Dorsomedial Hypothalamic Lesions Research Articles

Dorsomedial hypothalamic lesions counteract decreases in locomotor activity in male Syrian hamsters transferred from long to short day lengths.

The dorsomedial nucleus (DMN) of the hypothalamus has been implicated in seasonal control of reproduction. Syrian hamsters with DMN lesions, unlike control hamsters, do not undergo testicular regression after transfer from a long day length (14 h of light per day; LD) to a short day length (8 h of light per day; SD). SDs also markedly reduce hamster locomotor activity (LMA). To assess whether the DMN is a component of the neural circuitry that mediates seasonal variation in LMA, neurologically intact males (controls) and hamsters that had sustained lesions of the DMN (DMNx) were housed in an LD or SD photoperiod for 26 weeks. DMNx that prevented testicular regression counteracted decreases in LMA during 8 to10 weeks of SD treatment; steroid-independent effects of SDs did not override high levels of LMA in DMNx males. As in previous studies, testosterone (T) restoration increased LMA in LD but not SD castrated control males. In the present study, T also failed to increase LMA in SD-DMNx hamsters. The DMN is not necessary to maintain decreased responsiveness of locomotor activity systems to T in SDs, which presumably is mediated by other central nervous system androgen target tissues. Finally, DMNx did not interfere with the spontaneous increase in LMA exhibited by photorefractory hamsters after 26 weeks of SD treatment. We propose that DMN is an essential part of the substrate that mediates seasonal decreases in LMA as day length decreases but is not required to sustain decreased SD responsiveness to T or for development of refractoriness to SDs.

Dorsomedial Hypothalamic Lesions Block Syrian Hamster Testicular Regression in Short Day Lengths Without Diminishing Increased Testosterone Negative-Feedback Sensitivity1

The dorsomedial nucleus (DMN) of the hypothalamus, the only site within the mediobasal hypothalamus of Syrian hamsters that both binds melatonin and has abundant concentrations of androgen receptors, has been proposed as a target tissue for induction of seasonal changes in brain sensitivity to steroid negative feedback. We tested whether DMN ablation, which does not interfere with pineal gland secretion of melatonin in short day lengths, prevents testicular regression by altering sensitivity to steroid negative feedback. Hamsters with DMN lesions, unlike control hamsters, failed to undergo testicular regression after transfer from a long (14 h light/day) to a short day length (8 h light/day); however, increased negative-feedback inhibition of follicle-stimulating hormone by testosterone was not compromised by ablation of the DMN, indicating that this tissue is not an essential mediator of seasonal changes in feedback sensitivity. We propose a redundant neural network comprised of multiple structures, each of which contributes to neuroendocrine mechanisms, that determines the effect of short days on gonadal function.

Evidence for Time-of-Day Dependent Effect of Neurotoxic Dorsomedial Hypothalamic Lesions on Food Anticipatory Circadian Rhythms in Rats

The dorsomedial hypothalamus (DMH) is a site of circadian clock gene and immediate early gene expression inducible by daytime restricted feeding schedules that entrain food anticipatory circadian rhythms in rats and mice. The role of the DMH in the expression of anticipatory rhythms has been evaluated using different lesion methods. Partial lesions created with the neurotoxin ibotenic acid (IBO) have been reported to attenuate food anticipatory rhythms, while complete lesions made with radiofrequency current leave anticipatory rhythms largely intact. We tested a hypothesis that the DMH and fibers of passage spared by IBO lesions play a time-of-day dependent role in the expression of food anticipatory rhythms. Rats received intra-DMH microinjections of IBO and activity and body temperature (T b) rhythms were recorded by telemetry during ad-lib food access, total food deprivation and scheduled feeding, with food provided for 4-h/day for 20 days in the middle of the light period and then for 20 days late in the dark period. During ad-lib food access, rats with DMH lesions exhibited a lower amplitude and mean level of light-dark entrained activity and T b rhythms. During the daytime feeding schedule, all rats exhibited food anticipatory activity and T b rhythms that persisted during 2 days without food in constant dark. In some rats with partial or total DMH ablation, the magnitude of the anticipatory rhythm was weak relative to most intact rats. When mealtime was shifted to the late night, the magnitude of the food anticipatory activity rhythms in these cases was restored to levels characteristic of intact rats. These results confirm that rats can anticipate scheduled daytime or nighttime meals without the DMH. Improved anticipation at night suggests a modulatory role for the DMH in the expression of food anticipatory activity rhythms during the daily light period, when nocturnal rodents normally sleep.

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.

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.

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.

Faster gastric emptying of a liquid meal in rats after hypothalamic dorsomedial nucleus lesion.

