Metabolic impact of the glycerol channels AQP7 and AQP9 in adipose tissue and liver

Abstract

Obesity and secondary development of type 2 diabetes (T2D) are major health care problems throughout the developed world. Accumulating evidence suggest that glycerol metabolism contributes to the pathophysiology of obesity and T2D. Glycerol is a small molecule that serves as an important intermediate between carbohydrate and lipid metabolism. It is stored primarily in adipose tissue as the backbone of triglyceride (TG) and during states of metabolic stress, such as fasting and diabetes, it is released for metabolism in other tissues. In the liver, glycerol serves as a gluconeogenic precursor and it is used for the esterification of free fatty acid into TGs. Aquaporin 7 (AQP7) in adipose tissue and AQP9 in the liver are transmembrane proteins that belong to the subset of AQPs called aquaglyceroporins. AQP7 facilitates the efflux of glycerol from adipose tissue and AQP7 deficiency has been linked to TG accumulation in adipose tissue and adult onset obesity. On the other hand, AQP9 expressed in liver facilitates the hepatic uptake of glycerol and thereby the availability of glycerol for de novo synthesis of glucose and TG that both are involved in the pathophysiology of diabetes. The aim of this review was to summarize the current knowledge on the role of the two glycerol channels in controlling glycerol metabolism in adipose tissue and liver. Glycerol metabolismThe metabolic switching between feeding and fasting is central to everyday life and involves tight hormonal control with effects on muscle, adipose tissue, and liver that maintains an adequate handling of metabolic precursors to support energy demands. One of the molecules affected by metabolic switching is glycerol, which is a small 3-carbon alcohol that in the fed state is stored as the backbone of triglyceride (TG) mainly in adipose tissue.In the fed state, after ingestion of dietary fats (w90% TG), !30% of TG is fully hydrolyzed into free fatty acids (FFA) and glycerol. Glycerol rapidly enters the enterocytes of the small intestine and thereafter the circulation through the portal vein and is primarily metabolized by the liver (Lin 1977). In adipose tissue, the activity of glycerol kinase (GlyK), that catalyzes the initial phosphorylation of glycerol into glycerol-3-phosphate (G3P), is negligible and therefore glycerol is not normally utilized in adipose tissue. Instead G3P used for the synthesis of TG in the fed state is derived from glycolysis.During states of increased energy demand, such as fasting and exercise, adipocyte lipolysis is increased by activation of adipose TG lipase and hormone-sensitive

The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression

“…We observed a positive association of maternal U-As levels with expression of the aquaglyceroporin transporter, AQP9 , in female, but not male, fetal placenta, indicating that AQP9 may be upregulated in response to arsenic in a female sex-specific manner. This is in keeping with previous studies in animal models, showing upregulation of AQP9 in response to arsenic [34], as well as sex-specific regulation of AQP9 expression [35, 36]. These prior studies suggest that estrogen may play a role in facilitating transcription of AQP9 in liver cells, and suggest it may be useful to examine sex hormone dependent effects in placental tissue as well.…”

Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

“…35 MMP9 itself is involved in ECM remodeling, with increased expression during adipogenesis, 36 its expression is reduced after weight loss 37 and increased in obese stroma-vascular fraction 38 and in adipose tissue with obesity-associated insulin resistance. 39 Aquaporin AQP7 facilitates the efflux of glycerol from adipose tissue and AQP7 deficiency has been linked to triglyceride accumulation in adipose tissue, and adult onset obesity 40 ; its expression is down regulated in obese adipose tissue. 41 Among proteins involved in lipid metabolism, we identified obesity-dysregulated genes also depicted in the literature for their implication in metabolic disorders related to adipose tissue.…”

Beyond water homeostasis: Diverse functional roles of mammalian aquaporins

“…There are up to 13 mammalian AQPs, which are found in most tissues with functions ranging from the regulation of renal water balance [1], brain-fluid homeostasis [2], triglyceride cycling between adipocytes and the liver [3] and structural integrity of the eye lens [4]. Because of this, understanding AQP function is crucial for the study of healthy ageing as well as the onset of many disease states such as brain swelling following stroke or head injury [5], nephrogenic diabetes insipidus [6,7], cataracts [8], obesity [9], cancer cell proliferation and migration [10] and tumour angiogenesis [11].…”