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 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc-/- mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc-/- mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11beta-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc-/- mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc-/- mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc-/- mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc-/- mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc-/- mice, independently of adipose or liver renin-angiotensin system activation. These data suggest that CORT-inducible 11beta-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.
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PMID:Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone. 1759 30

Pediatric obesity is increasing worldwide and disproportionately affects the economically and socially disadvantaged. Obese children are at risk of developing the (dys)metabolic syndrome, insulin resistance, early-onset type 2 diabetes mellitus, polycystic ovarian syndrome, hypertension, hyperlipidemia, and obstructive sleep apnoea. Those with diabetes may have mixed features of type 1 and type 2 diabetes mellitus. Pediatric obesity is the result of persistent adverse changes in food intake, lifestyle, and energy expenditure. It may be because of underlying a genetic syndrome or a conduct disorder. Children living in urban settings often lack safe, affordable, and accessible recreational facilities. Tight educational schedules mean less free time, while computer games and television have become preferred recreational activities. More families are eating out or eating take-out meals and processed foods at home because of pressures of work and time constraints. Consumer advertising targeted at children and the ready availability of vending machines encourage unwise food choices. Some children eat excessively because they are depressed, anxious, sad, or lonely. Often families and obese children are aware of the need for healthy eating and exercise but are unable to translate knowledge into weight loss. Population-based measures such as public education, school meal reforms, child-safe exercise friendly environments, and school-based and community-based exercise programs have been shown to be successful to varying degrees, but there remain individuals who will need special help to overcome obesity. Overeating (e.g. binge eating) may be a manifestation of disordered coping behavior but may also be because of defects in the neural and hormonal control of appetite and satiety. New pharmacological approaches are targeting these areas. We need a coordinated approach involving government, communities, and healthcare providers to provide a continuum of population-based interventions, focused screening, and personalized multidisciplinary interventions for the obese child and family.
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PMID:An overview of pediatric obesity. 1799 Nov 36

Mice with a targeted disruption of bombesin receptor subtype-3 (BRS-3 KO) develop hyperphagia, obesity, hypertension, and impaired glucose metabolism. However, the factors contributing to their phenotype have not been clearly established. To determine whether their obesity is a result of increased food intake or a defect in energy regulation, we matched the caloric intake of BRS-3 KO mice to wild-type (WT) ad libitum (ad lib)-fed controls over 21 wk. Although BRS-3 KO ad lib-fed mice were 29% heavier, the body weights of BRS-3 KO pair-fed mice did not differ from WT ad lib-fed mice. Pair-feeding BRS-3 KO mice normalized plasma insulin but failed to completely reverse increased adiposity and leptin levels. Hyperphagia in ad lib-fed KO mice was due to an increase in meal size without a compensatory decrease in meal frequency resulting in an increase in total daily food intake. An examination of neuropeptide Y, proopiomelanocortin, and agouti-related peptide gene expression in the arcuate nucleus revealed that BRS-3 KO mice have some deficits in their response to energy regulatory signals. An evaluation of the satiety effects of cholecystokinin, bombesin, and gastrin-releasing peptide found no differences in feeding suppression by these peptides. We conclude that hyperphagia is a major factor leading to increased body weight and hyperinsulinemia in BRS-3 KO mice. However, our finding that pair-feeding did not completely normalize fat distribution and plasma leptin levels suggests there is also a metabolic dysregulation that may contribute to, or sustain, their obese phenotype.
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PMID:Factors contributing to obesity in bombesin receptor subtype-3-deficient mice. 1803 74

Maternal obesity is increasingly prevalent and may affect the long-term health of the child. We investigated the effects of maternal diet-induced obesity in mice on offspring metabolic and cardiovascular function. Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a palatable obesogenic diet (16% fat, 33% sugar) for 6 weeks before mating and throughout pregnancy and lactation. Offspring of control (OC) and obese dams (OO) were weaned onto standard chow and studied at 3 and 6 months of age. OO were hyperphagic from 4 to 6 weeks of age compared with OC and at 3 months locomotor activity was reduced and adiposity increased (abdominal fat pad mass; P<0.01). OO were heavier than OC at 6 months (body weight, P<0.05). OO abdominal obesity was associated with adipocyte hypertrophy and altered mRNA expression of beta-adrenoceptor 2 and 3, 11 beta HSD-1, and PPAR-gamma 2. OO showed resistance artery endothelial dysfunction at 3 months, and were hypertensive, as assessed by radiotelemetry (nighttime systolic blood pressure at 6 months [mm Hg] mean+/-SEM, male OO, 134+/-1 versus OC, 124+/-2, n=8, P<0.05; female OO, 137+/-2 versus OC, 122+/-4, n=8, P<0.01). OO skeletal muscle mass (tibialis anterior) was significantly reduced (P<0.01) OO fasting insulin was raised at 3 months and by 6 months fasting plasma glucose was elevated. Exposure to the influences of maternal obesity in the developing mouse led to adult offspring adiposity and cardiovascular and metabolic dysfunction. Developmentally programmed hyperphagia, physical inactivity, and altered adipocyte metabolism may play a mechanistic role.
Hypertension 2008 Feb
PMID:Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. 1808 52

