Maternal obesity and late effects on offspring metabolism.

OBJECTIVE: The aim of this study was to evaluate the late effects of maternal obesity induced by lesion of the ventromedial hypothalamus on offspring metabolism. MATERIALS AND METHODS: Thirty days after the bilateral lesion of the ventromedial hypothalamus, female rats were mated and divided into 2 groups of pregnant animals: Control (C) - false lesion (sham) and Obese (OB) - lesion. Three months after that, with the groups of mothers, offspring were divided into control and obese animals that received a normocaloric diet (C-N and OB-N), and control and obese animals that received a hypercaloric diet (C-H and OB-H). At 120 days of age, the animals were euthanized and their carcasses, feces and food were submitted to calorimetric analysis to determine energy balance and body composition. RESULTS: During the growth period, offspring from obese mothers showed higher values of body weight and food intake than controls. Obese animals showed higher body weight gain and gross food efficiency than control animals in adulthood. The hypercaloric diet led to increased metabolizable energy intake, percentage of absorbed energy and energy expenditure in both groups. Body composition was only affected by the association of hypercaloric diet and maternal obesity that led to increased body fat. CONCLUSIONS: Maternal obesity has led to the development of later overweight in offspring, suggesting fetal programming. According to the trend presented, it is believed that the prolonged intake of hypercaloric diets in adult animals may, as an additional effect, induce worsening of the overweight induced by maternal obesity.

Maternal obesity and late effects on offspring metabolism / Obesidade materna e efeitos tardios sobre o metabolismo da prole

Objective : The aim of this study was to evaluate the late effects of maternal obesity induced by lesion of the ventromedial hypothalamus on offspring metabolism.Materials and methods : Thirty days after the bilateral lesion of the ventromedial hypothalamus, female rats were mated and divided into 2 groups of pregnant animals: Control (C) – false lesion (sham) and Obese (OB) – lesion. Three months after that, with the groups of mothers, offspring were divided into control and obese animals that received a normocaloric diet (C-N and OB-N), and control and obese animals that received a hypercaloric diet (C-H and OB-H). At 120 days of age, the animals were euthanized and their carcasses, feces and food were submitted to calorimetric analysis to determine energy balance and body composition.Results : During the growth period, offspring from obese mothers showed higher values of body weight and food intake than controls. Obese animals showed higher body weight gain and gross food efficiency than control animals in adulthood. The hypercaloric diet led to increased metabolizable energy intake, percentage of absorbed energy and energy expenditure in both groups. Body composition was only affected by the association of hypercaloric diet and maternal obesity that led to increased body fat.Conclusions : Maternal obesity has led to the development of later overweight in offspring, suggesting fetal programming. According to the trend presented, it is believed that the prolonged intake of hypercaloric diets in adult animals may, as an additional effect, induce worsening of the overweight induced by maternal obesity. Arq Bras Endocrinol Metab. 2014;58(3):301-7.

Objetivo Avaliar os efeitos tardios da obesidade materna induzida por lesão do núcleo ventromedial do hipotálamo sobre o metabolismo da prole. Trinta dias após a lesão bilateral do hipotálamo ventromedial, ratos fêmeas foram colocadas para acasalar e divididas em dois grupos de animais gestantes: Controle (C) – falsa lesão e Obeso (OB) – lesionados. Três meses após o nascimento, de acordo com os grupos das mães, os filhotes foram divididos em animais controle e obesos que recebiam dieta normocalórica (C-N and OB-N) e animais controle e obesos que recebiam dieta hipercalórica (C-H and OB-H). Aos 120 dias de idade, os animais foram eutanasiados e as carcaças, fezes e ração foram submetidas à análise calorimétrica para determinação do balanço energético e composição corporal.Resultados Durante o período de crescimento, os filhos de mães obesas mostraram maiores valores de peso corporal e ingestão alimentar que animais controle. Os animais obesos apresentaram maiores valores de ganho de peso corporal e eficiência metabólica que os animais controle quando adultos. A dieta hipercalórica levou ao aumento da energia metabolizável, percentagem de energia absorvida e gasto energético para ambos os grupos. A composição corporal foi somente afetada pela associação da dieta hipercalórica com a obesidade materna que levou ao aumento da gordura corporal.Conclusões : A obesidade materna levou ao sobrepeso tardio na prole, sugerindo uma programação fetal. Pela tendência apresentada, acreditamos que a ingestão prolongada de dietas hipercalóricas em animais adultos possa induzir uma piora no quadro de sobrepeso induzido pela obesidade materna. Arq Bras Endocrinol Metab. 2014;58(3):301-7.

