thirst (5.8 or 5.4% NaCl, 1 ml/100 g body wt), extracellular thirst [polyethylene glycol (PG), 25% wt/vol, 0.5 ml/35 g body wt], or a combination of both thirsts, the DMN-L rats responded as well or better than the control animals when the test data were expressed as a percentage of the rat's base-line WI. Both groups were more responsive to PG when tested in the light phase. When injected with angiotensin II (200 micrograms/100 g body wt) both groups responded similarly. Therefore, whereas the DMN-L rats were hypodipsic in comparison to controls, they respond as well or better than control animals when classical thirst testing procedures are utilized. It is suggested that DMN-L may have "reset" WI similarly to the previously proposed reset for body weight and food intake.

Effect of insulin in rats with lesions of the dorsomedial hypothalamic nucleus

Four hours after insulin injection Dorsomedial Hypothalamic Nuclei (DMN) lesioned rats consumed an amount of food that was comparable to that eaten by injected sham-operated animals. However, the DMN lesioned rats are not as initially responsive to the food intake stimulating properties of insulin as are the controls. A second study showed ad lib fed and fasted lesioned animals displayed a lower plasma glucose concentration after insulin challenge than did respectively treated controls. This suggests the initial insulin-induced feeding of the lesioned rats was blunted when compared to the controls even in the face of lower plasma glucose levels. Although a previous investigation revealed that DMN lesions destroy glucoreceptor tissue, the present data shows that DMN lesioned rats will increase their food intake in the face of insulin challenge, albeit their initial feeding response to insulin challenge is somewhat blunted. Finally, the present study confirms a previous report in that DMN lesioned rats can competently meter their 24 hour calorie intake.

The effect of dorsomedial hypothalamic nuclei lesions on body weight regulation

Prior to hypothalamic surgery 1 group of male rats was placed on a partial starvation regimen to lower their body weight. A second group was fed ad libitum. Just before surgery the 2 groups were divided into 2 sub groups. Bilateral electrolytic lesions were then placed in the dorsomedial hypothalamic nucleus in some of the partially starved and some of the ad libitum fed rats. The remaining animals were sham operated. After surgery all groups were fed ad libitum. Following hypothalamic operation the group that before surgery had been fed ad libitum showed the previously reported postoperative hypophagia and reduced body weight. On the other hand, the rats that were partially starved prior to placement of the lesion, ate significantly more than ad libitum fed lesioned animals during the first 9 days after surgery. The body weights of the partially starved, lesioned rats increased steadily from the day of the operation while lesioned rats fed ad libitum showed an initial delay of ponderal growth. The data suggest that the transient postoperative increase in food intake of the partially starved, lesioned rats is an active process to bring the body weight of these animals up to a new but lowered ‘body weight set point’ initiated by the hypothalamic destruction. Since previous studies had shown that rats with a lesion in the dorsomedial nucleus have a normal body composition, it is suggested that the lesions change the animals' ‘body weight set point’ and not the ‘body fat set point’, as has been suggested after ventromedial and lateral hypothalamic lesions.

Feeding responses of rats with dorsomedial hypothalamic lesions given ip 2DG or glucose.

The glucoprivation effects of 2-deoxy-D-glucose (2DG) on feeding behavior were studied in rats with bilateral lesions of the dorsomedial hypothalamic nucleus (DMN) and sham-operated controls. The lesioned and sham-operated rats were injected intraperitoneally with 2DG (5% wt/vol) at doses of either 150 mg/kg, 300 mg/kg, or 500 mg/kg, or with saline ("control days"). At all doses significantly more sham-operated rats ate and showed an increased food consumption during the first few hours after 2DG injection when compared to saline control days. However, their 24-h food consumption was normal or less than normal, depending on the dose of 2DG. On the other hand, rats with DMN lesions (DMN-L) did not increase their food consumption during the 4 h after the injection at any of the 2DG doses. In a second experiment DMN-L and sham-operated controls were injected intraperitoneally with glucose (1.36 g/kg body wt or 2.72 g/kg body wt) or saline after an overnight fast. Glucose loads, compared to saline injections, significantly depressed the controls' food consumption only during the first hour of refeeding. On the other hand, glucose injections did not depress food intake of the DMN-L rats. It is suggested that DMN lesions may have either destroyed glucoreceptors in the DMN that monitor glucose or the glucoprivation effects caused by 2DG and/or glucoreceptive pathways that pass through the DMN.