An epidemic of overweight/obesity and type 2 diabetes, caused by overeating nutrient-poor energy-dense foods and a sedentary lifestyle, is spreading rapidly throughout the world. Abdominal obesity represents a serious threat to health because it increases the risk of developing many chronic diseases, including cardiovascular disease and cancer. Calorie restriction (CR) with adequate nutrition improves cardiometabolic health, prevents tumorigenesis and increases life span in experimental animals. The purpose of this review is to evaluate the metabolic and clinical implications of CR with adequate nutrition in humans, within the context of data obtained in animal models. It is unlikely that information regarding the effect of CR on maximal life span in humans will become available in the foreseeable future. In young and middle-aged healthy individuals, however, CR causes many of the same cardiometabolic adaptations that occur in long-lived CR rodents, including decreased metabolic, hormonal and inflammatory risk factors for diabetes, hypertension, cardiovascular disease and cancer. Unraveling the mechanisms that link calorie intake and body composition with metabolism and aging will be a major step in understanding the age-dependency of a wide range of human diseases and will also contribute to improve the general quality of life at old ages.
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PMID:Calorie restriction and cardiometabolic health. 1827 79

Overweight and obesity are highly prevalent in patients with bipolar disorder, and metabolic disorders also affect a significant portion of this population. Obesity and metabolic disorders cause significant economic burden and impair quality of life in both the general population and patients with bipolar disorder. This review examines the relationship between bipolar disorder and the metabolic syndrome, and the associated economic impact. The metabolic syndrome and bipolar disorder appear to share common risk factors, including endocrine disturbances, dysregulation of the sympathetic nervous system, and behaviour patterns, such as physical inactivity and overeating. In addition, many of the commonly used pharmacological treatments for bipolar disorder may intensify the medical burden in bipolar patients by causing weight gain and metabolic disturbances, including alterations in lipid and glucose metabolism, which can result in an increased risk for diabetes mellitus, hypertension, dyslipidaemia, cardiovascular disease and the metabolic syndrome. These medical co-morbidities and obesity have been associated with a worse disease course and likely contribute to the premature mortality observed in bipolar patients. Weight gain is also a major cause of treatment noncompliance, increased use of outpatient and inpatient services and, consequently, higher healthcare costs. Prevention of weight gain and metabolic disturbances or early intervention when these are present in bipolar disorder could result in significant health and economic benefits.
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PMID:Bipolar disorder and the metabolic syndrome: causal factors, psychiatric outcomes and economic burden. 1860 4

Human genetic data indicate impaired synthesis or processing of POMC results in obesity. We have used a mouse model of POMC deficiency (Pomc null) to explore the role of POMC-derived peptides in energy homeostasis. The phenotype of Pomc null mice recapitulates the clinical syndrome seen in humans congenitally lacking POMC. Loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding, emphasizing an important gene-environment interaction predisposing to obesity. Our studies indicate that POMC-derived peptides have influences on the response to a high fat diet, including a major influence on the dietary preference for fat. Pomc null mice are unusual in that obesity and hyperphagia develop in the absence of circulating glucocorticoid (GC). To investigate the interaction between GCs and the melanocortin system, we administered corticosterone to Pomc null mice. They appear hypersensitive to the adverse metabolic effects of GCs, developing hypertension, an exacerbation of both hyperphagia and obesity and a profound insulin resistance. GC treatment of Pomc null mice significantly increases the expression of the melanocortin antagonist agouti-related protein (AgRP). On-going studies in mice lacking both AgRP and Pomc will determine whether the metabolic phenotype seen with this GC therapy is due to a lack of melanocortin peptide, the unopposed action of AgRP or a combination of both.
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PMID:Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis. 1884 May 2