Relationships between ventromedial hypothalamic lesions and the expressions of neuron-related genes in visceral organs.

Although the ventromedial hypothalamus (VMH) is one of the centers of parasympathetic nervous system, to date, there has been little reported regarding the role of the hypothalamus in directly changing the expression of neuron-related genes in visceral organs. Recently it has been reported that VMH lesions can directly change the expression of neuron-related genes families in visceral organs. The present review focuses on the relationships between the central nervous system, including the VMH, and the expressions of neuron-related genes in visceral organs.

Studies of different female rat models of hypothalamic obesity.

Hypothalamic obesity (HO) is a major and unsolved problem in patients with medial hypothalamic lesions and is associated with hyperinsulinemia and hyperleptinemia. The purpose of this study was to create a rodent model that mimics metabolic changes in HO for use in therapeutic testing. Female Sprague-Dawley rats were used to test the individual and combined effects of two types of medial hypothalamic lesions: arcuate nucleus (ARC) lesions by injection of monosodium glutamate at neonatal age, and ventromedial nucleus (VMN) lesions by passing an anodal current through an electrode placed in the VMN at age 80 days. Adiposity in ARC-lesioned animals was associated with decreased food intake and stunted growth, while VMN lesions were associated with hyperphagia but not reduced growth. The greatest weight gain (weight at age 200 days 712 +/- 65 vs. 451 +/- 19 g in controls), hyperphagia (food intake 10 days following surgery 33 +/- 0.8 vs. 18.5 +/- 0.7 g/day in sham-treated rats), hyperinsulinemia and hyperleptinemia occurred in rats that received both ARC and VMN lesions. Thus, the combined medial hypothalamic lesions result in an obesity phenotype similar to that of patients that suffer from HO and are consequently more suitable for testing potential therapeutics for this disorder than lesions of single hypothalamic nuclei.

Gene expression profiling in rat pancreas after ventromedial hypothalamic lesioning.

OBJECTIVE: We previously reported that vagal hyperactivity produced by ventromedial hypothalamic (VMH) lesions stimulated cell proliferation of rat pancreatic islet B and acinar cells primarily through a cholinergic receptor mechanism. METHODS: This study examined how gene families involved in cell proliferation are regulated after VMH lesions formation. Total pancreatic RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and sham-VMH-lesioned rats were investigated using DNA microarray and real-time polymerase chain reaction. RESULTS: The VMH lesions regulated the genes that are involved in functions related to cellular growth and proliferation and neuronal development in the pancreas. Real-time polymerase chain reaction also confirmed that gene expressions of angiotensin II receptor-like 1 (AGTRL1) and proline rich 15 (PRR15) were down-regulated at day 3 after the VMH lesions. CONCLUSIONS: Ventromedial hypothalamic lesions may change the expression of cell proliferation-related genes and neuron-related genes in a rat pancreas.

Transforming growth factor-beta in the brain enhances fat oxidation via noradrenergic neurons in the ventromedial and paraventricular hypothalamic nucleus.

