Aquaglyceroporins: implications in adipose biology and obesity

Aquaporins (AQPs) are membrane water/glycerol channels that are involved in many physiological processes. Their primary function is to facilitate the bidirectional transfer of water and small solutes across biological membranes in response to osmotic gradients. Aquaglyceroporins, a subset of the AQP family, are the only mammalian proteins with the ability to permeate glycerol. For a long time, AQP7 has been the only aquaglyceroporin associated with the adipose tissue, which is the major source of circulating glycerol in response to the energy demand. AQP7 dysregulation was positively correlated with obesity onset and adipocyte glycerol permeation through AQP7 was appointed as a novel regulator of adipocyte metabolism and whole-body fat mass. Recently, AQP3, AQP9, AQP10 and AQP11 were additionally identified in human adipocytes and proposed as additional glycerol pathways in these cells. This review contextualizes the importance of aquaglyceroporins in adipose tissue biology and highlights aquaglyceroporins’ unique structural features which are relevant for the design of effective therapeutic compounds. We also refer to the latest advances in the identification and characterization of novel aquaporin isoforms in adipose tissue. Finally, considerations on the actual progress of aquaporin research and its implications on obesity therapy are suggested.     

Role of cell cycle regulators in adipose tissue and whole body energy homeostasis

In the course of the last decades, metabolism research has demonstrated that adipose tissue is not an inactive tissue. Rather, adipocytes are key actors of whole body energy homeostasis. Numerous novel regulators of adipose tissue differentiation and function have been identified. With the constant increase of obesity and associated disorders, the interest in adipose tissue function alterations in the XXIst century has become of paramount importance. Recent data suggest that adipocyte differentiation, adipose tissue browning and mitochondrial function, lipogenesis and lipolysis are strongly modulated by the cell division machinery. This review will focus on the function of cell cycle regulators in adipocyte differentiation, adipose tissue function and whole body energy homeostasis; with particular attention in mouse studies.     

Inter-organ regulation of adipose tissue browning

Adaptive thermogenesis is an important component of energy expenditure. Brown adipocytes are best known for their ability to convert chemical energy into heat. Beige cells are brown-like adipocytes that arise in white adipose tissue in response to certain environmental cues to dissipate heat and improve metabolic homeostasis. A large body of intrinsic factors and external signals are critical for the function of beige adipocytes. In this review, we discuss recent advances in our understanding of neuronal, hormonal, and metabolic regulation of the development and activation of beige adipocytes, with a focus on the regulation of beige adipocytes by other organs, tissues, and cells. Understanding the cellular and molecular mechanisms of inter-organ regulation of adipose tissue browning may provide an avenue for combating obesity and associated diseases.     

Interaction of mitochondrial porin with cytosolic proteins.

Intracellular phosphorylation is an important step in active uptake and utilization of carbohydrates. For example glucose and glycerol enter the liver cell along the extra intracellular gradient by facilitated diffusion through specific carriers and are concentrated inside the cell by phosphorylation via hexokinase or glycerol kinase. Depending on the function of the respective tissue the uptake of carbohydrates serves different metabolic purposes. In brain and kidney medulla cells which depend on carbohydrates, glucose and glycerol are taken up according to the energy demand. However, in tissues such as muscle which synthesize glycogen or like liver which additionally produce fat from glucose, the uptake of carbohydrates has to be regulated according to the availability of glucose and glycerol. How the reversible coupling of the kinases to the outer membrane pore and the mitochondrial ATP serves to fulfil these specific requirements will be explained as well as how this regulates the carbohydrate uptake in brain according to the activity of the oxidative phosphorylation and how this allows glucose uptake in liver and muscle to persist in the presence of high glucose 6-phosphate without activating the rate of glycolysis.     

