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)

A subclass of aquaporin (AQP) water channels, termed aquaglyceroporins, are also able to transport glycerol and perhaps urea and other small solutes. Although extensive data exist on the physiological roles of aquaporin-facilitated water transport, until recently the biological significance of glycerol transport by the mammalian aquaglyceroporins has been unknown. There is now compelling evidence for involvement of aquaglyceroporin- facilitated glycerol transport in skin hydration and fat cell metabolism. Mice deficient in AQP3 have dry skin, reduced skin elasticity and impaired epidermal biosynthesis. Mice lacking AQP7 manifest progressive adipocyte fat accumulation and hypertrophy. These skin and fat phenotypes are attributable to impaired glycerol transport. A potential implication of these findings is the possibility of modulation of aquaglyceroporin expression or function in the therapy of skin diseases and obesity.
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PMID:Physiological roles of glycerol-transporting aquaporins: the aquaglyceroporins. 1671 8

Advances in determining the mechanisms that underlie the control of energy balance in mammals have recently been provided by the discovery and characterization of aquaporin-7 (AQP7), a water-glycerol transporter that is present in the plasma membrane of fat-storing cells (adipocytes). Recent studies have shown that the absence of AQP7 expression in fat cells increases glycerol kinase activity, boosting triacylglycerol synthesis and ultimately leading to obesity. Thus, AQP7 operates as a glycerol channel in vivo, whereby adipocyte glycerol permeability has a key role in the regulation of fat accumulation.
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PMID:Aquaporin-7 and glycerol permeability as novel obesity drug-target pathways. 1676 46

Aquaporins are channels that allow the movement of water across the cell membrane. Some members of the aquaporin family, the aquaglyceroporins, also allow the transport of glycerol, which is involved in the biosynthesis of triglycerides and the maintenance of fasting glucose levels. Aquaporin-7 (AQP7) is a glycerol channel mainly expressed in adipocytes. The deletion of AQP7 gene in mice leads to obesity and type 2 diabetes. AQP7 modulates adipocyte glycerol permeability thereby controlling triglyceride accumulation and fat cell size. Furthermore, the coordinated regulation of fat-specific AQP7 and liver-specific AQP9 may be key to determine glucose metabolism in insulin resistance.
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PMID:Role of aquaporin-7 in the pathophysiological control of fat accumulation in mice. 1691 25

Disentangling the neuroendocrine systems that regulate energy homeostasis and adiposity has been a long-standing challenge in pathophysiology, with obesity being an increasingly important public health problem. Adipose tissue is no longer considered a passive bystander in body-weight regulation. It actively secretes a large number of hormones, growth factors, enzymes, cytokines, complement factors and matrix proteins, at the same time as expressing receptors for most of these elements, which influence fuel storage, mobilisation and utilisation at both central and peripheral sites. Thus, an extensive cross talk at a local and systemic level in response to specific external stimuli or metabolic changes underpins the multifunctional characteristics of adipose tissue. In addition to the already-known adipokines, such as IL, TNFalpha, leptin, resistin and adiponectin, more recently attention has been devoted to 'newcomers' to the 'adipose tissue arena', which include aquaporin, caveolin, visfatin, serum amyloid A and vascular endothelial growth factor. While in vitro and in vivo experiments have provided extremely valuable information, the advances in genomics, proteomics and metabolomics are offering a level of information not previously attainable to help unlock the molecular basis of obesity. The potential and power of combining pathophysiological observations with the wealth of information provided by the human genome, knock-out models, transgenesis, DNA microarrays, RNA silencing and other emerging technologies offer a new and unprecedented view of a complex disease, conferring novel insights into old questions by identifying new pieces to the unfinished jigsaw puzzle of obesity.
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PMID:The Sir David Cuthbertson Medal Lecture. Hunting for new pieces to the complex puzzle of obesity. 1718

The intracellular hydric balance is an essential process of mammalian cells. The water movement across cell membranes is driven by osmotic and hydrostatic forces and the speed of this process is dependent on the presence of specific aquaporin water channels. Since the molecular identification of the first water channel, AQP1, by Peter Agre's group, 13 homologous members have been found in mammals with varying degree of homology. The fundamental importance of these proteins in all living cells is suggested by their genetic conservation in eukaryotic organisms through plants to mammals. A number of recent studies have revealed the importance of mammalian AQPs in both physiology and pathophysiology and have suggested that pharmacological modulation of aquaporins expression and activity may provide new tools for the treatment of variety of human disorders, such as brain edema, glaucoma, tumour growth, congestive heart failure and obesity in which water and small solute transport may be involved. This review will highlight the physiological role and the pathological involvement of AQPs in mammals and the potential use of some recent therapeutic approaches, such as RNAi and immunotherapy, for AQP-related diseases. Furthermore, strategies that can be developed for the discovery of selective AQP-drugs will be introduced and discussed.
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PMID:Aquaporins as targets for drug discovery. 1769 10

The biological importance of the aquaporin family of water channels was recently acknowledged by the 2003 Nobel Prize for Chemistry awarded to the discovering scientist Peter Agre. Among the pleiotropic roles exerted by aquaporins in nature in both health and disease, the review addresses the latest acquisitions about the expression and regulation, as well as physiology and pathophysiology of aquaporins in the hepatobiliary tract. Of note, at least seven out of the thirteen mammalian aquaporins are expressed in the liver, bile ducts and gallbladder. Aquaporins are essential for bile water secretion and reabsorption, as well as for plasma glycerol uptake by the hepatocyte and its conversion to glucose during starvation. Novel data are emerging regarding the physio-pathological involvement of aquaporins in multiple diseases such as cholestases, liver cirrhosis, obesity and insulin resistance, fatty liver, gallstone formation and even microparasite invasion of intrahepatic bile ducts. This body of knowledge represents the mainstay of present and future research in a rapidly expanding field.
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PMID:Aquaporins in the hepatobiliary tract. Which, where and what they do in health and disease. 1817 45