We have previously reported that intracisternal administration of TGF-beta induces an increase in fat oxidation and that intracisternal administration of anti-TGF-beta antibody partially inhibits an increase in fat oxidation during treadmill running in rats. These results indicate a regulatory role of that TGF-beta in the brain on fat oxidation during exercise. However, it is not clear how TGF-beta in the brain enhance fat oxidation. We hypothesized that TGF-beta in the brain elicits its regulatory effects on fat oxidation via hypothalamic noradrenergic neurons, because some reports have demonstrated the important role of hypothalamic noradrenergic neurons in the regulation of fat oxidation during and after exercise. To examine this hypothesis, we measured the extracellular noradrenaline (NA) levels in the paraventricular hypothalamic nucleus (PVH), ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area, which are especially important in the regulation of energy metabolism, after intracisternal administration of TGF-beta by using an in vivo brain microdialysis. Microdialysis study revealed that intracisternal administration of TGF-beta3 caused increases in the NA levels in the PVH and VMH. Then, we investigated the impact of impairment of noradrenergic neurons in the PVH and VMH by neurotoxin 6-hydroxydopamine microinjection (NA-lesion) on the action of intracisternal administration of TGF-beta. The NA lesion completely abolished the regulatory effect of TGF-beta on fat oxidation. These results suggest that TGF-beta in the brain enhances fat oxidation via noradrenergic neurons in the PVH and VMH.

Inhibition of lesion-induced neurogenesis impaired behavioral recovery in adult ring doves.

We have previously shown that electrolytic lesion-induced neurogenesis in the ventromedial nucleus of the hypothalamus (VMN) is significantly correlated with the recovery of courtship behavior in adult male ring doves. Here we revealed that reduction of lesion-induced neurogenesis in VMN impaired the behavioral recovery suggesting therefore a causal link between neurogenesis and behavioral recovery. Our results lend support that adult neurogenesis is latent in repair of injured brain.

[Experimental model to induce obesity in rats]. / Modelo experimental para induzir obesidade em ratos.

The etiology of obesity is multifactorial and is becoming a problem of public health, due to its increased prevalence and the consequent repercussion of its comorbidities on the health of the population. The great similarity and homology between the genomes of rodents and humans make these animal models a major tool to study conditions affecting humans, which can be simulated in rats. Obesity can be induced in animals by neuroendocrine, dietary or genetic changes. The most widely used models to induce obesity in rats are a lesion of the ventromedial hypothalamic nucleus (VMH) by administering monosodium glutamate or a direct electrical lesion, ovariectomy, feeding on hypercaloric diets and genetic manipulation for obesity.

Acetylcholinesterase activity changes on visceral organs of VMH lesion-induced obese rats.

It is accepted that the tone of the parasympathetic nervous system increases after VMH lesion, whereas the sympathetic tone decreases. To reinforce investigations over outcomes from disturbances of the hypothalamic neuronal systems on peripheral autonomic nerve activity this study determined the acetylcholinesterase (AchE) activity in visceral organs, known as vagal targets, from VMH-lesioned obese rats. It was found that AchE activity was significantly increased in liver, pancreas, and stomach from these animals. However, it was not changed in kidneys, being decreased in spleen. The results suggest that AchE activity is enhanced in vagus innervated tissues to following up the unbalance of the autonomic nervous system as observed in VMH lesion-induced obesity.

Lesion-induced neurogenesis in the hypothalamus is involved in behavioral recovery in adult ring doves.

Although neurogenesis in the brain of adult vertebrates is region dependent, lesion induces generation of new neurons in non-neurogenic brain regions. These findings raise the question of the role of new neurons in brain repair and functional recovery. We addressed this question by applying previous observations that electrolytic lesion induced neurogenesis in the ventromedial nucleus (VMN) of the hypothalamus in adult ring doves. Such lesions disrupted the male's courtship behavior, which could be reinstated after rehabilitation with a female. We investigated whether lesion-induced newborn neurons in the VMN facilitate the recovery of courtship behavior in the lesioned birds. We conducted systematic observations of cytological, morphological, and neuroanatomical changes in the lesioned VMN, and concurrently we monitored behavioral changes. Using a multitude of specific cell markers, we found a well-circumscribed cellular zone that proliferated actively. This highly proliferative zone initially appeared along the periphery of the lesion site, where cells had high levels of expression of neuronal, glial, and neurovascular markers. As newborn neurons matured at the lesion site, the necrosis gradually decreased, whereas a downsized proliferative zone relocated to a region ventral to the VMN. Some of the mature neurons were found to project to the midbrain vocal nuclei. Restoration of these projection neurons coincided with the recovery of courtship vocalization. Finally, we found that a social factor, that is, when the male doves were cohoused with a mate, facilitated neurogenesis and behavioral recovery. These results suggest that lesion-induced neurogenesis contributes to behavioral recovery in adult animals.

