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.

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.

[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.

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.

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.

[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.

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

Lesión de los núcleos hipotalámicos ventromediales y secreción de insulina: correlaciones clínicas y experimentales / Ventromedial lesions and hypothalamically induced insulin release: clinical and experimental correlations

Los NHVM son un área de integración y comando de la liberación de GRF, de la sensación de saciedad y del tono simpático. Su lesión se traduce en una caída de GRF (y GH), predominando las AHL (parasimpático), con hiperinsulinismo, hiperfagia, lipogénesis acelerada, glicemia normal, lo que lleva a la constitución de un síndrome de obesidad hipotalámica. El crecimiento puede no ser afectado durante lapsos variables, aparentemente como consecuencia de la hiperinsulinemia

Hypothalamic obesity in the weanling rat: dietary self-selection, actual macro-nutrient intake, caloric regulation and response to subsequent low palatability diet.

Weanling male Sprague-Dawley rats received bilateral electrolytic lesions in the ventromedial hypothalamic nuclei (VMNL rats); sham-operated rats served as controls. For 28 post-operative d all animals were fed three equicaloric [16.9 kJ/g (4.03 kcal)] diets with different amounts of macronutrients in each (HCD = high-carbohydrate diet, HFD = high-fat diet and HPD = high-protein diet). VMNL rats selected more than controls from HCD (P less than 0.05) and HFD (P less than 0.01) but similar amounts from the HPD. The total intake from all three diets was greater (P less than 0.001) than that of the controls, but in percent of total diet intakes, VMNL selected proportions comparable to the controls. In terms of macronutient intake, VMNL rats ingested more than controls from each (carbohydrate, P less than 0.001; fat, P less than 0.05; protein, P less than 0.01). Again, in percent of total macronutrient intake, they ingested proportions comparable to the controls. Lee Index (P less than 0.001) was greater and body weight gain/kJ (kcal) smaller (P less than 0.001) in VMNL rats than in controls. However, body weight gains were normal. For the following 14 d, one group of VMNL rats and one control group continued to self-select from the three diets while another VMNL and control group received lab chow [14.2 kJ/g (3.39 kcal)]. Analysis of variance showed a lesion effect for the Lee Index (P less than 0.001) and Lee Index gain /kJ(kcal) (P less than 0.01) but body weight gains and caloric intake were normal among the groups, ie the VMNL rats switched to chow decreased their caloric intake to control levels. On sacrifice, white and brown fat percent protein (P less than 0.001 for both), carcass lipid (P less than 0.001) and protein (P less than 0.01) and plasma insulin (P less than 0.001) showed lesion effects, but there were no differences among the groups in plasma glucose, glycerol, total protein and free-fatty acids. Availability of palatable diets immediately following VMN lesion placement in weanling rats will result in hyperphagia that after one month recedes to normophagia, whether the rats are fed palatable or less palatable diets. Availability of a less palatable diet (chow) following presentation of palatable diets will not result in diminished caloric intake, body weight, obesity and hyperinsulinemia.