Abstract
Aquaporin-7 (AQP7) is a water/glycerol transporting protein expressed in adipocyte plasma membranes. We report here remarkable age-dependent hypertrophy in adipocytes in AQP7-deficient mice. Wild type and AQP7 null mice had similar growth at 0-16 weeks as assessed by body weight; however, by 16 weeks AQP7 null mice had 3.7-fold increased body fat mass. Adipocytes from AQP7 null mice of age 16 weeks were greatly enlarged (diameter 118 mum) compared with wild type mice (39 mum). Adipocytes from AQP7 null mice also accumulated excess glycerol (251 versus 86 nmol/mg of protein) and triglycerides (3.4 versus 1.7 mumol/mg of protein). In contrast, at age 4 weeks, adipocyte volume and body fat mass were comparable in wild type and AQP7 null mice. To investigate the mechanism(s) responsible for the progressive adipocyte hypertrophy, glycerol permeability and fat metabolism were studied in adipocytes isolated from the younger mice. Plasma membrane glycerol permeability measured by [(14)C]glycerol uptake was 3-fold reduced in AQP7-deficient adipocytes. However, adipocyte lipolysis, measured by free fatty acid release and hormone-sensitive lipase activity, and lipogenesis, measured by [(14)C]glucose incorporation into triglycerides, were not affected by AQP7 deletion. These data suggest that adipocyte hypertrophy in AQP7 deficiency results from defective glycerol exit and consequent accumulation of glycerol and triglycerides. Increasing AQP7 expression/function in adipocytes may reduce adipocyte volume and fat mass in obesity.
Highlights
From the ‡Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143, the §Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan, and the ¶Genome Information Research Center, Osaka University, Osaka 565-0871, Japan
Averaged adipocyte area was increased in AQP7 null mice (5322 Ϯ 157 versus 2014 Ϯ 67 m2), suggesting that the greater fat mass in the AQP7 null mice is a consequence of adipocyte hypertrophy
We found marked adipocyte hypertrophy and increased fat mass in AQP7-deficient mice, which developed progressively after age 6 weeks
Summary
From the ‡Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143, the §Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan, and the ¶Genome Information Research Center, Osaka University, Osaka 565-0871, Japan. Adipocyte lipolysis, measured by free fatty acid release and hormone-sensitive lipase activity, and lipogenesis, measured by [14C]glucose incorporation into triglycerides, were not affected by AQP7 deletion These data suggest that adipocyte hypertrophy in AQP7 deficiency results from defective glycerol exit and consequent accumulation of glycerol and triglycerides. Impaired glycerol transport in AQP3-deficient epidermal cells produced a low glycerol concentration in epidermis and stratum corneum (with normal serum glycerol), resulting in reduced stratum corneum hydration, elasticity, and biosynthesis, each of which could be corrected by glycerol replacement therapy [7]. These studies provided evidence for a physiological role for aquaporin-facilitated glycerol transport. Mechanistic analysis of adipocyte hypertrophy in AQP7 deficiency suggests pharmacological modulation of adipocyte AQP7 as a possible therapy in obesity
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