Microlesions of the ventromedial nucleus of the hypothalamus: effects on sociosexual behaviors in male rats.

Electrolytic microlesions aimed at the dorsomedial portion of the ventromedial nucleus (VMN) of the hypothalamus were generated, and effects on copulation, 50-kHz vocalizations, scent marking, and sexual motivation were measured. Male rats were tested before and after lesions, after castration, and after testosterone replacement. Three control groups were used: One received sham surgery, another received no surgery or testosterone replacement, and a 3rd received lesions primarily outside the VMN. VMN lesions produced impairments in testosterone's ability to restore ultrasonic vocalizations and scent marking, assessed with 2 different test methods. Copulation, sexual motivation, and weight gain were largely unaffected, although some differences were observed in copulatory efficiency. The authors conclude that the integrity of the VMN is important for full expression of sociosexual behaviors in male rats.

Functional restoration of acoustic units and adult-generated neurons after hypothalamic lesion.

The hypothalamus of the adult ring dove contains acoustic units that respond to species-specific coo vocalization. Loss of nest coo leads to unsuccessful breeding. However, the recovery of nest coo in some doves suggests that these units are capable of self-renewal. We have previously shown that lesioning the hypothalamus generates the addition of new neurons at the lesioned area. In this study, we sought to determine whether lesion-induced new neurons are involved in the recovery of coo-responsive units. We systematically recorded electrical activity in the ventromedial nucleus (VMN) of the hypothalamus, before and after lesion, for varying periods up to 3 months. Recordings were made when the birds were at rest (spontaneous discharge) and when the birds were exposed to acoustic stimulations (evoked discharge). Concurrently, the lesioned area was monitored for changes in cell types by using bromodeoxyuridine (BrdU) to label newly divided cells and NeuN to identify mature neurons. For 1 month after lesion, there was no sign of electrical activity, and only BrdU-labeled cells were present. When the first electrical activity occurred, it displayed abnormal spontaneous bursting patterns. The mature discharge patterns (both spontaneous and evoked) occurred after detection of BrdU+/NeuN+ double-labeled cells 2-3 months postlesion and were similar to those found in intact and sham-lesioned birds. Double-labeled cells bore morphologic characteristics of a neuron and were confirmed with z-stack analysis using confocal laser scanning microscopy. Moreover, double-labeled cells were not stained for glial fibrillary acidic protein (GFAP), suggesting that they were neurons. The number of coo-responsive units was significantly correlated with that of BrdU+/NeuN+ cells. Furthermore, the marker for recording sites revealed that coo-responsive units were colocalized with BrdU+/NeuN+ cells. Taken together, the evidence strongly suggests that lesion-induced addition of new neurons promotes the functional recovery of the adult hypothalamus.

Conducta pseudopsicopática y lesiones cerebrales / Pseudopsychopathic behaviour and brain injuries

Ya en el siglo XIX aparece la primera y más famosa referencia a cambios de conducta social secundarios a lesiones frontales, se trata del famoso caso de Phineas Gage. Durante el siglo XX diversas descripciones de casos de lesión cerebral centran en la región frontal orbital o ventromedial el síndrome de pseudopsicopatía o de sociopatía adquirida. Este síndrome se caracteriza por pérdida de la conducta socialmente adecuada con irritabilidad, agresividad ocasional, desorganización de la conducta, alteración de la toma de decisiones, egocentrismo, desinhibición e incluso conductas delictivas. Este patrón aparece en adultos que han sufrido una lesión en esta región prefrontal. Cuando las lesiones se dan en la primera infancia las características son aún más destacadas, con alteración del razonamiento moral y falta de culpabilidad hacia las propias acciones. Este síndrome conductual puede ir acompañado de rendimiento intelectual y prefrontal cognitivo absolutamente normal, sobre todo en lesiones adultas. En el caso de lesiones infantiles acostubran a aparecer trastornos cognitivos frontales variables (AU)

Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling.

