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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathophysiological and pharmacological concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in the cerebrospinal fluid (CSF) induce anorexia in normal rats. Obesity in humans and rodents is associated with increased TNF-alpha messenger RNA and protein levels in various cell types. This suggests that obese individuals may have differential regulation of cytokine production and dissimilar responsiveness to cytokines. In the present study, we investigated the effects of the intracerebroventricular (ICV) microinfusion of TNF-alpha (50, 100, and 500 ng/rat), IL-1 beta (1.0, 4.0, and 8.0 ng), and TNF-alpha (100 ng) plus IL-1 beta (1.0 ng) on obese (fa/fa) and lean (Fa/Fa) Zucker rats. The results show that: TNF-alpha and IL-1 beta, and the concomitant administration of TNF-alpha and IL-1 beta decreased the short-term (4 hours), nighttime (12 hours), and total daily food intakes in obese and lean rats; IL-1 beta was more potent relative to TNF-alpha; obese rats showed greater responsiveness to IL-1 beta: 8.0 ng IL-1 beta, for example, decreased the 12-hour food intake by 52% in obese and 22% in lean rats. On the other hand, obese and lean rats did not exhibit a significantly different responsiveness to the anorexia induced by 50, 100, or 500 ng TNF-alpha at the 4-hour period; and the concomitant ICV administration of TNF-alpha and IL-1 beta induced anorexia with additive (4-hour period) or synergistic (12-hour and 24-hour periods) effects in obese rats. The effect of TNF-alpha plus IL-1 beta in lean rats was greater than additive for the 12-hour and 24-hour periods. The difference in suppression of total daily food intake by TNF-alpha plus IL-1 beta in obese (-43%) versus lean (-23%) rats was significantly different (p < 0.01). The results show that obese (fa/fa) and lean (Fa/Fa) Zucker rats have differential responsiveness to the ICV microinfusion of two different classes of cytokines.
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PMID:Differential responsiveness of obese (fa/fa) and lean (Fa/Fa) Zucker rats to cytokine-induced anorexia. 906 14

Recently it has been postulated that membrane fatty acid composition may be involved in the pathogenesis of insulin resistance and non-insulin dependent diabetes mellitus (NIDDM). The aim of this study was to determine whether alterations in tissue phospholipid (PL) fatty acids are present in hyperglycemic and hyperinsulinemic Psammomys obesus. On a native diet of salt bush, P. obesus (Israeli sand rat) remains lean and free of diabetes; however, when placed on a normal laboratory chow, a significant proportion of these animals develops a number of metabolic disorders associated with NIDDM, providing an ideal animal model of obesity and NIDDM. Four groups of mature P. obesus were studied: group A: normoglycemic and normoinsulinemic; group B: normoglycemic and hyperinsulinemic; group C: hyperglycemic and hyperinsulinemic; and group D: hyperglycemic and hypoinsulinemic. In liver and red gastrocnemius muscle, there were no significant differences between groups A, B, and C in fatty acid composition of PL. Minor differences in individual fatty acids were demonstrated in group D animals (increased liver 20:4n-6 and increased muscle 22:5n-3); however, the unsaturation indices in liver and muscle were not significantly different between any of the groups. In considering that the minor changes in group D animals were not demonstrated in hyperinsulinemic group B animals or hyperglycemic, hyperinsulinemic group C animals, it is likely that the differences in group D animals were secondary to the more severe disturbances in glucose homeostasis and hypoinsulinemia present in these animals. The results of this study suggest that in this rodent diabetic model significant disturbances in glucose homeostasis and hyperinsulinemia may develop independently of changes in tissue fatty acid composition.
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PMID:Non-insulin dependent diabetes mellitus in Psammomys obesus is independent of changes in tissue fatty acid composition. 907 69