The effects of dorsomedial hypothalamic (DMH) nucleus lesion on body weight, plasma glucose levels, and the gastric emptying of a liquid meal were investigated in male Wistar rats (170-250 g). DMH lesions were produced stereotaxically by delivering a 2.0-mA current for 20 s through nichrome electrodes (0.3-mm tip exposure). In a second set of experiments, the DMH and the ventromedial hypothalamic (VMH) nucleus were lesioned with a 1.0-mA current for 10 s (0.1-mm tip exposure). The medial hypothalamus (MH) was also lesioned separately using a nichrome electrode (0.3-mm tip exposure) with a 2.0-mA current for 20 s. Gastric emptying was measured following the orogastric infusion of a liquid test meal consisting of physiological saline (0.9% NaCl, w/v) plus phenol red dye (6 mg/dl) as a marker. Plasma glucose levels were determined after an 18-h fast before the lesion and on the 7th and 15th postoperative day. Body weight was determined before lesioning and before sacrificing the rats. The DMH-lesioned rats showed a significantly faster (P < 0.05) gastric emptying (24.7% gastric retention, N = 11) than control (33.0% gastric retention, N = 8) and sham-lesioned (33.5% gastric retention, N = 12) rats, with a transient hypoglycemia on the 7th postoperative day which returned to normal by the 15th postoperative day. In all cases, weight gain was slower among lesioned rats. Additional experiments using a smaller current to induce lesions confirmed that DMH-lesioned rats had a faster gastric emptying (25.1% gastric retention, N = 7) than control (33.4% gastric retention, N = 17) and VMH-lesioned (34.6% gastric retention, N = 7) rats. MH lesions resulted in an even slower gastric emptying (43.7% gastric retention, N = 7) than in the latter two groups. We conclude that although DMH lesions reduce weight gain, they do not produce consistent changes in plasma glucose levels. These lesions also promote faster gastric emptying of an inert liquid meal, thus suggesting a role for the DMH in the regulation of gastric motility.

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.

Neurons in the hypothalamic paraventricular nucleus mediate the serotonergic stimulation of renin secretion

The aim of the present study was to resolve which hypothalamic nucleus is necessary for the serotonergic control of renin secretion. RU 24969 is considered a serotonin (5-HT 1A/5-HT 1B) agonist, while p-chloramphetamine is a 5-HT releaser. Both drugs reliably elevate plasma levels of renin when injected peripherally. Previous studies suggest that serotonergic neurons, projecting to the hypothalamus, mediate the effect of p-chloroamphetamine on renin secretion. Discrete cell-selective lesions were made with ibotenic acid in three hypothalamic sites: the paraventricular, the dorsomedial or the ventromedial nuclei. Two weeks after surgery rats were injected with RU 24969 (5 mg/kg, i.p.) or p-chloroamphetamine (8 mg/kg, i.p.). The renin response to both RU 24969 and p-chloroamphetamine was significantly reduced in rats with histologically verified paraventricular lesions compared to vehicle treated controls. In contrast, the renin response to p-chloroamphetamine remained unchanged in rats with either dorsomedial or ventromedial hypothalamic lesions. Thus, these results are consistent with the hypothesis that 5-HT receptors located on cell bodies in the paraventricular nucleus mediate the renin response to a serotonin agonist and releaser. Furthermore, they confirm previous studies that suggest that 5-HT neurons regulate renin secretion through central receptors.

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.

Growth hormone secretion and ultradian rhythms in growth-retarded rats with dorsomedial hypothalamic lesions

Rats with lesions of the dorsomedial nucleus of the hypothalamus (DMN-L) are hypophagic and have reduced linear growth and body weight, but normal body composition. Male Sprague-Dawley rats (170–190 g) housed individually under a 12:12 L:D schedule with lights out at 1430 hr received jugular cannulas, and on return to precannulation body weight (4.2±0.6 days), they received bilateral electrolytic DMN-L or sham-operations (SHAM). Rats with DMN-L (n=8) were hypophagic postsurgery and weighed less ( p<0.05) than SHAM at six days postlesion surgery. The difference in body weight between the two groups continued to expand over the next four weeks. Six days postsurgery, the rats were bled (RBC's returned in 10% BSA-saline) every 15 minutes between 0600–1215 hr and growth hormone (GH) subsequently assayed. The total GH secretion, as computed from the area under each rat's ultradian pattern, was similar in both groups (DMN-L versus SHAM, 2952.2±346.5 versus 2950.4±337.5). Using the PULSAR computer program, the baseline secretion (12.2±4.0 versus 11.8±2.7 ng/ml), total number of peaks (2.4±0.4 versus 2.4±0.2), and interpeak interval (2.8±0.5 versus 2.7±0.4, hr) were not significantly different between the DMN-L and SHAM rats, respectively. These data show that the growth-retarded DMN-L rat does not have a deficiency in total growth hormone secretion or an altered ultradian pattern, at a time when their body weight is diverging from the sham-operated controls. These data give further support to the previously suggested concept of a DMN-L reduced change in body weight ‘set-point’ or the alteration of an, as yet, undefined growth factor.

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.

Pair-feeding of sham-operated controls to rats with dorsomedial hypothalamic lesions: New evidence for an ‘organismic’ set point

Weanling male Sprague-Dawley rats received electrolytic lesions in the dorsomedial hypothalamic nuclei (DMNL rats) and sham operations, respectively, and were maintained on lab chow ad libitum for 23 days (Expt. 1) and 55 days (Expt. 2). Following this period, one group of sham-operated controls was pair-fed to the DMNL rats, which were hypophagic compared to a second sham-operated group that was fed ad libitum. This period lasted 27 days (Expt. 1) and 24 days (Expt. 2). Although pair-fed controls were heavier than DMNL rats, they showed normal food utilization (EFU) in Expt. 1 and reduced EFU in Expt. 2. Pair-fed controls also had decreased carcass fat, hypoglycemia, hypoinsulinemia, hypotriglyceridemia and enhanced in vitro epididymal fat pad glucose oxidation when compared to DMNL rats. These data suggest that pair-fed controls cannot cope as efficiently with the reduced influx of substrate as do DMNL rats. Evidently, the reduced amount of food the DMNL rats spontaneously eat is adequate for their reduced body size, whereas this is not the case in the pair-fed controls. This is taken as evidence for a harmonious readjustment by DMN lesions of both body size and food intake and the underlying homeostatic processes and supports our concept of an ‘organismic’ set point that has been released by the DMN lesions.

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.