Abstract
Glycerol is an important metabolite for the control of lipid accumulation in white adipose tissue (WAT) and liver. We aimed to investigate whether exogenous administration of leptin improves features of non-alcoholic fatty liver disease (NAFLD) in leptin-deficient ob/ob mice via the regulation of AQP3 and AQP7 (glycerol channels mediating glycerol efflux in adipocytes) and AQP9 (aquaglyceroporin facilitating glycerol influx in hepatocytes). Twelve-week-old male wild type and ob/ob mice were divided in three groups as follows: control, leptin-treated (1 mg/kg/d) and pair-fed. Leptin deficiency was associated with obesity and NAFLD exhibiting an AQP3 and AQP7 increase in WAT, without changes in hepatic AQP9. Adipose Aqp3 and hepatic Aqp9 transcripts positively correlated with markers of adiposity and hepatic steatosis. Chronic leptin administration (4-weeks) was associated with improved body weight, whole-body adiposity, and hepatosteatosis of ob/ob mice and to a down-regulation of AQP3, AQP7 in WAT and an up-regulation of hepatic AQP9. Acute leptin stimulation in vitro (4-h) induced the mobilization of aquaglyceroporins towards lipid droplets (AQP3) and the plasma membrane (AQP7) in murine adipocytes. Our results show that leptin restores the coordinated regulation of fat-specific AQP7 and liver-specific AQP9, a step which might prevent lipid overaccumulation in WAT and liver in obesity.
Highlights
We12 and others[28,29,30] have reported that aquaglyceroporins AQP3 and AQP7 facilitate glycerol outflow from adipocytes in response to the lipolysis induced by the β -adrenergic agonist isoproterenol
We previously described that after subcellular fractionation of quiescent 3T3-L1 adipocytes, AQP3 was located in the plasma membrane and cytosolic fraction, whereas AQP7 was expressed in the subfractions of lipid droplets and the rest of the cytoplasm[12]
Adipocyte lipolysis is the process that controls the breakdown of TG into glycerol and free fatty acids (FFA), which are released into the circulation and used as energy substrates in metabolic organs[7,37]
Summary
The coordinated regulation of aquaglyceroporins in adipocytes and hepatocytes plays a key role in maintaining the control of fat accumulation in adipose tissue and liver, as well as whole-body glucose homeostasis[9,18,19]. In this regard both obesity and NAFLD are associated with a dysregulation of aquaglyceroporins in adipose tissue and liver. Previous in vitro studies of our group have shown that leptin repressed AQP7 expression in differentiated human adipocytes via PI3K/Akt/mTOR signalling, suggesting a negative feedback regulation in lipolytic states to limit glycerol release from fat cells[12]. The aim of the present study was to analyze whether the beneficial effects of chronic leptin administration in vivo on hepatosteatosis are mediated via the coordinated regulation of aquaglyceroporins in adipose tissue and liver in wild type and leptin-deficient ob/ob mice
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