It has been debated for the past two decades whether non-insulin-dependent diabetes mellitus (NIDDM) is caused by insulin deficiency or insulin resistance. In this review we summarise the data which unequivocally indicate that insulin response to glucose is grossly deficient in patients with impaired glucose tolerance and NIDDM. Furthermore, we review the findings for Psammomys obesus (the sand rat), an animal with spontaneous obesity, insulin resistance and diabetes which has been used as the prototype for "hyperinsulinaemic NIDDM". A large proportion of circulating insulin in this animal consists of proinsulin and its split products, apparently resulting from hyperglycaemia-driven overstimulation of the beta cell, with depletion of its insulin stores. In vitro studies demonstrate that this "glucose toxic" effect can be reproduced in Psammomys islets but not in those of normal rats. This would indicate that increased demand for insulin production leads to aberrations in proinsulin production and processing only in beta cells with inherent (genetic?) defects. We also point to clinical findings which cast doubt on the practical importance of insulin resistance for the glucose homeostasis of NIDDM patients. In these cases, moderate doses of insulin administered by insulin pumps can induce near-normoglycaemia in NIDDM.
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PMID:From sand rats to diabetic patients: is non-insulin-dependent diabetes mellitus a disease of the beta cell? 934 48

Modifications of (D-Trp32) neuropeptide Y (NPY) led to the development of potential peptide-based lower molecular weight (500-800 Da) NPY feeding antagonists. One compound, WRYamide (N-Ac-Trp-Arg-Tyr-NH2), blocked NPY-induced feeding for 1 to 4 h when injected intrahypothalamically (i.h.t.) at 1 to 40 microgram. Schedule-induced feeding was also antagonized for up to 24 h by 20 microgram of WRYamide, i.h.t. Injection of 2.5 mg/kg (1 mg/rat) of WRYamide, i.v., also reduced significantly schedule-induced feeding for 4 h. A conditioned taste aversion could not be classically conditioned to saccharin using WRYamide as the unconditioned stimulus. These results may lead to the development of systemically active anti-obesity drugs.
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PMID:WRYamide, a NPY-based tripeptide that antagonizes feeding in rats. 972 64

Animal species with genetic or nutritionally induced insulin resistance, diabetes and obesity (diabesity) may be divided into two broad groups: those with resilient pancreatic beta-cells, e.g. ob/ob mice and fa/fa rats, capable of long-lasting compensatory insulin over-secretion, and those with labile beta-cells in which the secretion pressure leads to irreversible beta-cell degranulation, e.g. db/db mice, Macaca mulatta primates, ZDF diabetic rats. Prominent in this group is the Israeli desert gerbil Psammomys obesus (sand rat), which features low insulin receptor density in liver and muscle. On a diet of relatively high energy, the capacity of insulin to activate the receptor tyrosine kinase (TK) is reduced, in the face of hyperinsulinemia. With the following hyperglycemia, the rising insulin resistance imposes a vicious cycle of insulinemia and glycemia, accentuating the TK activation failure and the beta-cell failure. Among various factors affecting the insulin signaling pathway, multisite phosphorylation, including serine and threonine on the receptor beta-subunit, due to overexpression of certain protein kinase C isoforms, seems to be responsible for the inhibition of the critical step of TK phosphorylation activity. The compromised TK activation is reversible by diet restriction which restores to normal the glycemia and insulinemia. The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin resistance syndrome and type 2 diabetes, particularly in populations emerging from a food scarce environment into nutritional affluence, inappropriate to the human metabolic capacity. It is suggested that the "thrifty gene" is characterized by a low threshold for insulin secretion and low capacity for insulin clearance. Thus, nutritionally-induced hyperinsulinemia is potentiated and becomes the primary phenotypic expression of the thrifty gene, linked to the insulin receptor signaling pathway malfunction.
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PMID:Cellular mechanism of nutritionally induced insulin resistance: the desert rodent Psammomys obesus and other animals in which insulin resistance leads to detrimental outcome. 1021 43

