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Frank Svec
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ABSTRACT: Incretins are hormones that are released after ingestion of a meal and augment the secretion of insulin. Current research suggests that GLP-1 (glucagon-like peptide 1) is the most important. Their action is terminated by enzymes known as dipeptidyl peptidase-4 (DPP-4). The observation that the incretin response may be diminished in individuals with type 2 diabetes mellitus has led to advances in the management of this disease. Agents that act as incretin mimetics, such as exenatide and liraglutide, and DPP-4 inhibitors, such as sitagliptin phosphate and saxagliptin, improve glycated hemoglobin levels either as monotherapy or in combination with other agents. Importantly, these agents either lead to weight loss or are weight neutral and are associated with a low risk of hypoglycemia--properties that further contribute to their clinical utility.
The Journal of the American Osteopathic Association 07/2010; 110(7 Suppl 7):eS20-4.
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ABSTRACT: The cachexia-anorexia syndrome, in which patients suffering from chronic illness lack the desire to eat and experience weight loss, creates a serious clinical problem when patients are attempting to overcome the disease process. Endotoxin (ET) has many actions in the brain and peripheral injections can affect regulation of monoamines in brain areas as diverse as the olfactory lobes and the locus coeruleus. Certainly, ET is involved in the febrile process and it plays a prominent role in the regulation of food intake and maintenance of body weight during chronic illnesses. Monoamine neurotransmitters in specific regions of the hypothalamus also participate in the regulation of food intake and body weight and have been well characterized. In this regard, the hypothalamic perifornical nucleus (PFN) is of interest to our lab due to its role in drug-induced anorexia caused by amphetamines. It is also the most sensitive site in the hypothalamic monoaminergic system that involves dopamine (DA) and epinephrine (EPI). DA antagonist, stereotaxically placed in this site, can stimulate feeding, and specific injections of DA or EPI can result in a 70-90% decrease in food intake, even in food-deprived animals. We have shown in our studies that ET in a dose (0.2 mg/kg of lipopolysaccharide) that does not induce noticeable ambulatory (lack of movement) effects (related to malaise) can cause a significant decrease in food intake in lean Zucker rats. We hypothesize that exogenous ET causes an increase in the extracellular concentrations of monoamines in the perifornical hypothalamus, which in turn can mediate the decrease in food intake. Microdialysis was utilized to measure extracellular concentrations of EPI, norepinephrine, 5-hydroxyindoleacetic acid, DA, and serotonin or 5-hydroxytryptamine. These measurements were taken at a post-ET time period that coincides with an ET-induced decrease (4x) in food intake. Extracellular DA and EPI both significantly increased in the PFN in response to injection of ET. Increases in extracellular DA were dose related and were significant (p < 0.05) compared to zero baseline and saline at both doses of ET. No statistically significant differences were found in 5-hydroxyindoleacetic acid, norepinephrine, and serotonin in microdialysates of this part of the hypothalamus. The present data suggest that catecholamines, namely DA and EPI which are known to decrease food intake, in the PFN may be involved in the regulation of decreases in food intake caused by peripherally administered ET. This does not rule out a role for locally produced inflammatory molecules in the brain in this process.
Neuroendocrinology 11/2009; 91(1):48-55. · 2.38 Impact Factor
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ABSTRACT: The 5 HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetraline (8-OH-DPAT) increases the food intake of satiated Zucker rats, both lean and obese. Associated with this increased intake are changes in the hypothalamic content of serotonin and its metabolite, 5-HIAA (5-hydroxyindole-3-acetic acid); serotonin is increased while the level of 5-HIAA is decreased. Analysis of individual 5-HIAA/5-hydroxytryptamine (5-HT) ratios, a measure of serotonin turnover indicate that 8-OH DPAT affected serotonin turnover equally and dramatically in both phenotypes. This would be an expected physiological action of an autofeedback mechanism by a 5-HT(1A) receptor agonist. Dehydroepiandrosterone (DHEA) at doses as low as 10 mg/kg blocks the 8-OH-DPAT-induced increase in food intake but does not alter food intake of control satiated Zucker rats. The mechanism of DHEA's action was investigated by monitoring the steroid's effect on hypothalamic neurotransmitters in this satiated model. DHEA by itself induced some change in 5-HIAA in the obese satiated model but not the lean. 8-OH-DPAT, by itself, dramatically decreased serotonin turnover in either lean or obese rats, and DHEA combined with 8-OH-DPAT did not further change serotonin turnover, suggesting DHEA may work through mechanisms other than monoamines to cause its inhibition of 8-OH-DPAT-induced behavioral effects at such low doses.