Liver-derived hyperleptinemia induced in normal rats by adenovirus-induced gene transfer causes rapid disappearance of body fat, whereas the endogenous adipocyte-derived hyperleptinemia of obesity does not. Here we induce liver-derived hyperleptinemia in rats with adipocyte-derived hyperleptinemia of acquired obesity caused by ventromedial hypothalamus lesioning (VMH rats) or by feeding 60% fat (DIO rats). Liver-derived hyperleptinemia in obese rats caused only a 5-7% loss of body weight, compared to a 13% loss in normoleptinemic lean animals; but in actual grams of weight lost there was no significant difference between obese and lean groups, suggesting that a subset of cells remain leptin-sensitive in obesity. mRNA and protein of a putative leptin-resistance factor, suppressor of cytokine signaling (SOCS)-1 or -3, were both increased in white adipose tissues (WAT) of VMH and DIO rats. Since transgenic overexpression of SOCS-3 in islets reduced the lipopenic effect of leptin by 75%, we conclude that the increased expression of SOCS-1 and -3 in WAT of rats with acquired obesity could have blocked leptin's lipopenic action in the leptin-resistant WAT population.

Effects of intraventricular administration of neuropeptide Y on feeding behavior in fasted female rats with ventromedial hypothalamic lesions.

The role of ventromedial hypothalamic nucleus (VMN) in feeding behavior induced by central administration of porcine neuropeptide Y (NPY) in fasted female rats was investigated focusing on the effect of the intracerebroventricular (i.c.v.) injection of NPY on food intake in rats with VMN lesions after 24 h of food deprivation. Cumulative food intake was measured 1, 3 and 6 h after injection. In Exp. 1, the i.c.v. injection of NPY into intact rats stimulated food intake compared with the injection of saline 1 and 3 h after the injections in a dose dependent manner (1 h; NPY 1 microgram, 3.29 +/- 0.43, 2 micrograms, 4.64 +/- 0.88, 5 micrograms, 5.15 +/- 0.61 vs. saline 2.48 +/- 0.42 g, P < 0.05 in 2 and 5 micrograms). 5 micrograms of NPY significantly stimulated food intake 6 h later. In Exp. 2, i.c.v. injection of NPY (2 micrograms) in VMN-lesioned rats showed no significant effect on food intake compared with the injection of saline 3 weeks after VMN lesioning (1 h; NPY 2 micrograms, 2.46 +/- 0.58 vs. saline 2.39 +/- 0.12 g). These results suggest that central administration of NPY enhances food intake in fasted female rats and that the VMN is one of the crucial sites of NPY induced feeding.

[Development of complete liver cirrhosis in hyperphagia-induced fatty liver]. / Entwicklung einer kompletten Lebercirrhose bei Hyperphagie-bedingter Fettleber.

The progression of alimentary fatty liver to liver cirrhosis is a very rare observation. During the year after surgical extirpation of a suprasellar craniopharyngioma in a seven years old boy developed severe obesity and again six years later at autopsy a complete liver cirrhosis with fatty liver was established. Injury of the ventromedial hypothalamic nuclei and resulting hyperphagia is the reason for the obesity following suprasellar tumours. The pathogenesis of liver cirrhosis following alimentary fatty liver is not completely evident up to now, such a progression is possible--as shown in this case--also in children and within a short period.

[Role of the ventromedial nucleus of the rats thalamus in food-procuring movements]. / Rol ventromedialnogo iadra talamusa shchuriv v organizatsii izhodobuvnykh rukhiv.

