Hypothalamic-pituitary-adrenal axis function in the Zucker obese rat.

Plotsky, PM; Thrivikraman, K. V.; Watts, Alan G.; Hauger, Richard L.

doi:10.1210/endo.130.4.1312431

Cited by 45 publications

(33 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These observations have led to the hypothesis that the actions of corticosterone in obesity are due to an inhibitory action on central CRH, especially in the hypothalamic nuclei that are involved in the integration of both endocrine and autonomic nervous system function in relation to energy balance [43,44]. Specifically in the fa/fa rat, it was concluded that lower CRH tone in the hypothalamus is due to defects in regulation of the HPA axis proximal to the region of the CRH system that mediates feedback inhibition of corticosterone secretion because the pituitaryadrenal axis had normal response to a CRH challenge [44]. It then follows that the beta-cell biochemical defects observed in 5-week-old fa/fa rats might be under the control of an already abnormally-regulated HPA axis [45].…”

Section: Discussionmentioning

confidence: 99%

Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats

Kibenge

Chan

1996

Diabetologia

View full text Add to dashboard Cite

Summary Adrenalectomy prevents development of obesity and hyperinsulinaemia in obese (fa/fa)Zucker rats, thereby implicating the hypothalamopituitary-adrenal axis in the pathogenesis of obesity. In this study glucose-induced insulin secretion and glucokinase activity were investigated in isolated islets from adrenalectomized and control obese and lean female rats. Islets from control fa/fa rats were more sensitive to glucose with a half-maximal effective concentration (ECs0) of 6.1 + 2.0 mmol. 1-1 compared with 10.6 + 2.7 mmol. 1-1 for adrenalectomized fa/fa rat islets. Adrenalectomy did not alter the islet sensitivity to glucose in the lean rats (ECs0 of 9.4+1.5mmo1.1-1 and 9.3+2.0mmo1-1-1 for adrenalectomized and control lean rats respectively). Mannoheptulose did not inhibit insulin secretion from control obese rats; however at concentrations of 1.0 mmol 9 1-1 or more it significantly inhibited glucose-induced insulin secretion in adrenalectomized obese and lean, and control lean rat islets (p < 0.05).In adrenalectomized fa/fa islets the glucokinase K m was increased twofold compared with the control fa/fa rats (9.5 + 1.5 mmol. 1-1 vs 5.0 + 1.5 mmol. 1-1, respectively), but there was no significant change in glucokinase K m in the lean rat islets after adrenalectomy. Mannoheptulose (10 mmol. 1-1) caused a significant reduction in glucose phosphorylation in disrupted islets of adrenalectomized fa/fa and lean, and of control lean rats, but not of control fa/fa rats. These data demonstrate that development of abnormal regulation of glycolysis in pancreatic islet beta cells offa/ fa rats, as indicated by the insulin response to mannoheptulose and glucokinase activity, is dependent on an intact hypothalamo-pituitary-adrenal axis. [Diabetologia (1996) 39: 190-198] Key words Insulin secretion, mannoheptulose, adrenalectomy, glucokinase, hypothalamo-pituitary-adrenal axis, islets of Langerhans.Hyperinsulinaemia is a characteristic of human obesity and the genetically transmitted obesity syndromes Abbreviations: ADX, Adrenalectomy/adrenalectomized; CRH, corticotrophin releasing hormone; DMEM, Dulbecco's modified Eagle's medium; ECs0; half-maximal effective concentration; HPA, hypothalamo-pituitary-adrenal; MH, mannoheptulose; Hepes, 4-(2-hydroxyethyl)-l-piperazineethane sulphonic acid.high-carbohydrate diet plays a significant role in the development of obesity and hyperinsulinaemia in these rats [2]. Increased sensitivity to glucose of the pancreatic beta cells of fa/fa rats in both the preobese [3][4][5] and adult stages [6][7][8][9] is observed. This increased response offa/fa rats to glucose stimulation might be related to changes in the primary glucose sensing mechanisms of the pancreatic islet beta cells because sensitivity to other stimulants is not different from that observed in lean rats [9].Glucokinase, for which there is growing evidence as the primary pancreatic beta-cell glucose sensor [10], is reported to have increased sensitivity to glucose in fa/fa rat isolated islets [11]. The activity of glucoki...