AJP Regulatory Integrative and Comparative Physiology 05/2005; 288(4):R928-35. · 3.34 Impact Factor
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ABSTRACT: Obesity is a chronic condition, and long-term treatment will most likely be needed. Approved prescription medications for weight loss appear to have similar efficacy in controlled studies. No predictors of responsiveness in an individual patient or class of patients have been established. The choice of a medication is based on the underlying medical indication or contraindication of a particular drug, concurrent medication, age of the patient, need for monitoring, anticipation of the length of therapy, and the preference of a patient. Behavioral and dieting interventions, and increased physical activity are considered the primary means to promote and maintain weight loss. Weight-loss medications should be considered only as an adjunct for patients who are at substantial risk because of their obesity and in whom non-pharmacologic treatments have not resulted in sufficient weight loss to improve health or to prevent weight regain.
The Journal of the Louisiana State Medical Society: official organ of the Louisiana State Medical Society 02/2005; 157 Spec No 1:S56-64.
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ABSTRACT: Hypothalamic neurotransmitter levels were compared between groups of Zucker rats. Animals were grouped by gender, phenotype and preference for dietary fat. Before sacrifice all animals consumed a standard rat chow diet and were fasted overnight. Five rats from each of eight groups were assayed. Hypothalamic regions (lateral, LH; ventromedial, VMH; paraventricular, PVN) and the raphe were isolated and analyzed for dopamine, norepinephrine, epinephrine, serotonin and 5-hydroxyindoleacetic acid. A factorial analysis of variance was used to compare the concentrations of these biogenic amines in the four regions across phenotypic, gender and fat preference profiles. No differences were demonstrated between groups based upon fat food preference. Epinephrine and 5-HIAA content varied between lean and obese animals but there were no differences in the content of serotonin, norepinephrine or dopamine. The results are consistent with the hypothesis that the obese animal eats more because it releases less of the satiety-inducing neurotransmitter serotonin in the hypothalamus.
Nutritional Neuroscience 11/2002; 5(5):321-6. · 1.56 Impact Factor
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ABSTRACT: Effects of dehydroepiandrosterone and quinapril on nephropathy in obese Zucker rats.Background The obese Zucker rat exhibits insulin resistance, develops nephropathy at an early age, and may be a model of diabetic nephropathy. Dehydroepiandrosterone (DHEA) may ameliorate many of the factors that contribute to diabetic nephropathy, while angiotensin-converting enzyme inhibitors are known to be effective. One marker of nephropathy is the expression of -smooth muscle actin.
Kidney International 12/2000; 59(1):37-43. · 6.61 Impact Factor
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ABSTRACT: The obese Zucker rat has a genetically flawed leptin system and is a model of hyperphagia, obesity, hyperlipidemia, and markedly elevated leptin levels. Dehydroepiandrosterone (DHEA) administration reduces hyperphagia, hyperlipidemia, and obesity in Zucker rats. Since serum leptin levels are associated with body fat, we wondered what the effects of fat pad weight reduction from DHEA administration would have on leptin levels. This experiment investigated the effects of DHEA on intra-abdominal fat pads, serum lipids, and peripheral leptin in male lean and obese Zucker rats that were administered DHEA in their food from 4 weeks of age to 20 weeks. Lean and obese rats received plain chow or chow containing DHEA. Additional chow-fed groups of lean and obese weight-matched controls and obese pair-fed rats helped to control for the reduced body weight, food intake, and fat pad weights seen with DHEA administration. DHEA administration to lean Zucker rats reduced body weight and fat pad weights, but leptin levels showed a lower trend. Among obese rats, both DHEA treatment and pair-feeding reduced body weight and fat pad weights, but only DHEA lowered leptin levels. The weight-matched controls had reductions in fat pad weights similar to the DHEA-treated group, but with increased leptin levels. Thus, DHEA may exert a small, independent effect on leptin levels in this animal model, but the reduction is less than what would be expected.
Proceedings of The Society for Experimental Biology and Medicine 02/2000; 223(3):258 - 262.
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ABSTRACT: Serum dehydroepiandrosterone levels peak in young adulthood and then fall over a time course that roughly parallels the age-associated decrements in many physiologic processes. Experiments using animal models have shown that supplemental dehydroepiandrosterone exerts very favorable effects on these functions. It stimulates the immune system, reduces obesity, protects against atherosclerosis, reduces insulin resistance, and increases life span. These observations have led to speculation that dehydroepiandrosterone may be an antiaging hormone. This review summarizes recent evidence that links dehydroepiandrosterone to effects on the physiologic processes associated with aging in both animals and humans. It emphasizes the differences between the results from animals and human studies and notes that as yet neither the mechanism of action of dehydroepiandrosterone nor the category of steroid hormone to which it belongs is resolved.
(C) Lippincott-Raven Publishers.
