title: Estrogen prevents increased hepatic aquaporin-9 expression and glycerol uptake during starvation.
abstract: In starvation, glycerol is released from adipose tissue and serves as an important precursor for hepatic gluconeogenesis. By unknown sex-specific mechanisms, women suppress the endogenous glucose production better than men and respond to metabolic stress with higher plasma glycerol levels. Hepatic glycerol uptake is facilitated by aquaporin-9 (AQP9), a broad-selectivity neutral solute channel, and represents an insulin-regulated step in supplying gluconeogenesis with glycerol. In the present study, hepatic AQP9 abundance was increased 2.6-fold in starved male rats as assessed by immunoblotting and immunohistochemistry. By contrast, starvation had no significant effect on hepatic AQP9 expression in female rats. Coordinately, plasma glycerol levels remained unchanged with starvation in male rats, whereas it was increased in female rats. The different responses to starvation were paralleled by higher glycerol permeability in basolateral hepatocyte membranes from starved male rats compared with starved females. Ovariectomy led to a starvation-response pattern identical to that observed in male rats with increased hepatic AQP9 expression and unchanged plasma glycerol levels. In cultured hepatocytes, 17β-estradiol and the selective estrogen receptor α-agonist, propyl pyrazole triol, caused a decrease in AQP9 expression. Our results support that a sex-specific regulation of the hepatic glycerol channel AQP9 during starvation contributes to the higher plasma glycerol levels observed in women during fasting and possibly results in a lower cytosolic availability of glycerol. Furthermore, the sexual dimorphism in the hepatic handling of glycerol during starvation might be explained by 17β-estradiol preventing the starvation-induced increase in hepatic AQP9 abundance.
authors: Dept. of Biomedicine, the Water and Salt Research Center, Aarhus Univ., Wilhelm Meyers Allé 3, DK-8000 Aarhus, Denmark. jl@ana.au.dk
authors: Janne
authors: J
authors: Lebeck
authors: Patrizia
authors: P
authors: Gena
authors: Heidi
authors: H
authors: O'Neill
authors: Mariusz T
authors: MT
authors: Skowronski
authors: Sten
authors: S
authors: Lund
authors: Giuseppe
authors: G
authors: Calamita
authors: Jeppe
authors: J
authors: Praetorius
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005990:Glycerol / Q000097:blood / Q000378:metabolism*; D005991:Glycerol Kinase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008627:Mercuric Chloride / Q000494:pharmacology; D009919:Orchiectomy; D010052:Ovariectomy; D010539:Permeability / Q000187:drug effects; D010636:Phenols; D010693:Phloretin / Q000494:pharmacology; D019518:Postprandial Period / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013217:Starvation / Q000097:blood / Q000378:metabolism*; D014867:Water / Q000378:metabolism
chemical_list: C491637:Aqp9 protein, rat; D020346:Aquaporins; D001786:Blood Glucose; D004967:Estrogens; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D010636:Phenols; D011720:Pyrazoles; D014867:Water; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol; D008627:Mercuric Chloride; D005991:Glycerol Kinase; D005990:Glycerol; D010693:Phloretin