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

C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.
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PMID:Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors. 1685 50

This study examines the actions of the novel enzyme-resistant, NH2-terminally modified GIP analog (Hyp(3))GIP and its fatty acid-derivatized analog (Hyp(3))GIPLys(16)PAL. Acute effects are compared with the established GIP receptor antagonist (Pro(3))GIP. All three peptides exhibited DPP IV resistance, and significantly inhibited GIP stimulated cAMP formation and insulin secretion in GIP receptor-transfected fibroblasts and in clonal pancreatic BRIN-BD11 cells, respectively. Likewise, in obese diabetic ob/ob mice, intraperitoneal administration of GIP analogs significantly inhibited the acute antihyperglycemic and insulin-releasing effects of native GIP. Administration of once daily injections of (Hyp(3))GIP or (Hyp(3))GIPLys(16)PAL for 14 days resulted in significantly lower plasma glucose levels (P < 0.05) after (Hyp(3))GIP on days 12 and 14 and enhanced glucose tolerance (P < 0.05) and insulin sensitivity (P < 0.05 to P < 0.001) in both groups by day 14. Both (Hyp(3))GIP and (Hyp(3))GIPLys(16)PAL treatment also reduced pancreatic insulin (P < 0.05 to P < 0.01) without affecting islet number. These data indicate that (Hyp(3))GIP and (Hyp(3))GIPLys(16)PAL function as GIP receptor antagonists with potential for ameliorating obesity-related diabetes. Acylation of (Hyp(3))GIP to extend bioactivity does not appear to be of any additional benefit.
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PMID:Antagonistic effects of two novel GIP analogs, (Hyp3)GIP and (Hyp3)GIPLys16PAL, on the biological actions of GIP and longer-term effects in diabetic ob/ob mice. 1729 87

Type 2 diabetes results from progressive pancreatic beta-cell dysfunction caused by chronic insulin resistance. Activation of c-Jun NH2-terminal kinase (JNK) inhibits insulin signaling in cultured cells and in vivo and thereby promotes insulin resistance. Conversely, the peroxisome proliferator-activated receptor (PPAR) gamma synthetic ligands thiazolidinediones (TZDs) enhance insulin sensitivity. Here, we show that the TZDs rosiglitazone and troglitazone inhibit tumor necrosis factor-alpha-induced JNK activation in 3T3-L1 adipocytes. Our results indicate that PPARgamma mediates this inhibitory action because 1) it is reproduced by other chemically unrelated PPARgamma agonist ligands and blocked by PPARgamma antagonists; 2) it is enhanced by PPARgamma overexpression; and 3) it is abrogated by PPARgamma RNA interference. In addition, we show that rosiglitazone inhibits JNK activation and promotes the survival of pancreatic beta-cells exposed to interleukin-1beta. In vivo, the abnormally elevated JNK activity is inhibited in peripheral tissues by rosiglitazone in two distinct murine models of obesity. Moreover, rosiglitazone fails to enhance insulin-induced glucose uptake in primary adipocytes from ob/ob JNK1-/- mice. Accordingly, we demonstrate that the hypoglycemic action of rosiglitazone is abrogated in the diet-induced obese JNK1-deficient mice. In summary, we describe a novel mechanism based on targeting the JNK signaling pathway, which is involved in the hypoglycemic and potentially in the pancreatic beta-cell protective actions of TZDs/PPARgamma.
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PMID:Hypoglycemic action of thiazolidinediones/peroxisome proliferator-activated receptor gamma by inhibition of the c-Jun NH2-terminal kinase pathway. 1741 98