1. The present authors have previously developed a transgenic rat carrying a chimeric gene of the mouse whey acidic protein promoter and the structural portion of human growth hormone (GH) gene. Among this (hGH-TG) rat, a line (low GH rat) missing a male-specific pulsatile GH secretary pattern due to suppression of endogenous GH secretion and having a continuous low GH (hGH and rat GH) level in the peripheral circulation was identified. The latter rat was also characterized as having severe obesity with age. This strain (low Gh rat) was used to correlate the sex-specific secretory pattern of GH with the sex-specific expression of cytochrome P450 (CYP) in rat. 2. Comparisons were made between the low GH rat and the non-transgenic rat as to the expression of liver microsomal CYP isozymes. The following enzyme activities were assessed: testosterone (T) hydroxylation and oxidation; ethoxyresorufin O-dealkylation (EROD); bunitrolol (BTL) 4-hydroxylation and T5 alpha-reduction. Protein expression of CYP1A, CYP2C11, CYP2D, CYP2E1, CYP3A2 and CYP4A1 were also assessed by Western blot analysis. 3. Enzyme activities and protein expression of CYP2C11 (T16 alpha and 2alpha-hydroxylase and 17-oxidase activities) and CYP3A2 (T6beta and 2beta-hydroxylase activities) levels, which are known to be higher in the male than in the female rat, were significantly lower in the adult male low GH rat than in the control male rat. In contrast, CYP2A1 (T7 alpha-hydroxylase) and T5-alpha-reductase activities, which are known to be specifically elevated in the female, were significantly higher in the adult male low GH rat than in the control male rat. Thus, the loss of male-specific secretory pattern of GH results in feminization of the pattern of expression of CYP and T5 alpha-reductase activity in the liver. 4. In contrast to other GH-deficient models so far studied, an increase in CYP4A1 and a decrease in CYP2E1 protein expression were observed in the low GH rat. These trends are consistent with the characteristic phenotype of obesity in the transgenic rat because CYP4A1 and CYP2E1 enhance fatty acid excretion and glyconeogenesis from fatty acids respectively.
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PMID:Characterization of hepatic cytochrome P450 isozyme composition in the transgenic rat expressing low level human growth hormone. 1064 7

Obesity and Type 2 diabetes are now major public health issues in developed nations and have reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican-Americans, African-Americans, and Australian Aborigines. These groups all show hyperinsulinemia and insulin resistance, which have been demonstrated to be future predictors of Type 2 diabetes and have also been suggested as key factors in the etiology of the Metabolic Syndrome. It is now increasingly recognized that Type 2 diabetes is part of a cluster of cardiovascular disease (CVD) risk factors comprising the Metabolic Syndrome. This group is at very high risk of atherosclerosis because each of the risk factors in the Metabolic Syndrome cluster in its own right is an important CVD risk factor. They also contribute cumulatively to atherosclerosis. A key strategy in reducing macrovascular disease lies in the better understanding of the Metabolic Syndrome--glucose intolerance, hypertension, hyperlipidemia, and central obesity. Although it has been suggested that hyperinsulinemia/insulin resistance is the central etiological factor for the Metabolic Syndrome, epidemiological data do not support the idea that this can account for all of the cluster abnormalities. We have animal and human data suggesting that hyperleptinemia rather than, or synergistically with, hyperinsulinemia may play a central role in the genesis of the CVD risk factor cluster that constitutes the syndrome. Studies in Psammomys obesus (the Israeli sand rat) suggest hyperinsulinemia/insulin resistance is an early metabolic lesion in the development of obesity and Type 2 diabetes. This animal also develops other features of the Metabolic Syndrome, making it an excellent model to investigate etiology. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes, and dyslipidemia. It also develops hyperleptinemia and leptin insensitivity, and hyperleptinemia is correlated with insulin resistance independent of changes in body weight. It is likely that a similar sequence occurs in the transition from the prediabetic state to Type 2 diabetes in humans. More recently, other potential players in the etiology of the Metabolic Syndrome have been suggested including endothelial dysfunction and acetylation-stimulating protein (ASP). It has been suggested that endothelial dysfunction may be an antecedent for both Type 2 diabetes and the Metabolic Syndrome. In addition, ASP is a serious new candidate for an important role in insulin resistance. The ASP pathway plays a critical role in fatty acid metabolism and storage, and it has been suggested that ineffective storage of fatty acids by adipocytes due to a defect in the ASP pathway may lead to insulin resistance and Type 2 diabetes.
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PMID:Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players. 1084 50

