Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
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PMID:Cytokine dysregulation, inflammation and well-being. 1616 5

The neuroendocrine system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions, such as antigen presentation, antibody production, lymphocyte activity, proliferation and traffic, and the secretion of cytokines including the selection of T helper (Th)1 or Th2 cytokine responses. During inflammation, the activation of the stress system, through induction of a Th2 shift protects the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones, substance P, ATP and the activation of the corticotropin-releasing hormone/substance P-histamine axis may actually facilitate inflammation, through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor (TNF)-alpha and CRP production. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression and atherosclerosis. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
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PMID:Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. 1771 84

Rats that had been injected with monosodium glutamate (MSG) neonatally were studied for up to 70 weeks and compared with age-matched control rats to study changes in glucose tolerance and in sympathetic and sensory nerves. At 61 and 65 weeks of age, there were significant differences in glucose tolerance between the MSG and control groups, and the MSG group had raised fasting blood glucose. These changes were not associated with changes in the number of beta-cells in the islets of Langerhans. In addition, the diabetic MSG-treated rats had central obesity and cataracts. Hypoalgesia to thermal stimuli was present in MSG-treated rats as early as 6 weeks and persisted at 70 weeks. However, no differences were observed in the distribution of substance P, the neurokinin-1 receptor or calcitonin gene-related peptide in the dorsal horn of L3-L5 at this age (70 weeks). Diabetic MSG-treated animals at 65 and 70 weeks of age had significantly reduced noradrenaline concentrations in the heart, tail artery and ileum, while concentrations in the adrenal gland and corpus cavernosum were significantly increased. There was also a significant increase in adrenal adrenaline, dopamine and serotonin, largely attributable to changes in weight of the adrenal gland in the MSG-treated animals. The results indicate that MSG-treated animals develop a form of type II diabetes by about 60 weeks of age, and that there are significant changes in amine levels in various tissues associated with these developments.
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PMID:Sensory and autonomic nerve changes in the monosodium glutamate-treated rat: a model of type II diabetes. 1791 58

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO.
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PMID:Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists. 1828 79

Obesity is one of the main risk factors for osteoarthritis (OA). For many years the association of obesity and OA has been simply attributed to the effects of overload on weight-bearing joints, and epidemiological surveys have shown a strict correlation between an increased body mass index and the severity of knee or hip OA, as well as some relief of pain and disability following weight loss. Instead, there is now a growing body of evidence that obesity is a complex syndrome in which an abnormal activation of neuroendocrine and pro-inflammatory pathways leads to an altered control of food intake, fat expansion and metabolic changes. Activated white adipose tissue increases the synthesis of pro-inflammatory cytokines, such as IL-6, IL-1, IL-8, TNFalpha, IL-18, while regulatory cytokines, such as IL-10, are decreased. Adipocytes also produce peculiar cytokines, namely adipokines, that exert multiple effects, being capable of promoting synovial inflammation, cartilage degrading enzymes, and bone matrix remodeling. Furthermore, pro-inflammatory cytokines stimulate adipocytes to synthesize neuropeptides, such as substance P and nerve growth factor, that have been shown to be critical in regulating both the appetite and cartilage homeostasis. In this scenario, where the influence of obesity on OA stems from a complex interaction of genetic, metabolic, neuroendocrine, and biomechanical factors, there may be various different potential targets for OA therapy.
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PMID:Obesity and inflammation--targets for OA therapy. 2019 91

Ghrelin and its receptor are important regulators of metabolic functions, including appetite, energy expenditure, fat accumulation, and growth hormone (GH) secretion. The ghrelin receptor is characterized by an ability to signal even without any ligand present with approximately 50% of the maximally ghrelin-induced efficacy-a feature that may have important physiological implications. The high basal signaling can be modulated either by administration of specific ligands or by engineering of mutations in the receptor structure. [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P was the first inverse agonist to be identified for the ghrelin receptor, and this peptide has been used as a starting point for identification of the structural requirements for inverse agonist properties in the ligand. The receptor binding core motif was identified as D-Trp-Phe-D-Trp-Leu-Leu, and elongation of this peptide in the amino-terminal end determined the efficacy. Attachment of a positively charged amino acid was responsible for full inverse agonism, whereas an alanin converted the peptide into a partial agonist. Importantly, by use of mutational mapping of the residues critical for the modified D-Trp-Phe-D-Trp-Leu-Leu peptides, it was found that space-generating mutations in the deeper part of the receptor improved inverse agonism, whereas similar mutations located in the more extracellular part improved agonism. Modulation of the basal signaling by mutations in the receptor structure is primarily obtained by substitutions in an aromatic cluster that keep TMs VI and VII in close proximity to TM III and thus stabilize the active conformation. Also, substitution of a Phe in TM V is crucial for the high basal activity of the receptor as this residue serves as a partner for Trp VI:13 in the active conformation. It is suggested that inverse agonist and antagonist against the ghrelin receptor provide an interesting possibility in the development of drugs for treatment of obesity and diabetes and that improved structural understanding of the receptor function facilitates the drug development.
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PMID:Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis. 2103 26