Type 2 diabetes is associated with obesity, insulin resistance, hyperglycemia, hyperphagia, polyuria, body weight gain, excessive secretion of glucocorticoids (GCs), thymus involution, adrenal gland hypertrophy, diabetic nephropathy, etc. We examined the effect of cerebrocrast, a new antidiabetic agent (synthesized in the Latvian Institute of Organic Synthesis), on body weight, food and water intake, urine output, and on changes of organ weight: that is, kidney, thymus, adrenal gland of normal rats. Cerebrocrast was administered at doses of 0.05 and 0.5 mg kg(-1) per os (p.o.) once a day for three consecutive days, and its effects were observed from 3 to 27 days after the last administration. Cerebrocrast, during the experimental period, decreased body weight by an average of approximately 32.3%, food intake by about 10-15% at the beginning of the experiments and by 22.6% at the end of the experiments, especially at a dose of 0.5 mg kg(-1). Water intake and urine output in comparison with controls were decreased. The daily food intake decreased about 1.0 and 2.1 g by administering single cerebrocrast doses of 0.05 and 0.5 mg kg(-1) body weight (b.w.), respectively, but by administering for three consecutive days, food intake decreased by about 2.2 and 3.4 g, respectively. The weekly body weight gain decreased by administering a single dose of cerebrocrast by 2.61 and 2.51 g, respectively, and by triple administration it decreased by 4.36 and 3.07 g, respectively. Cerebrocrast has long-lasting effects on these parameters and on thymus and adrenal gland weight. As cerebrocrast decreased glucose levels in normal and streptozotocin (STZ)-induced diabetic rats, it also promoted glucose uptake by the brain, intensified insulin action and formation de novo of insulin receptors. We can conclude that cerebrocrast may regulate food intake and body weight through glucose sensing by proopiomelanocortin (POMC) neurons, that are involved in control of glucose homeostasis, stimulation of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion, activation of MC4-Rs and inhibition of neuropeptide Y (NPY) in the ARC of the hypothalamus, affecting the kidney, and causing decreased urine output and water intake. Moreover, it could stimulate secretion of vasopressin. By administration of cerebrocrast thymus mass was increased, thereby preventing the action of GCs. As cerebrocrast inhibited L- and T-type calcium channels, it can prevent vasoconstriction of kidney arterioles and aldosterone secretion that have significant roles in the development of hypertension and diabetic nephropathy. These properties of cerebrocrast are important for treatment of Type 2 diabetes and its consequent development of hypertension and diabetic nephropathy.
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PMID:Effect of cerebrocrast on body and organ weights, food and water intake, and urine output of normal rats. 1903 18

Protein or calorie restriction during gestation and/or suckling induces hyperphagia and increases the susceptibility to develop obesity, glucose intolerance and hypertension in adulthood. The mechanisms by which early nutrient restriction affects the normal physiological regulation of feeding as well as to what extent the metabolic programming of hyperphagia contributes to the long-term risk of obesity and insulin resistance remain, however, to be determined. Here the temporal pattern of food intake and the behavioural satiety sequence were investigated in the offspring of Sprague-Dawley rats fed a control (C) or a low-protein (LP) diet throughout pregnancy and lactation. During the first two months of their post-natal life, protein-restricted animals exhibited hyperphagia characterized by a delayed appearance of satiety, an increase in meal size and reduced latency to eat. Protein-restricted pups also exhibited an enhanced expression of the orexigenic peptides Agouti-related protein and neuropeptide Y and decreased hypothalamic levels of the anorexigenic peptide pro-opiomelanocortin. At 8 months, LP rats still consumed larger meals than their control counterparts but they ingested daily the same amount of food as control offspring and exhibited enhanced abdominal fat and increased levels of triglycerides and fatty acids in serum. These observations indicate that the hyperphagia observed in young LP rats results from a decreased action of negative feedback signals critical to meal termination and an enhanced function of the positive signals that initiate and maintain eating. These results also suggest that perinatal malnutrition programmes obesity through a mechanism independent of its effects on feeding behaviour.
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PMID:Perinatal undernutrition-induced obesity is independent of the developmental programming of feeding. 1910 Jul 59

Intrauterine growth restriction (IUGR) is associated with an increased prevalence of renal malfunction. Two principal pathogenetic pathways appear to be involved: on the one hand non-renal mechanisms such as hypertension and type 2 diabetes, both associated with previous IUGR, predispose to secondary renal damage; on the other hand, renal mechanisms are involved such as the reduced number of nephrons in low-birth-weight children, which is a risk factor for future renal failure. In addition, glomerular diseases show a severer course in IUGR children. The course of the nephrotic syndrome is less favourable, and IgA nephropathy is associated with a higher prevalence of glomerular sclerosis. Data from animal experiments suggest an increased susceptibility of glomeruli to inflammatory stimuli and reduced regenerative capacities. However, not only prenatal environment, but also postnatal hyperalimentation is responsible for the manifestation of renal disease after IUGR.
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PMID:[Intrauterine growth restriction and renal function--a long-term problem?]. 1920 97


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