The induction of learned helpless (LH) behavior in rats is a widely used model of unipolar depression. Recent studies have linked depression with hypertension and insulin resistance as observed in obesity, but the propensity of these disorders to manifest depression has not been reported. In this study, the LH behavioral paradigm was exploited in a model of hypertension (Dahl rat) and of insulin resistance (Zucker rat) to determine the propensity of these models to develop depression and to examine the profile of markers for the propensity of the cardiovascular system (plasma renin activity) and of the hypothalamus-pituitary-adrenal axis (corticosterone) in the display of propensity to depression. Results show that Zucker rats displayed the lowest propensity to the development of LH behavior (12%), followed by the control Sprague-Dawley rats (27%), and then Dahl rats (66%). In contrast, congenital learned helpless (cLH) rats, a genetically bred strain for animal depression, had the highest propensity (>90%). A gender effect was observed in the Zucker and cLH rats, with females showing an increased propensity to develop LH behavior. Plasma renin activity in the Dahl and Sprague-Dawley rats after the LH stress paradigm was not significantly different from baseline. In contrast, Zucker rats, with the lowest propensity to LH behavior, demonstrated a threefold increase in plasma renin activity after stress. Congenital LH rats, with the highest propensity to LH behavior, exhibited a significantly lower increase (43%) in plasma renin activity after stress. Hyporesponsive hypothalamus-pituitary-adrenal (HPA) axis functioning correlated with propensity of LH behavior. Stress-induced corticosterone levels increased under twofold in cLH rats, whereas they increased more than sevenfold in Zucker rats. Taken together, these studies suggest that whereas genetically prone hypertensive rats have a very high propensity to depression, insulin-resistant rats have a profound resistance to depression. Moreover, a hyporesponsive HPA axis may be a marker for disorders that are comorbid with depression, whereas a hyperresponsive renin-angiotensin system may be indicative of resilience.
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PMID:Hypertension and insulin resistant models have divergent propensities to learned helpless behavior in rodents. 1091 50

Psammomys obesus (the Israeli sand rat) has been well studied as an animal model of Type 2 diabetes. However, obesity phenotypes in these animals have not been fully characterized. We analyzed phenotypic data including body weight, percentage body fat, blood glucose and plasma insulin concentration for over 600 animals from the Psammomys obesus colony at Deakin University to investigate the relationships between body fat, body weight and Type 2 diabetes using regression analysis and general linear modelling. The body weight distribution in Psammomys obesus approximates a normal distribution and closely resembles that observed in human populations. Animals above the 75th percentile for body weight had increased body fat content and a greater risk of developing diabetes. Increased visceral fat content was also associated with elevated blood glucose and plasma insulin concentrations in these animals. A familial effect was also demonstrated in Psammomys obesus, and accounted for 51% of the variation in body weight, and 23-26% of the variation in blood glucose and plasma insulin concentrations in these animals. Psammomys obesus represents an excellent animal model of obesity and Type 2 diabetes that exhibits a phenotypic pattern closely resembling that observed in human population studies. The obesity described in these animals was familial in nature and was significantly associated with Type 2 diabetes.
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PMID:Characterization of obesity phenotypes in Psammomys obesus (Israeli sand rats). 1146 8

It is well-known that excessive salt intake induces elevation of blood pressure and that hypertension often coexists with insulin resistance. However, the contribution made by salt intake to the development of insulin resistance remains unclear. In this minireview, the insulin resistance seen in three salt-sensitive rat models (the high-salt-fed Sprague-Dawley rat, the Dahl salt-sensitive rat and the chronically angiotensin II (AII)-infused rat) are presented. One notable observation common to all three models was that, despite their insulin-resistance, the early insulin signaling steps leading from activation of IR and IRSs to activation of PI 3-kinase Akt were apparently enhanced. This suggests that the molecular mechanism underlying the insulin resistance related to the salt-sensitive hypertension is unique. Other factors known to cause insulin resistance--e.g., obesity--actually suppress early insulin signaling, but for insulin resistance related to high-salt intake, the impaired step must be further downstream in the insulin signaling pathway. What's more, increased oxidative stress appears to be crucially involved in both AII- and high-salt-induced insulin resistance. Additional study will be necessary to fully clarify the mechanism underlying insulin resistance induced by a high-salt diet; nonetheless, the findings presented suggest the importance of developing new therapeutic approaches--e.g., potassium supplementation and anti-oxidant administration--to the treatment of insulin resistance and hypertension.
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PMID:Contribution of salt intake to insulin resistance associated with hypertension. 1277 Jun 8


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