Overweight and metabolic and hormonal parameter disruption are induced in adult male mice by manipulations during lactation period.
ABSTRACT Neonatal manipulations (10 min of maternal separation plus s.c. sham injection, daily for the first 21 d of life) determine overweight in male adult mice. In this work, we investigated the mechanisms underlying mild obesity and the alteration of caloric balance. Neonatally manipulated mice become overweight after onset of maturity, showing increased fat tissue and hypertrophic epididymal adipocytes. Increase in body weight occurs in the presence of a small increase in daily food intake (significant only in the adult period) and the absence of a decrease in spontaneous locomotor activity, while the calculated caloric efficiency is higher in manipulated mice, especially in adulthood. Fasting adult animals show hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and hyperleptinemia. Soon after weaning and in the adulthood, plasma corticosterone and adrenocorticotropin (ACTH) are also significantly increased. Thus, neonatal manipulations in nongenetically susceptible male mice program mild obesity, with metabolic and hormonal alterations that are similar to those found in experimental models of diabetes mellitus, suggesting that this metabolic derangement may have at least part of its roots early on in life and, more interestingly, that psychological and nociceptive stimuli induce these features.
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ABSTRACT: Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans and it blocks the action of insulin in cultured cells and whole animals. To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFalpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.Nature 11/1997; 389(6651):610-4. · 38.60 Impact Factor
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ABSTRACT: Two separate lines--diabetic and partially diabetes-resistant--have been isolated from the sand rat (Psammomys obesus), each with different growth characteristics in response to diets of varying digestible caloric densities (high energy, HE, 2.93 kcal/g, or low energy, LE, 2.38 kcal/g). Over a two week period all animals consumed similar quantities (c. 125 g) irrespective of the diet consumed. Weight gains were as follows: diabetic line on HE diet - 59.7 g, on LE - 46.2 g; non-diabetic animals from the diabetes-resistant line on HE - 44 g. Only animals from the diabetic line, fed the HE diet, developed hyperinsulinemia, obesity and diabetes. The energy cost of weight gain for the diabetic line fed either HE or LE diets was 6.0 - 6.3 kcal/g whereas for the diabetes-resistant line on the HE diet, the cost of growth was 50% higher at 9.3 kcal/g. These differences could be due either to alterations in the content of tissue laid down or to differences in energy expenditure. It has already been established that diet-induced obesity and diabetes develop in the diabetic line with features typical of insulin resistance in the metabolism of the pancreas, liver and peripheral tissues. Some of the animals of the diabetes-resistant line may also develop diabetes over a long time period and go through a phase of transient hyperinsulinemia-normoglycemia. This may represent an intermediate stage in the development of the diabetic syndrome and serve as a model of type 2 diabetes in man.Journal of basic and clinical physiology and pharmacology 4(1-2):57-68.
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ABSTRACT: The main characteristic of the postnatal development of the stress system in the rat is the so-called stress hypo-responsive period (SHRP). Lasting from postnatal day (pnd) 4 to pnd 14, this period is characterized by very low basal corticosterone levels and an inability of mild stressors to induce an enhanced ACTH and corticosterone release. During the last years, the mouse has become a generally used animal in stress research, also due to the wide availability of genetically modified mouse strains. However, very few data are available on the ontogeny of the stress system in the mouse. This study therefore describes the postnatal ontogeny of peripheral and central aspects of the hypothalamic-pituitary-adrenal (HPA) axis in the mouse. We measured ACTH and corticosterone in blood and CRH, urocortin 3 (UCN3), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) transcripts in the brain at postnatal days 1, 2, 4, 6, 9, 12, 14 and 16. Our results show that we can subdivide the postnatal development of the HPA axis in the mouse in two phases. The first phase corresponds to the SHRP in the rat and lasts from right after birth (pnd 1) until pnd 12. Basal corticosterone levels were low and novelty exposure did not enhance corticosterone or ACTH levels. This period is further characterized by a high expression of CRH in the paraventricular nucleus (PVN) of the hypothalamus. Expression levels of GR in the hippocampus and UCN3 in the perifornical area are low at birth but increase significantly during the SHRP, both reaching the highest expression level at pnd 12. In the second phase, the mice have developed past the SHRP and were now exhibiting enhanced corticosterone basal levels and a response of ACTH and corticosterone to mild novelty stress. CRH expression was decreased significantly, while expression of UCN3 and GR remained high, with a small decrease at pnd 16. The expression of MR in the hippocampus was very dynamic throughout the postnatal development of the HPA axis and changed in a time and subregion specific manner. These results demonstrate for the first time the correlation between the postnatal endocrine development of the mouse and gene expression changes of central regulators of HPA axis function.International Journal of Developmental Neuroscience 06/2003; 21(3):125-32. · 2.69 Impact Factor