Adipose tissue constitutes the most important source of glycerol in the
body. AQP7 is the most representative glycerol channel and the first identified
in human and rodents adipose tissue 82-84, adipocytes 85,86 and adipose
endothelial cells 87-90. Nevertheless,
alternative glycerol pathways have also been detected in human adipocytes, such
as AQP3 76,86,91, AQP9 92, AQP10 87 and AQP11 93.

The fundamental role of AQP7 in facilitating glycerol efflux from the
adipocyte into the bloodstream was achieved after its characterization as a
glycerol channel 85. Obese
insulin-resistant db+/db+ mice showed higher AQP7 expression 85 and similarly,
an increase in AQP7 mRNA was also observed in adipose tissue of a rodent model
of T2D with obesity 94. This suggests
that AQP7 dysregulation may lead to an augmented input of glycerol for hepatic
gluconeogenesis and, consequently, to increased glucose in the bloodstream, in
T2D 82. Furthermore,
AQP7 knockout mice showed adipocyte hypertrophy and early obesity onset due to the
accumulation of glycerol, which stimulates glycerol kinase (GK), leading to TAG
accumulation 95,74. Controversially,
susceptibility for obesity was not observed in other AQP7 knockout mice 90,96. Despite the different
phenotypes described in distinct AQP7 knockout mice, all confirmed the involvement
of AQP7 in glycerol metabolism. Moreover, although no obvious correlation was
found between adipose AQP7 expression/glycerol metabolism and related metabolic
complications in humans 97, genome-wide
analysis found AQP7 gene linked to T2D 98, MetS 99 and obesity,
the latter just for female participants 100. Gender
differences concerning the role of AQP7 in adipose tissue metabolism have also
been reported, where higher fasting circulating levels of glycerol have been
found in women comparing to men. Obese women showed higher AQP7 expression than
men in both subcutaneous and visceral adipose tissue, suggesting an association
between impaired AQP7 expression and obesity, at least in women 89,101.

AQP7 gene expression is upregulated in mice and human in the fasting state
or during exercise, whereas during the feeding state it is downregulated and
its abundance is inversely related with plasma insulin levels 85.
Transcription of AQP7 gene is inhibited by the increase of plasma insulin
levels through a negative insulin response element (IRE) located in the
promoter region of AQP7 gene 102,103 and by
blockage of the phosphatidylinositol-3 kinase (PI3K) pathway 92,103. On the other
hand, peroxisome proliferator-activated receptor gamma (PPAR?) was demonstrated
to upregulate AQP7 97,103,81. PPAR? is
also essential for adipocyte differentiation by regulating the transcription of
several adipose genes, including AQP7, and, in differentiating adipocytes, an
increase in AQP7 expression along with adipocyte differentiation was observed, suggesting
a cell differentiation-dependent regulation 85,104. Indeed, thiazolidinediones
(synthetic PPAR?) and insulin sensitizers were reported to upregulate AQP7 94,102,103, whereas insulin
resistance inducers such as leptin 92,101, TNF-?,
adrenergic agonists and steroids, downregulate AQP7 expression 105. Lipogenic
hormones, such as ghrelin, also control AQP7 regulation, decreasing its
expression while promoting TAG accumulation 106.

During fasting, low plasma insulin levels and catecholamine induce AQP7
gene transcription and AQP7 translocation to the plasma membrane, promoting
glycerol release from adipocytes 85. A
recent study in human primary adipocytes proposed
a molecular mechanism explaining
how glycerol release is controlled in adipocytes by interaction of AQP7 with
perilipin 1 (PLIN1)
and protein kinase A (PKA). In
lipogenic conditions, AQP7 and PLIN1 physically
interact in the adipocyte whereas in
the lipolytic state, catecholamine-activated
PKA phosphorylation
of the N-terminus of AQP7 reduces the complexation favoring
AQP7 translocation to the plasma membrane 107.  

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Studies with obese individuals showed a differential regulation of AQP7
depending on the type of adipose depot, subcutaneous or visceral; low AQP7
expression was detected in subcutaneous fat leading to fat accumulation and
adipocyte hypertrophy. In contrast, increased AQP7 levels were observed in
visceral fat, which can be correlated with increased lipolysis 81,76. Knowing that
subcutaneous adipose tissue is more insulin sensitive than visceral adipose
tissue, AQP7 downregulation might represent a mechanism of protection
attempting to prevent lipid depletion and consequent lipotoxicity to peripheral
organs 81.

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