Aquaporins have multiple distinct roles in mammalian physiology. Phenotype analysis of aquaporin-knockout mice has confirmed the predicted role of aquaporins in osmotically driven transepithelial fluid transport, as occurs in the urinary concentrating mechanism and glandular fluid secretion. Aquaporins also facilitate water movement into and out of the brain in various pathologies such as stroke, tumour, infection and hydrocephalus. A major, unexpected cellular role of aquaporins was revealed by analysis of knockout mice: aquaporins facilitate cell migration, as occurs in angiogenesis, tumour metastasis, wound healing, and glial scar formation. Another unexpected role of aquaporins is in neural function - in sensory signalling and seizure activity. The water-transporting function of aquaporins is likely responsible for these roles. A subset of aquaporins that transport both water and glycerol, the 'aquaglyceroporins', regulate glycerol content in epidermal, fat and other tissues. Mice lacking various aquaglyceroporins have several interesting phenotypes, including dry skin, resistance to skin carcinogenesis, impaired cell proliferation, and altered fat metabolism. The various roles of aquaporins might be exploited clinically by development of drugs to alter aquaporin expression or function, which could serve as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer.
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PMID:Mammalian aquaporins: diverse physiological roles and potential clinical significance. 1848 62

Liver X receptors (LXRs) alpha and beta are nuclear oxysterol receptors with a key role in cholesterol, triglyceride, and glucose metabolism. In LXRbeta(-/-) mice on a normal diet, there is a reduction in size of perigonadal fat pad and, on high-fat diet there is resistance to obesity. In the present study, we investigated the reason for the resistance of LXRbeta(-/-) mice to weight gain. In LXRbeta(-/-) mice we found pancreatic exocrine insufficiency with reduced serum levels of amylase and lipase, reduced proteolytic activity in feces, chronic inflammatory infiltration, and, in the ductal epithelium, an increased apoptosis without compensatory proliferation. Electron microscopy revealed ductal dilatation with intraductal laminar structures characteristic of cystic fibrosis. To investigate the relationship between LXRbeta and pancreatic secretion, we studied the expression of LXRbeta and the water channel, aquaporin-1 (AQP1), in the ductal epithelium of the pancreas. In WT mice, ductal epithelial cells expressed LXRbeta in the nuclei and AQP1 on the plasma membrane. In LXRbeta(-/-) mice neither LXRbeta nor AQP1 was detectable. Moreover, in WT mice the LXR agonist (T2320) increased AQP1 gene expression. These data demonstrate that in LXRbeta(-/-) mice dietary resistance to weight gain is caused by pancreatic insufficiency and that LXRbeta regulates pancreatic exocrine secretion through the control of AQP1 expression. Pancreatic exocrine insufficiency is the main cause of malabsorption syndrome responsible for weight loss in adults and growth failure in children. Several genes are known to be involved in the pathogenesis and susceptibility to pancreatic insufficiency. LXRbeta should be included in that list.
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PMID:Pancreatic exocrine insufficiency in LXRbeta-/- mice is associated with a reduction in aquaporin-1 expression. 1880 27

Knockout mice have been informative in the discovery of unexpected biological functions of aquaporins. Knockout mice have confirmed the predicted roles of aquaporins in transepithelial fluid transport, as in the urinary concentrating mechanism and glandular fluid secretion. A less obvious, though predictable role of aquaporins is in tissue swelling under stress, as in the brain in stroke, tumor and infection. Phenotype analysis of aquaporin knockout mice has revealed several unexpected cellular roles of aquaporins whose mechanisms are being elucidated. Aquaporins facilitate cell migration, as seen in aquaporin-dependent tumor angiogenesis and tumor metastasis, by a mechanism that may involve facilitated water transport in lamellipodia of migrating cells. The ' aquaglyceroporins', aquaporins that transport both glycerol and water, regulate glycerol content in epidermis, fat and other tissues, and lead to a multiplicity of interesting consequences of gene disruption including dry skin, resistance to skin carcinogenesis, impaired cell proliferation and altered fat metabolism. An even more surprising role of a mammalian aquaporin is in neural signal transduction in the central nervous system. The many roles of aquaporins might be exploited for clinical benefit by modulation of aquaporin expression/function - as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer.
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PMID:Knock-out models reveal new aquaporin functions. 1909 87

There is considerable potential for translating knowledge of aquaporin structure, function and physiology to the clinic. One area is in aquaporin-based diagnostics. The discovery of AQP4 autoantibodies as a marker of the neuromyelitis optica form of multiple sclerosis has allowed precise diagnosis of this disease. Other aquaporin-based diagnostics are possible. Another area is in aquaporin-based genetics. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and cataracts, and functionally significant aquaporin polymorphisms are beginning to be explored. Perhaps of greatest translational potential is aquaporin-based therapeutics. Information largely from aquaporin knockout mice has implicated key roles of aquaporin-facilitated water transport in transepithelial fluid transport (urinary concentrating, gland fluid secretion), water movement into and out of the brain, cell migration (angiogenesis, tumor metastasis, wound healing) and neural function (sensory signaling, seizures). A subset of aquaporins that transport both water and glycerol, the 'aquaglyceroporins', regulate glycerol content in epidermal, fat and other tissues, and are involved in skin hydration, cell proliferation, carcinogenesis and fat metabolism. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of edematous states, cancer, obesity, wound healing, epilepsy and glaucoma. These exciting possibilities and their associated challenges are reviewed.
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PMID:Aquaporins: translating bench research to human disease. 1944 80


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