Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome X-like alterations in adulthood of neonatally overfed rats

Plagemann, Andreas; Harder, Thomas; Rake, Annett; Voits, Mechthild; Fink, Heidrun; Rohde, Wolfgang; Dörner, G

doi:10.1016/s0006-8993(99)01662-5

Cited by 306 publications

(254 citation statements)

References 58 publications

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“…This is similar to the result obtained in the 100-day-old OP rats after they had become obese (Experiment 2) and also similar to published evidence seen in prepubertal OP rats that had been raised in small litters or had already become obese. 54,55 While these peptides are known to be inhibited by a rise in leptin or insulin, 56 levels of these hormones were not consistently altered in the prepubertal OP rats of the present study, indicating that they are unlikely to play a major role in producing the reduction in NPY and AgRP. Since these peptides are also known to be suppressed by the consumption of a high-fat diet, 14,57 their role in stimulating the eating, weight gain and body fat accrual of prepubertal OP rats on this energy-rich diet remains unclear.…”

Section: Discussioncontrasting

confidence: 59%

Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight

et al. 2007

Int J Obes

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Objective: Male Sprague-Dawley rats maintained from birth on a high-fat diet were examined to determine whether a specific measure before puberty can identify and allow one to characterize prepubertal rats at normal weight with high vs low risk for adult obesity. Materials and methods: Measures from weaning (day 21) to around puberty (day 45) were taken of weight gain, absolute body weight and daily energy intake on a high-fat diet and related to the amount of body fat accumulated at maturity (80-100 days of age). Rats identified by a specific prepubertal measure as obesity-prone (OP) vs obesity-resistant (OR) were then characterized before and after puberty. Results: Prepubertal weight gain from days 30 to 35 of age was the strongest and earliest positive correlate of ultimate body fat accrual in adult rats. The highest (8-10 g/day) compared to lowest (5-7 g/day) weight-gain scores identified accurately and reproducibly distinct OP and OR subgroups at day 35 that became obese or remained lean, respectively, as adults. The OP rats with rapid prepubertal weight gain and 50% greater adiposity at maturity (day 100) exhibited the expected phenotype of already-obese rats. These included elevated levels of leptin, insulin, triglycerides and glucose, increased galanin (GAL) peptide levels in the paraventricular nucleus (PVN) and reduced neuropeptide Y (NPY) levels in the arcuate nucleus (ARC). Before puberty (day 35), the OP rats with normal fat pad weights, energy intake and endocrine profile similar to OR rats exhibited these disturbances characteristic of obese rats. They had decreased capacity for fat oxidation in muscle, increased GAL expression in PVN and reduced expression of NPY and agouti-related protein in ARC. Conclusion: Prepubertal weight gain can identify OP rats on day 35 when they have minimal body fat but exhibit specific metabolic and neurochemical disturbances expected to promote obesity and characteristics of already-obese adult rats.

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Section: Discussioncontrasting

confidence: 59%

Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight

et al. 2007

Int J Obes

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“…The litter effect on body weight was maintained for a period into adulthood (10 wk) in accord with previous studies (4,16,45), which have also shown increased fat mass and fat cell number as a result of early overnutrition. Our observations also show the development of hyperleptinemia but not hyperinsulinemia in the SL animals along with the greater body weight gain.…”

Section: Discussionmentioning

confidence: 87%

“…Reducing the number of pups per mother to 3-4 led to an early increase in body weight and fat mass compared with a normal litter of 10 -12 pups (4,16). Recent studies in rats indicate that overnutrition in the early postnatal period results in persisting hyperphagia, obesity, hyperleptinaemia, hyperinsulinaemia, impaired glucose tolerance, elevated triglycerides, and increased systolic pressure (45).…”

mentioning

confidence: 99%

Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers

Velkoska¹,

Cole²,

Morris³

2005

American Journal of Physiology-Endocrinology and Metabolism

118

109

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Early life nutrition impacts on subsequent risk of obesity and hypertension. Several brain chemicals responsible for both feeding and cardiovascular regulation are altered in obesity. We examined effects of early postnatal overnutrition on blood pressure, brain neuropeptide Y (NPY), and adiposity markers. Rat pup litters were adjusted to either 3 or 12 male animals (overnutrition and control, respectively) on day 1 of life. After weaning, rats were given either a palatable high-fat diet or standard chow. Smaller litter pups were significantly heavier by 17 days of age. By 16 wk, the effect of litter size was masked by that of diet, postweaning. Small and normal litter animals fed a high-fat diet had similar increases in body weight, plasma insulin, leptin, and adiponectin concentrations, leptin mRNA, and fat masses relative to chow-fed animals. An increase in 11␤-hydroxysteroid dehydrogenase-1 mRNA in white adipose tissue, and a decrease in uncoupling protein-1 mRNA in brown adipose tissue in both small litter groups at 16 wk of age, may represent a programming effect of the altered litter size. NPY concentration in the paraventricular nucleus of the hypothalamus was reduced in high fat-fed groups. Blood pressure was significantly elevated at 13 wk in high-fat-fed animals. This study demonstrates that overnourishment during early postnatal development leads to profound changes in body weight at weaning, which tended to abate with maturation. Thus the effects of long-term dietary intervention postweaning can override those of litter size-induced obesity.

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“…The hyperleptinaemia exhibited by the obese SL rats suggested that a state of leptin resistance might exist at the hypothalamic level [15][16][17][18], explaining the hyperphagia observed in this model [22,45,49]. In order to study this issue further, mRNA levels encoding the different leptin receptor isoforms were determined in the hypothalamus of NL, SL and LL rats.…”

Section: Discussionmentioning

confidence: 99%

A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat

et al. 2004

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Aim/hypothesis: Perinatal overfeeding predisposes humans and rats to obesity and diabetes in later life. One classical model for studying the effect of early feeding is manipulation of the size of rat litters. Rats growing up in small litters gain more weight than rats growing up in normal-sized litters. Interestingly, these obese rats maintain this phenotype in adulthood. Conversely, rats raised in large litters show a delay in growth and a decrease in body weight. The aim of this work was to assess the hypothalamic control mechanisms of food intake regulated by perinatal feeding. Methods: Leptin levels were analysed using RIA. Leptin receptor mRNA levels were analysed using RT-PCR. Neuropeptide mRNA levels were analysed using in situ hybridisation. Results: Perinatally overfed neonatal male rats exhibited hyperleptinaemia and a decrease in hypothalamic mRNA levels of the long isoform of the leptin receptor (OB-Rb), explaining their leptin resistance. Moreover, this obese model showed an increase in the mRNA expression of cocaine-and amphetamine-regulated transcript, neuropeptide Y and agouti-related protein in the hypothalamic arcuate nucleus (ARC). In contrast, perinatally underfed neonatal male rats with hypoleptinaemia showed an increase in hypothalamic mRNA of the short isoforms of the leptin receptor. Furthermore, they exhibited an increase in expression of neuropeptide Y and agoutirelated protein in the ARC. Conclusions/interpretation: Rats overfed during early postnatal life show a leptinresistant state mediated by down-regulation of the hypothalamic OB-Rb. These data, together with the increased expression of neuropeptide Y and agouti-related protein in specific neurons in the ARC, might indicate the existence of regulated programming in this nucleus and may provide a new aetiopathogenic concept in susceptibility to obesity.

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Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome X-like alterations in adulthood of neonatally overfed rats

Cited by 306 publications

References 58 publications

Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight

Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight

Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers

A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat

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