Current Opinion in Endocrinology Diabetes and Obesity 03/1996; 3(2). · 3.62 Impact Factor
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Southern Medical Journal 08/1989; 82(9):1195. · 0.83 Impact Factor
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ABSTRACT: To understand the mechanism(s) of appetite modulation by DHEA, we have undertaken a series of studies to examine the effects of DHEA on neurotransmitters and neuropeptides known to affect appetitive behavior. Here, we report the effect of DHEA on serum enterostatin-VPDPR or E, a pentapeptide known to cause selective diminution in fat intake. Four-week-old lean (fa/+) and obese (fa/fa) Zucker rats were divided into control and treatment groups. DHEA-treated groups received powdered chow containing 0.6% DHEA ad lib for 16 weeks. Another group of obese rats was pair fed to match the intake of the obese DHEA-treated rats. At the end of this period, trunk blood was collected from fasted rats for assay of E-like immunoreactivity (E-LI) by ELISA. DHEA treatment caused a significant diminution in circulating E-LI in both lean (control: 2030 ± 226; treated: 752 ± 145 ng/mL; n = 10, p < 0.0001) and obese (control: 2489 ± 391, n = 6; treated: 1123 ± 185 ng/mL, n = 7; p = 0.0003) rats. Because DHEA treatment decreases caloric intake and body weight, we examined the effect of caloric intake and body weight on E-LI levels. Serum ELI levels were lower in the obese DHEA-treated group compared to that of obese pair fed (pair fed: 1589 ± 313, n = 6; DHEA: 1123 ± 185 ng/mL, n = 7), but the differences were statistically insignificant (p = 0.185). Also, both weight-matched lean and obese control rats had significantly (p < 0.008) higher E-LI than their DHEA-treated counterparts. To examine whether the decrease in serum E-LI following DHEA treatment could be due to increased peptide metabolism, the rate of disappearance of endogenous E-LI from serum (obese control and DHEA-treated) at 37°C was evaluated. The results show an attenuation of peptide metabolism in serum from DHEA-treated rats, a finding contrary to our expectations. In summary, DHEA treatment lowers serum E-LI levels both in lean and obese Zucker rats. This decrement in peptide level is not secondary to changes in body weight or caloric intake due to DHEA, or due to altered serum peptide metabolism. Although DHEA appears to be a potent modulator of E-LI levels, the relationship between DHEA and E-LI in relation to appetitive behavior remains to be clarified.
Physiology & Behavior.
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ABSTRACT: Zucker rats, lean and obese, treated with low dose intraperitoneal injections of streptozocin become hyperglycemic within 24h. Insulin levels fall, although the obese animal remains hyperinsulinemic. Associated with these changes in glucose and insulin there are transient decreases in caloric intake. Macronutrient selection studies show that protein consumption decreases. There is a trend for fat intake to decrease. The levels of hypothalamic neurotransmitters in the lean animals are not altered by streptozocin. The levels of 5-hydroxyindoleacetic acid increases in the streptozocin-treated obese animal in the paraventricular region, ventromedial region and the raphe. Serotonin is also significantly increased in the paraventricular region of the obese rat. These results suggest that acutely, treatment with streptozocin injures pancreatic islets, causing, in turn, decreases in insulin levels so that hyperglycemia ensues in both phenotypes. Associated with these perturbations are decreases in caloric intake. The magnitude of change in insulin levels is much greater in the obese rat. It is hypothesized that in the obese Zucker rat decrements in food intake are mediated by increase in serotonin turnover in the hypothalamus and these changes are related to changes of insulin levels. These data support the concept that circulating insulin affects hypothalamic neurotransmitters.
Nutritional Neuroscience 7(5-6):317-24. · 1.56 Impact Factor
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ABSTRACT: Recent studies have demonstrated that neuropeptide Y (NPY) reduced the neural production of dehydroepiandrosterone (DHEA) in frog hypothalamic explants. The objective of this study was to assess if DHEA can block the NPY induced increase in food intake in lean and obese Zucker rats. Rats were given one of the following four treatments: sterile water/dimethylsulfoxide (DMSO), NPY/DMSO, water/DHEA, and NPY/DHEA. Immediately after administration of their respective treatment, rats were exposed to macronutrients for 4 h and food intake was monitored. NPY caused a significant increase in total calories consumed compared to control. Co-administration of DHEA along with NPY blocked this NPY dependent effect. These results suggest that DHEA blocks the over-eating in satiated rats induced by NPY. Measurement of changes in regional hypothalamic and raphe monoamine neurotransmitters known to affect food intake suggested a possible role of serotonin fluctuations in the ventromedial hypothalamus (VMH) guiding this behaviour.
Nutritional Neuroscience 9(5-6):225-32. · 1.56 Impact Factor