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats

Kibenge

Chan

1996

Diabetologia

View full text Add to dashboard Cite

show abstract

“…The activity of the hypothalamopituitary-adrenal axis (HPA) is reportedly increased in rodent and human obesity. Thus, in the genetically obese fa/fa rat, plasma corticosterone levels were shown to be elevated in response to stress or to feeding, while such was not always the case in the basal state, depending on both the sex and the timing of the sample within the circadian rhythm (Plotsky et al, 5 Walker et al, 6 Pacak et al, 7 Havel et al, 8 Richard et al, 9 Timofeeva and Richard, 10 Timofeeva et al, 11 Livingstone et al, 12,13 unpublished personal observation). In these rats, urinary excretion of corticosterone metabolites was increased 12,14,15 and their adrenal glands were hyperplastic.…”

Section: Glucocorticoids and Neuropeptide Ymentioning

confidence: 99%

“…In these rats, urinary excretion of corticosterone metabolites was increased 12,14,15 and their adrenal glands were hyperplastic. 5,8,12,13 These defects were partly attributed to impaired negative feedback control of the HPA axis, due to lower levels of mineralocorticoid (MR) receptors in the hippocampus but unchanged number of glucocorticoid receptors (GR). 16 MR receptors appear to be more influential during stress than in the basal state.…”

Section: Glucocorticoids and Neuropeptide Ymentioning

confidence: 99%

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

2004

View full text Add to dashboard Cite

Glucocorticoids are important hormones in the regulation of metabolic homeostasis. We infused normal rats with dexamethasone given intracerebroventricularly (i.c.v.) for 3 days. This resulted in hyperphagia, hyperinsulinemia, and marked insulin resistance. Similar metabolic defects were observed following i.c.v. infusion of neuropeptide Y (NPY) in normal rats. As central dexamethasone infusion enhanced NPY content in the arcuate nucleus, it suggested that its metabolic effects are mediated by NPY. Moreover, due to the lack of effects observed in vagotomized animals, activation of the parasympathetic nervous system by central dexamethasone infusion is proposed. Glucocorticoid action is known to involve prereceptor metabolism by enzymes such as 11b-HSD-1 that converts inactive into active glucocorticoids. Mice overexpressing 11b-HSD-1 in adipose tissue were shown to be obese and insulin resistant. We recently observed that adipose tissue 11b-HSD-1 mRNA expression is increased at the onset of high-fat diet-induced obesity and positively correlated with the degree of hyperglycemia. In human obesity, increased adipose tissue 11b-HSD-1 expression and activity were also reported. Resistin is a new adipose tissue-secreted hormone shown to play a role in glucose homeostasis by increasing hepatic glucose production and inhibiting muscle and adipose tissue glucose utilization. We observed increased adipose tissue resistin expression in the early phase of highfat diet-induced obesity as well as decreased resistin expression in response to leptin. A positive correlation between glycemia and adipose tissue resistin expression further suggested a role of this hormone in the development of insulin resistance. The melanocortin system is another important player in the regulation of energy balance. Peripheral administration of a melanocortin agonist decreased food intake and body weight and favored lipid oxidation, effects that were more marked in obese than in lean rats. It is proposed that both resistin and melanocortin agonists may influence adipose tissue 11b-HSD-1, thereby decreasing or enhancing glucose metabolism.