Peripheral administration of a specific neurokinin-1 receptor (NK-1R) antagonist to mice leads to reduced weight gain and circulating levels of insulin and leptin after high-fat diet (HFD). Here, we assessed the contribution of substance P (SP) and NK-1R in diet-induced obesity using NK-1R deficient [knockout (KO)] mice and extended our previous findings to show the effects of SP-NK-1R interactions on adipose tissue-associated insulin signaling and glucose metabolic responses. NK-1R KO and wild-type (WT) littermates were fed a HFD for 3 wk, and obesity-associated responses were determined. Compared with WT, NK-1 KO mice show reduced weight gain and circulating levels of leptin and insulin in response to HFD. Adiponectin receptor mRNA levels are higher in mesenteric fat and liver in NK-1 KO animals compared with WT, after HFD. Mesenteric fat from NK-1R KO mice fed with HFD has reduced stress-activated protein kinase/c-Jun N-terminal kinase and protein kinase C activation compared with WT mice. After glucose challenge, NK-1R KO mice remove glucose from the circulation more efficiently than WT and pair-fed controls, suggesting an additional peripheral effect of NK-1R-mediated signaling on glucose metabolism. Glucose uptake experiments in isolated rat adipocytes showed that SP directly inhibits insulin-mediated glucose uptake. Our results further establish a role for SP-NK-1R interactions in adipose tissue responses, specifically as they relate to obesity-associated pathologies such as glucose intolerance and insulin resistance. Our results highlight this pathway as an important therapeutic approach for type 2 diabetes.
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PMID:Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. 2146 95

Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. Here we assessed the effects of SP on weight gain in response to HFD and determined glucose metabolism in Tac1-deficient (Tac1(-/-)) mice. The effect of SP on the expression of molecules that may predispose to reduced glucose uptake was also determined in isolated human mesenteric, omental, and sc preadipocytes. We show that although weight accumulation in response to HFD was similar between Tac1(-/-) mice and wild-type littermates, Tac1(-/-) mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase C, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. Preincubation of human mesenteric preadipocytes with the protein kinase C pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. Lastly, SP also induced insulin receptor substrate-1 phosphorylation in mature human sc adipocytes. Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.
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PMID:Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways. 2200 27

Mast cells are important in the development of allergic and anaphylactic reactions, but also in acquired and innate immunity. There is also increasing evidence that mast cells participate in inflammatory diseases, where they can be activated by non-allergic triggers, such as neuropeptides and cytokines, often having synergistic effects as in the case of substance P (SP) and IL-33. Secretion of vasoactive mediators, cytokines and proteinases contribute to the development of coronary artery disease (CAD), as well as to diet-induced obesity and the metabolic syndrome. Mast cells may be able to orchestrate such different biological processes through their ability to release pro-inflammatory mediators selectively without the degranulation typical of allergic reactions. Recent evidence suggests that mitochondrial uncoupling protein 2 (UCP2) and mitochondrial translocation regulate mast cell degranulation, but not selective mediator release. Better understanding of these two processes and how mast cells exert both immunostimulatory and immunosuppressive actions could lead to the development of inhibitors of release of specific mediators with novel therapeutic applications.
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PMID:Mast cells in allergic and inflammatory diseases. 2239 Jun 90

Asthma is a chronic inflammatory disease of the lungs. Both the number of cases and severity of asthma have been increasing without a clear explanation. Recent evidence suggests that obesity, which has also been increasing alarmingly, may worsen or precipitate asthma, but there is little evidence of how obesity may contribute to lung inflammation. We propose that mast cells are involved in both asthma and obesity by being the target and source of adipocytokines, 'alarmins' such as interleukin-9 (IL-9) and interleukin-33 (IL-33), and stress molecules including corticotropin-releasing hormone (CRH) and neurotensin (NT), secreted in response to the metabolic burden. In particular, CRH and NT have synergistic effects on mast cell secretion of vascular endothelial growth factor (VEGF). IL-33 augments VEGF release induced by substance P (SP) and tumor necrosis factor (TNF) release induced by NT. Both IL-9 and IL-33 also promote lung mast cell infiltration and augment allergic inflammation. These molecules are also expressed in human mast cells leading to autocrine effects. Obese patients are also less sensitive to glucocorticoids and bronchodilators. Development of effective mast cell inhibitors may be a novel approach for the management of both asthma and obesity. Certain flavonoid combinations may be a promising new treatment approach.
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PMID:Do mast cells link obesity and asthma? 2306 5


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