Interaction of mitochondrial porin with cytosolic proteins

Summary Intracellular phosphorylation is an important step in active uptake and utilization of carbohydrates. For example glucose and glycerol enter the liver, cell along the extra intracellular gradient by facilitated diffusion through specific carriers and are concentrated inside the cell by phosphorylation via hexokinase or glycerol kinase. Depending on the function of the respective tissue the uptake of carbohydrates serves different metabolic purposes. In brain and kidney medulla cells which depend on carbohydrates, glucose and glycerol are taken up according to the energy demand. However, in tissues such as muscle which synthesize glycogen or like liver which additionally produce fat from glucose, the uptake of carbohydrates has to be regulated according to the availability of glucose and glycerol. How the reversible coupling of the kinases to the outer membrane pore and the mitochondrial ATP serves to fulfil these specific requirements will be explained as well as how this regulates the carbohydrate uptake in brain according to the activity of the oxidative phosphorylation and how this allows glucose uptake in liver, and muscle to persist in the presence of high glucose 6-phosphate without activating the rate of glycolysis.     

GPR120: a critical role in adipogenesis,inflammation, and energy metabolism in adipose tissue

It is well known that adipose tissue has a critical role in the development of obesity and metabolic diseases and that adipose tissue acts as an endocrine organ to regulate lipid and glucose metabolism. Accumulating in the adipose tissue, fatty acids serve as a primary source of essential nutrients and act on intracellular and cell surface receptors to regulate biological events. G protein-coupled receptor 120 (GPR120) represents a promising target for the treatment of obesity-related metabolic disorders for its involvement in the regulation of adipogenesis, inflammation, glucose uptake, and insulin resistance. In this review, we summarize recent studies and advances regarding the systemic role of GPR120 in adipose tissue, including both white and brown adipocytes. We offer a new perspective by comparing the different roles in a variety of homeostatic processes from adipogenic development to adipocyte metabolism, and we also discuss the effects of natural and synthetic agonists that may be potential agents for the treatment of metabolic diseases.     

Newly discovered endocrine functions of white adipose tissue: possible relevance in obesity-related diseases

During recent years our view of adipose tissue has been revolutionized. White adipose tissue (WAT) is no longer seen as mere energy store or provider of thermal and mechanical insulation. Neglect of WAT has been overcome by surprising discoveries in recent years, changing the view of this tissue towards a highly endocrine organ that is involved in a wide variety of physiological and pathophysiological processes. In this brief article we will focus on new developments in adipocyte and WAT biology. The appreciation of WAT as an endocrine organ will provide the basis for new and promising perspectives in the management of obesity and obesity-related diseases including diabetes, mellitus type II and arterial hypertension.     

Metabolic syndrome as a risk factor for neurological disorders

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic ‘bodyweight/appetite/satiety set point,’ resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer’s disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer’s disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer’s disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.     

OX40 promotes obesity-induced adipose inflammation and insulin resistance

Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4⁺ T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation. The effects of OX40 on IR are mechanistically linked to the promotion of T cell activation, Th1 cell differentiation and proliferation—as well as the attenuation of Treg suppressive activity and the enhancement of proinflammatory cytokine production—in adipose tissues. Furthermore, OX40 expression on T cells was positively associated with obesity in humans, suggesting that our findings are clinically relevant. In summary, our study revealed that OX40 in CD4⁺ T cells is crucial for adipose tissue inflammation and IR development. Therefore, the OX40 signaling pathway may be a new target for preventing or treating obesity-related IR and T2DM.     

Ablation of kallikrein 7 (KLK7) in adipose tissue ameliorates metabolic consequences of high fat diet-induced obesity by counteracting adipose tissue inflammation in vivo

Vaspin is an adipokine which improves glucose metabolism and insulin sensitivity in obesity. Kallikrein 7 (KLK7) is the first known protease target inhibited by vaspin and a potential target for the treatment of metabolic disorders. Here, we tested the hypothesis that inhibition of KLK7 in adipose tissue may beneficially affect glucose metabolism and adipose tissue function. Therefore, we have inactivated the Klk7 gene in adipose tissue using conditional gene-targeting strategies in mice. Klk7-deficient mice (ATKlk7 ^?/?) exhibited less weight gain, predominant expansion of subcutaneous adipose tissue and improved whole body insulin sensitivity under a high fat diet (HFD). ATKlk7 ^?/? mice displayed higher energy expenditure and food intake, most likely due to altered adipokine secretion including lower circulating leptin. Pro-inflammatory cytokine expression was significantly reduced in combination with an increased percentage of alternatively activated (anti-inflammatory) M2 macrophages in epigonadal adipose tissue of ATKlk7 ^?/?. Taken together, by attenuating adipose tissue inflammation, altering adipokine secretion and epigonadal adipose tissue expansion, Klk7 deficiency in adipose tissue partially ameliorates the adverse effects of HFD-induced obesity. In summary, we provide first evidence for a previously unrecognized role of KLK7 in adipose tissue with effects on whole body energy expenditure and insulin sensitivity.     