The most common form of diabetes, type 2 diabetes (T2D) is a major Public Health issue which is receiving a great deal of attention both in industrial and public research, in order to develop new and more effective drugs. The hyperglycaemia of T2D is the result of two interdependent defects : decreased biological efficacy of insulin in target tissues (insulin resistance), and a decreased capacity for beta cells to secrete insulin in response to glucose. Furthermore, hyperglycaemia evolves with time and even with rigorous treatment there is a progressive deterioration of glucose homeostasis. Seventy five percent of DT2 patients are obese and show a perturbed lipid profile. beta-cell plasticity is a unique property of these cells to adapt their number and volume (beta-cell mass) and their function to the increased secretory demand linked to insulin resistance. This is well documented in physiological (pregnancy) as well in pathophysiological conditions (obesity, acromegaly). Although the lack of reliable techniques makes it very difficult to document it in humans, this property is likely altered in DT2, mainly as a consequence of the prolonged exposure of islet cells to high plasma levels of glucose and free fatty acids (gluco-lipotoxicity). The mechanisms by which hyperglycaemia and hyperlipidemia exert their deleterious effects on the beta-cell include the generation of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) and Advanced Glycosylation End Products (AGE). Altogether the prevailing clinical and experimental data urge us to consider that the pathophysiology of DT2 lies, at least in part, the inability of beta-cells to adapt their functional mass to the prevailing insulin demand. This re-evaluation of the pathophysiology of DT2 stimulates the research of new therapeutic approaches aimed at maintaining and/or restoring the functional beta-cell mass by targeting the mechanisms responsible for its decrease.
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PMID:[Anatomical and functional plasticity of pancreatic beta-cells and type 2 diabetes]. 1793 2

A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.
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PMID:Discovery of orally bioavailable 1,3,4-trisubstituted 2-oxopiperazine-based melanocortin-4 receptor agonists as potential antiobesity agents. 1877 Dec 54

Depending on type and inclusion level, dietary fibre may increase and maintain satiety and postpone the onset of hunger. This 7-week study evaluated the effect of fibre fermentability on physiological satiety-related metabolites and voluntary food intake (VFI) in dogs. Sixteen healthy adult dogs were fed a low-fermentable fibre (LFF) diet containing 8.5 % cellulose or a high-fermentable fibre (HFF) diet containing 8.5 % sugarbeet pulp and 2 % inulin. Large intestinal fibre degradation was evaluated by apparent faecal digestibility of nutrients and faecal SCFA and NH3 concentrations. Postprandial blood samples were obtained to determine postprandial plasma glucose, insulin, total peptide tyrosine-tyrosine (PYY), total glucagon-like peptide-1 (GLP-1) and total ghrelin concentrations. At the end of the study, the dogs were given a single meal of a dry dog food to determine VFI. Dogs fed the HFF diet had a significantly higher large intestinal fibre degradation and production of SCFA compared with the dogs fed the LFF diet. The HFF-fed dogs tended (P = 0.058) to show a lower VFI at the end of the study. No treatment effects were found for postprandial plasma glucose, PYY, GLP-1 and ghrelin responses. The concentrations of these metabolites could not be related to the observed difference in VFI. The inclusion of fermentable fibre in canine diets may contribute to the prevention or mitigation of obesity through its effects on satiety. The underlying mechanisms require further investigation.
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PMID:The effects of dietary fibre type on satiety-related hormones and voluntary food intake in dogs. 1914 13

This study assessed the effects of resistance training (RT) on energy restriction-induced changes in body composition, protein metabolism, and the fractional synthesis rate of mixed muscle proteins (FSRm) in postmenopausal, overweight women. Sixteen women (age 68 +/- 1 years, BMI 29 +/- 1 kg/m(2), mean +/- s.e.m.) completed a 16-week controlled diet study. Each woman consumed 1.0 g protein/kg/day. At baseline (weeks B1-B3) and poststudy (weeks RT12-RT13), energy intake matched each subject's need and during weeks RT1-RT11 was hypoenergetic by 2,092 kJ/day (500 kcal/day). From weeks RT1 to RT13, eight women performed RT 3 day/week (RT group) and eight women remained sedentary (SED group). RT did not influence the energy restriction-induced decrease in body mass (SED -5.8 +/- 0.6 kg; RT -5.0 +/- 0.2 kg) and fat mass (SED -4.1 +/- 0.9 kg; RT -4.7 +/- 0.5 kg). Fat free mass (FFM) and total body water decreased in SED (-1.6 +/- 0.4 and -2.1 +/- 0.5 kg) and were unchanged in RT (-0.3 +/- 0.4 and -0.4 +/- 0.7 kg) (group-by-time, P < or = 0.05 and P = 0.07, respectively). Protein-mineral mass did not change in either group (SED 0.4 +/- 0.2 kg; RT 0.1 +/- 0.4 kg). Nitrogen balance, positive at baseline (2.2 +/- 0.3 g N/day), was unchanged poststudy. After body mass loss, postabsorptive (PA) and postprandial (PP) leucine turnover, synthesis, and breakdown decreased. Leucine oxidation and balance were not changed. PA and total (PA + PP) FSRm in the vastus lateralis were higher after weight loss. RT did not influence these protein metabolism responses. In summary, RT helps older women preserve FFM during body mass loss. The comparable whole-body nitrogen retentions, leucine kinetics, and FSRm between groups are consistent with the lack of differential protein-mineral mass change.
Obesity (Silver Spring) 2009 Jul
PMID:Resistance training preserves fat-free mass without impacting changes in protein metabolism after weight loss in older women. 1924 71