show abstract

“…OB-induced increases in ACTH release could be directly responsible for the elevated glucocorticoid levels often found in obesity (22). Glucocorticoid receptors are colocalized in CRF cells in the PVN of the hypothalamus (26), and glucocorticoids can inhibit hypothalamic CRF synthesis/release via negative feedback (43). Thus, in the presence of severely elevated plasma OB, as found in obese individuals, two major effects could prevent OB from reducing body weight via enhanced CRF release (Fig.…”

Section: Figmentioning

confidence: 99%

“…5. In obese fa/fa rats with high corticosterone levels, hypothalamic CRF content and portal secretion of CRF are reduced, and adrenalectomy in these animals results in enhanced portal CRF secretion (17,43). Adrenalectomy also eliminates hyperphagia and excessive weight gain in obese fa/fa rats (23) as well as in obese rats with ventromedial hypothalamic lesions (24) and ob/ob mice (25).…”

Section: Figmentioning

confidence: 99%

Corticotropin-releasing Factor and Adrenocorticotrophic Hormone as Potential Central Mediators of OB Effects

Raber¹,

Chen²,

Mucke³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

OB (leptin) has been identified as a factor that suppresses appetite and stimulates metabolism. Attention has focused on the hypothalamus as its potential site of action, but OB could also act on other brain regions. In addition, the paradox of high OB levels in obese humans remains unresolved. Here we show in mice that both the long and short form of the OB receptor are expressed not only in the hypothalamus but also in the amygdala and pituitary. Recombinant murine OB elicited the release of corticotropin-releasing factor from superfused brain slice preparations containing hypothalamus or amygdala. Because corticotropin-releasing factor inhibits appetite and stimulates metabolism, it may be a key mediator of central OB effects. Recombinant OB also induced pituitary release of adrenocorticotrophic hormone. Because adrenocorticotrophic hormone-induced elevation of plasma glucocorticoid levels can inhibit corticotropin-releasing factor release via negative feedback, the OB effects on pituitary adrenocorticotrophic hormone release may be pertinent to human obesity, which combines increased plasma glucocorticoid levels with elevated levels of OB. An imbalance between the effects of OB on corticotropin-releasing factor release from the hypothalamus and on adrenocorticotrophic hormone release from the pituitary could contribute to obesity.Obesity is a cause of serious health problems, and new research on the ob gene, which encodes an adipose tissue-derived hormone (OB or leptin) that suppresses appetite and stimulates metabolism (1, 2), raises hopes for therapeutical intervention. Little is known about the molecular factors mediating OB effects. Increasing evidence supports a central site of action for OB. Infusion of OB into the lateral ventricles of normal or OB-deficient ob/ob mice decreases feeding (3). Although the hypothalamus has been identified as a potential site of action of OB (4), OB may also act on other regions. Short and long forms of the OB receptor (OB-R) 1 differing in the length of their intracellular domain are formed by differential splicing, but only the long OB-R form can activate janus kinase (JAK) and lead to phosphorylation of signal transducers and activators of transcription (STAT) proteins. The JAK/STAT pathway has been proposed to mediate the effects of OB on body weight (5). The function of the short OB-R form has not been identified yet, but this form could also have an important role in mediating central effects of OB.Although neuropeptide Y has been implicated as a potential central mediator of OB effects (4), recent evidence indicates that additional factors may be involved (6). OB-deficient ob/ob mice treated with OB show strong Fos protein immunoreactivity in the paraventricular nucleus (PVN) (7). It is interesting in this context that corticotropin-releasing factor (CRF) acting at the PVN inhibits food intake and stimulates metabolic rate in genetically obese animals and lean controls (8 -10). Furthermore, conditions that increase hypothalamic CRF production also diminish food in...

show abstract

Hypothalamic-pituitary-adrenal axis function in the Zucker obese rat.

Cited by 45 publications

References 2 publications

Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats

Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

Corticotropin-releasing Factor and Adrenocorticotrophic Hormone as Potential Central Mediators of OB Effects

Contact Info

Product

Resources

About