Méndez-Giménez-de-los-Galanes, L. (Leire)
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- Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C(Nature, 2018) Unamuno, X. (Xabier); Sainz, N. (N.); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Llorente-Ortega, M. (Marcos); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Ramírez, L. (L.); Méndez-Giménez-de-los-Galanes, L. (Leire)Background/Objectives: Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. Subjects/Methods: The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg−1 day−1 ) and pair-fed]. Results: Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Conclusions: Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.
- Aquaporin-11 contributes to TGF-β1-Induced endoplasmic reticulum stress in human visceral adipocytes: role in obesity-associated inflammation(MDPI, 2020) Balaguer, I. (Inmaculada); Valenti, V. (Víctor); Calamita, G. (Giuseppe); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Malagon, M.M. (María M.); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia); Méndez-Giménez-de-los-Galanes, L. (Leire)Aquaporin-11 (AQP11) is expressed in human adipocytes, but its functional role remains unknown. Since AQP11 is an endoplasmic reticulum (ER)-resident protein that transports water, glycerol, and hydrogen peroxide (H2O2), we hypothesized that this superaquaporin is involved in ER stress induced by lipotoxicity and inflammation in human obesity. AQP11 expression was assessed in 67 paired visceral and subcutaneous adipose tissue samples obtained from patients with morbid obesity and normal-weight individuals. We found that obesity and obesity-associated type 2 diabetes increased (p < 0.05) AQP11 mRNA and protein in visceral adipose tissue, but not subcutaneous fat. Accordingly, AQP11 mRNA was upregulated (p < 0.05) during adipocyte differentiation and lipolysis, two biological processes altered in the obese state. Subcellular fractionation and confocal microscopy studies confirmed its presence in the ER plasma membrane of visceral adipocytes. Proinflammatory factors TNF-α, and particularly TGF-β1, downregulated (p < 0.05) AQP11 mRNA and protein expression and reinforced its subcellular distribution surrounding lipid droplets. Importantly, the AQP11 gene knockdown increased (p < 0.05) basal and TGF-β1-induced expression of the ER markers ATF4 and CHOP. Together, the downregulation of AQP11 aggravates TGF-β1-induced ER stress in visceral adipocytes. Owing to its "peroxiporin" properties, AQP11 overexpression in visceral fat might constitute a compensatory mechanism to alleviate ER stress in obesity.
- Pancreatic aquaporin-7: a novel target for anti-diabetic drugs?(Frontiers Media, 2018) Ezquerro-Ezquerro, S. (Silvia); Soveral, G. (Graca); Frühbeck, G. (Gema); Rodriguez, A. (Amaia); Silva, I.V. (Ines V.) da; Méndez-Giménez-de-los-Galanes, L. (Leire)Aquaporins comprise a family of 13 members of water channels (AQP0-12) that facilitate a rapid transport of water across cell membranes. In some cases, these pores are also permeated by small solutes, particularly glycerol, urea or nitric oxide, among other solutes. Several aquaporins have been identified in the pancreas, an exocrine and endocrine organ that plays an essential role in the onset of insulin resistance and type 2 diabetes. The exocrine pancreas, which accounts for 90% of the total pancreas, secretes daily large volumes of a near-isotonic fluid containing digestive enzymes into the duodenum. AQP1, AQP5, and AQP8 contribute to fluid secretion especially from ductal cells, whereas AQP12 allows the proper maturation and exocytosis of secretory granules in acinar cells of the exocrine pancreas. The endocrine pancreas (10% of the total pancreatic cells) is composed by the islets of Langerhans, which are distributed in α, β, δ, ε, and pancreatic polypeptide (PP) cells that secrete glucagon, insulin, somatostatin, ghrelin and PP, respectively. AQP7, an aquaglyceroporin permeated by water and glycerol, is expressed in pancreatic β-cells and murine studies have confirmed its participation in insulin secretion, triacylglycerol synthesis and proliferation of these endocrine cells. In this regard, transgenic AQP7-knockout mice develop adult-onset obesity, hyperinsulinemia, increased intracellular triacylglycerol content and reduced β-cell mass in Langerhans islets. Moreover, we have recently reported that AQP7 upregulation in β-cells after bariatric surgery, an effective weight loss surgical procedure, contributes, in part, to the improvement of pancreatic steatosis and insulin secretion through the increase of intracytoplasmic glycerol in obese rats. Human studies remain scarce and controversial, with some rare cases of loss-of function mutations of the AQP7 gene being associated with the onset of type 2 diabetes. The present Review is focused on the role of aquaporins in the physiology and pathophysiology of the pancreas, highlighting the role of pancreatic AQP7 as a novel player in the control of β-cell function and a potential anti-diabetic-drug.
- Increased aquaporin-7 expression is associated with changes in rat brown adipose tissue whitening in obesity: impact of cold exposure and bariatric surgery(2023) Valenti, V. (Víctor); Wenting-Hernández-Pardos, A. (Ana); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Álvarez-Cienfuegos, J. (Javier); Soveral, G. (Graca); Becerril, S. (Sara); Frühbeck, G. (Gema); da Silva, I.V. (Inés V.); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Méndez-Giménez-de-los-Galanes, L. (Leire); Moncada-Durruti, R. (Rafael)Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2 , Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4( ?)C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2 , Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy.
- Role of aquaporins in the improvement of adiposity and non-alcoholic fatty liver disease after bariatric surgery(2017-08-07) Méndez-Giménez-de-los-Galanes, L. (Leire); Frühbeck, G. (Gema); Rodriguez, A. (Amaia)The regulation of aquaglyceroporins in metabolic tissues is important for the control of fat accumulation, glucose homeostasis and insulin secretion. Obesity and insulin resistance are associated with changes in the expression of adipose tissue aquaglyceroporins, one of the main sources of plasma glycerol. Moreover, the coordinated regulation of aquaglyceroporins in adipose tissue and liver is impaired in both pathologies. The overall aim of the present thesis was to analyze whether the altered expression of aquaglyceroporins in adipose tissue, liver and pancreas is recovered in diet-induced obese rats submitted to two different bariatric surgery techniques, namely sleeve gastrectomy or gastric plication.