The characteristics of ballistic food-procuring movements were studied in albino rats. After electrolytic destruction of ventromedial nucleus of thalamus (VM) of contralaterally preferred extremity the number of attempts and frequency of movements were determined to increase with a decrease of their duration. The restoration of parametres of movements took place during a week. A phase structure of movements also undergoes some modifications: in the case of invariance of initial ballistic components, conditioned by strict links of programme one-side switching off of VM tells on the following components, subject to correction. Re-teaching, requiring the modification of motor programme caused considerable difficulties in rats with switched off VM. The obtained results illustrate the significance of rats' VM in the formation and realization of motor programmes.

Body weight gain after VMH lesions in adult female rats guanethidine-sympathectomized at birth.

The role of the sympathetic nervous system in body weight gain produced by lesions of the ventromedial nucleus of the hypothalamus (VMH) was studied in adult female rats that had been sympathectomized from birth for 3 weeks with daily injections of guanethidine (0.01 ml/g body weight) starting the second day after birth. Female littermates injected with 0.15 M NaCl served as controls. Body weight gain during the dynamic phase after the VMH lesion was the same in the sympathectomized and control groups of rats, whereas the treated rats gained weight at a slower rate than the controls in the static phase. The increase in food intake stimulated by the VMH lesion peaked sooner and remained elevated longer in the controls than in the experimental animals despite the similar increases in body weight gain. These results indicate that the sympathetic nervous system may play an important role in body weight gain during the static phase following a VMH lesion in adulthood.

Relación entre las lesiones electrolíticas del núcleo hipotalámico ventromedial y la diabetes mellitus insulino dependiente inducida por streptozotocina

Dada la función reguladora del sistema nervioso sobre el endocrino se busca analizar la correlación entre la lesión del núcleo hipotalámico ventromedial (HVM) y la severidad de la diabetes inducida por estreptozotocina (STZ). Se utilizan 29 ratas divididas en cuatro grupos: Grupo I: lesión del HVM e inyección de SS (murieron por complicaciones respiratorias); Grupo III: lesión del HVM e inyección de STZ; Grupo IV: lesión ficticia del HVM e inyección de STZ. Se observan por un período de 6 a 8 semanas. Se exploran semanalmente valores de química sanguínea como glicemia, colesterol y triglicéridos y se mide el peso corporal; cada dos días se determina el consumo de agua y en el momento del sacrificio se pesa la grasa perirrenal y se fijan los cerebros para determinar tamaño y sitio de la lesión. Los resultados muestran que el grupo III es el más afectado en cuanto a severidad de la diabetes y velocidad de deterioro de los animales; mientras que el grupo I sólo muestra aumento de peso corporal pero sin evidencia de diabetes. Todo parece indicar que el aumento de la ingesta inducido por la lesión del "núcleo de la sacidad" y por la misma diabetes produce efectos aditivos sobre el cuadro patológico

Morphological alterations of the rat submandibular gland caused by lesion of the ventromedial nucleus of the hypothalamus

As características morfológicas da glândula submandibular de ratos foram estudadas em diferentes períodos de tempo (5, 10, 20, 40 e 90 dias) após a lesäo do núcleo ventromedial do hipotálamo. O arranjo estrutural da glândula submandibular foi o mesmo em ratos com lesäo do núcleo ventromedial e nos ratos controle ou com lesäo fictícia. No primeiro grupo, entretanto, o septo estava estreito, dificultando a definiçäo dos compartimentos lobulares. Alteraçöes do parênquima foram bastante evidentes nos ratos lesados, com hipotrofia acinar e aumento no número de ductos granulosos. Os componentes submandibulares restantes, entretanto, näo apresentaram alteraçöes quando comparados com aqueles dos animais controles. Em resumo, a lesäo do núcleo ventromedial do hipotálamo produz as seguintes mudanças na glândula submandibular do rato: 1) diminuiçäo da massa glandular; 2) hipotrofia acinar; e 3) aumento no número de ductos granulosos