Gases, such as nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H(2)S), and sulfur dioxide (SO(2)) are known toxic pollutants in the air. However, they are now recognized as important signaling molecules synthesized in animals and humans from arginine, glycine (heme), and cysteine, respectively. At physiological levels, NO, CO, and SO(2) activate guanylyl cyclase to generate cGMP which elicits a variety of responses (including relaxation of vascular smooth muscle cells, hemodynamics, neurotransmission, and cell metabolism) via cGMP-dependent protein kinases. H(2)S is also a crucial regulator of both neurological function and endothelium-dependent relaxation through cGMP-independent mechanisms involving stimulation of membrane K(ATP) channels and intracellular cAMP signaling. Additionally, NO, CO, and H(2)S confer cytoprotective and immunomodulatory effects. Moreover, NH(3) is a major product of amino acid catabolism and profoundly affects the function of neurons and the vasculature through glutamine-dependent inhibition of NO synthesis. Emerging evidence shows that amino acids are not only precursors for these endogenous gases, but are also regulators of their production in a cell-specific manner. Thus, recent advances on gaseous signaling have greatly expanded our basic knowledge of amino acid biochemistry and nutrition. These exciting discoveries will aid in the design of new nutritional and pharmacological means to prevent and treat major health problems related to developmental biology and nutrient metabolism, including intrauterine growth restriction, preterm birth, aging, neurological disorders, cancer, obesity, diabetes, and cardiovascular disease.
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PMID:Amino acids and gaseous signaling. 1926 54

Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH(3)]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine-stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 micromol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123-induced increase in resting myocardial perfusion of approximately 40%, not different between lean and obese subjects (BQ123-induced increase in flow: lean 0.12 +/- 0.20, obese 0.32 +/- 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123-induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine-stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity.
Obesity (Silver Spring) 2010 Jan
PMID:Role of endogenous ET-1 in the regulation of myocardial blood flow in lean and obese humans. 1954 7

The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2), produced in lateral hypothalamic neurons, are critical regulators of feeding behavior, the reward system, and sleep/wake states. Orexin-producing neurons (orexin neurons) are regulated by various factors involved in regulation of energy homeostasis and sleep/wakefulness states. Bombesin receptor subtype 3 (BRS3) is an orphan receptor that might be implicated in energy homeostasis and is highly expressed in the hypothalamus. However, the neural pathway by which BRS3 regulates energy homeostasis is largely unknown. We examined whether BRS3 is involved in the regulation of orexin neurons. Using a calcium imaging method, we found that a selective BRS3 agonist [Ac-Phe-Trp-Ala-His-(tauBzl)-Nip-Gly-Arg-NH2] increased the intracellular calcium concentration of orexin neurons. However, intracellular recordings from slice preparations revealed that the BRS3 agonist hyperpolarized orexin neurons. The BRS3 agonist depolarized orexin neuron in the presence of tetrodotoxin. Moreover, in the presence of GABA receptor blockers, picrotoxin and CGP55845, the BRS3 agonist induced depolarization and increased firing frequency. Additionally, double-label in situ hybridization study revealed that Brs3 mRNA was expressed in almost all orexin neurons and many cells around these neurons. These findings suggest that the BRS3 agonist indirectly inhibited orexin neurons through GABAergic input and directly activated orexin neurons. Inhibition of activity of orexin neurons through BRS3 might be an important pathway for regulation of feeding and sleep/wake states. This pathway might serve as a novel target for the treatment of obesity.
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PMID:Activation of bombesin receptor subtype-3 influences activity of orexin neurons by both direct and indirect pathways. 2046 15


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