Physiological roles of glycerol-transporting aquaporins: the aquaglyceroporins

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. Received 20 January 2006; received after revision 21 February 2006; accepted 20 March 2006     

Adiponectin as a tissue regenerating hormone: more than a metabolic function

The great interest that scientists have for adiponectin is primarily due to its central metabolic role. Indeed, the major function of this adipokine is the control of glucose homeostasis that it exerts regulating liver and muscle metabolism. Adiponectin has insulin-sensitizing action and leads to down-regulation of hepatic gluconeogenesis and an increase of fatty acid oxidation. In addition, adiponectin is reported to play an important role in the inhibition of inflammation. The hormone is secreted in full-length form, which can either assemble into complexes or be converted into globular form by proteolytic cleavage. Over the past few years, emerging publications reveal a more varied and pleiotropic action of this hormone. Many studies emphasize a key role of adiponectin during tissue regeneration and show that adiponectin deficiency greatly inhibits the mechanisms underlying tissue renewal. This review deals with the role of adiponectin in tissue regeneration, mainly referring to skeletal muscle regeneration, a process in which adiponectin is deeply involved. In this tissue, globular adiponectin increases proliferation, migration and myogenic properties of both resident stem cells (namely satellite cells) and non-resident muscle precursors (namely mesoangioblasts). Furthermore, skeletal muscle could be a site for the local production of the globular form that occurs in an inflamed environment. Overall, these recent findings contribute to highlight an intriguing function of adiponectin in addition to its well-recognized metabolic action.     

Pseudocholinesterase in obesity: Hypercaloric diet induced changes in experimental obese mice

Summary Pseudocholinesterase activity is significantly higher in liver and serum, but lower in adipose tissue of genetically obese, diabetic and gold thioglucose treated mice. Similar enzyme changes were also observed in lean mice on a high carbohydrate diet. A marked reduction (40%) in PChE activity occurred in the liver of genetically diabetic mice when starved for 24 h. These observations suggest that pseudocholinesterase induction in the liver and repression in the adipose tissue is affected by excessive calorie intake in obesity. This provides a model to study the biological function of PChE in health and disease.Acknowledgments. We thank Dr Charles A. Janeway Child Health Centre and Faculty of Medicine, Memorial University of Newfoundland for financial support.     

Melatonin,mitochondria, and the metabolic syndrome

A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed.     

WNK signalling pathways in blood pressure regulation

Hypertension (high blood pressure) is a major public health problem affecting more than a billion people worldwide with complications, including stroke, heart failure and kidney failure. The regulation of blood pressure is multifactorial reflecting genetic susceptibility, in utero environment and external factors such as obesity and salt intake. In keeping with Arthur Guyton’s hypothesis, the kidney plays a key role in blood pressure control and data from clinical studies; physiology and genetics have shown that hypertension is driven a failure of the kidney to excrete excess salt at normal levels of blood pressure. There is a number of rare Mendelian blood pressure syndromes, which have shed light on the molecular mechanisms involved in dysregulated ion transport in the distal kidney. One in particular is Familial hyperkalemic hypertension (FHHt), an autosomal dominant monogenic form of hypertension characterised by high blood pressure, hyperkalemia, hyperchloremic metabolic acidosis, and hypercalciuria. The clinical signs of FHHt are treated by low doses of thiazide diuretic, and it mirrors Gitelman syndrome which features the inverse phenotype of hypotension, hypokalemic metabolic alkalosis, and hypocalciuria. Gitelman syndrome is caused by loss of function mutations in the thiazide-sensitive Na/Cl cotransporter (NCC); however, FHHt patients do not have mutations in the SCL12A3 locus encoding NCC. Instead, mutations have been identified in genes that have revealed a key signalling pathway that regulates NCC and several other key transporters and ion channels in the kidney that are critical for BP regulation. This is the WNK kinase signalling pathway that is the subject of this review.