Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase

Abstract

In adipocytes, hydrolysis of triglycerides results in the release of free fatty acids and glycerol. Aquaporin 7 (AQP7), a member of aquaglyceroporins, is known to permeabilize glycerol and water. We recently generated Aqp7-knockout (KO) mice and demonstrated that such mice have low plasma glycerol levels and impaired glycerol release in response to ␤3-adrenergic agonist, suggesting that AQP7 acts as a glycerol gateway molecule in adipocytes for the efficient release of glycerol in vivo. Although there was no difference in body weight between WT and KO mice until 10 weeks of age, here we found that KO mice developed adult-onset obesity. The body weight and fat mass increased significantly in KO mice compared with WT mice after 12 weeks of age. Adipocytes of KO mice were large and exhibited accumulation of triglycerides compared with WT mice. The KO mice developed obesity and insulin resistance even at a young age after consumption of high-fat͞high-sucrose diet. We demonstrated the enhanced glycerol kinase enzymatic activity in Aqp7-KO and -knockdown adipocytes. A series of our results indicate that AQP7 disruption elevates adipose glycerol kinase activity, accelerates triglycerides synthesis in adipocytes, and, finally, develops obesity.adipocyte ͉ insulin resistance ͉ triglyceride ͉ fatty acid

Defective channels lead to an impaired skin barrier

“…Among these, the aquaglyceroporin AQP3 is the most abundantly expressed aquaporin in the keratinocytes of the epidermis (BouryJamot et al, 2006). AQP7 is found in adipocytes throughout the body, including the hypodermis of the skin, where it is involved in adipocyte metabolism and the regulation of fat accumulation through glycerol transport (Hara-Chikuma et al, 2005;Hibuse et al, 2005). However, it appears that dendritic cells in the skin also express AQP7 (Hara-Chikuma et al, 2012), where it has been shown to be involved in antigen uptake and the initiation of primary immune responses.…”

The Sir David Cuthbertson Medal Lecture Hunting for new pieces to the complex puzzle of obesity

“…Fat cells of AQP7-knock-out mice exhibit an increase in glycerol kinase activity, which stimulates triacylglycerol synthesis, ultimately leading to adipocyte hypertrophy and subsequent development of obesity. The control exerted by AQP7 over the efflux of glycerol from fat cells further highlights its role in aged mice as a determinant of wholebody glucose homeostasis and insulin sensitivity (Hibuse et al 2005). Interestingly, the coordinated regulation of fat-specific AQP7 and liver-specific AQP9 may be key to determining glucose metabolism in physiology and insulin resistance .…”

“…Originally named AQPap, this water-glycerol pore was cloned from human adipose tissue (Kuriyama et al 1997;Kishida et al 2001;Kondo et al 2002). AQP7 deficiency in adipocytes has been associated with adult-onset obesity in mice; thus, providing evidence that AQP7 functions as a glycerol channel in vivo whereby adipocyte glycerol permeability exerts a key role in the regulation of fat accumulation (Maeda et al 2004;Hara-Chikuma et al 2005;Hibuse et al 2005;Wintour & Henry 2006). Fat cells of AQP7-knock-out mice exhibit an increase in glycerol kinase activity, which stimulates triacylglycerol synthesis, ultimately leading to adipocyte hypertrophy and subsequent development of obesity.…”

Dissecting the Roles of Aquaporins in Renal Pathophysiology Using Transgenic Mice

“…AQP3-facilitated glycerol transport by epidermal keratinocytes is involved in maintaining high glycerol in epidermis and stratum corneum to support skin hydration and biosynthetic functions (12). AQP7-facilitated glycerol transport in adipocytes appears to be important in regulating fat cell glycerol content to prevent adipocyte hypertrophy and progressive fat accumulation (13,14). Other new roles of AQPs in cell migration and proliferation are discussed further below.…”