Abstract
Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAPfl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAPadipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAPfl/fl mice, ATRAPadipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAPfl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAPadipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders.
Highlights
As the number of overweight and obese patients continues to increase worldwide, studies on the resulting health risks have gained significant attention [1,2]
2o.4n.aWHhiigteh-AFdatipDosietTissue angiotensin II type-1 receptor (AT1R)-associated protein (ATRAP) mRNA Expression in ATRAPadipoq Mice Is Comparable to ATRAPfl/fl Mice oBneacaHuisgeh-tFhaetrDe iewt ere no differences in physiological and metabolic parameters, adipocyte morBpehcoaluosgey, tahnedreadwiperoesenmo adcrifofperheangceesinifinltrpahtiyosniobloegtwiceael natnhde AmTeRtaAbPolfli/cfl paanrdamAeTtRerAs,Paaddipiopqocmyitcee moonrHphFoDloogryL, aFnDd, wadeipeoxsaemminaecdrotphheaAgTeRinAfiPltrmatRioNnAbetxwperesnsitohne iAnTtRheAWPflA/flTa.nAdsAsThRowAnPaidnipoFq imguicre o6nA, high-fat diet (HFD) or low3 o-ffa16t diet (LFD), we examined the ATRAP mRNA expression in the white adipose tissue (WAT)
We report that wild-type mice fed an HFD showed decreased endogenous ATRAP expression in the WAT concomitant with the enhanced progression of dietary obesity and insulin resistance
Summary
As the number of overweight and obese patients continues to increase worldwide, studies on the resulting health risks have gained significant attention [1,2]. Recent studies have focused on the pathological molecular mechanisms by which chronic adipose tissue inflammation and dysregulation of adipokines contribute to systemic insulin resistance in the progression of visceral fat obesity [7,8,9]. The excessive activation of AT1R signaling increases oxidative stress and chronic inflammation, which results in the induction of insulin resistance. Angiotensin II type-1 receptor-associated protein promotes the constitutive internalization of AT1R, and is likely to be an endogenous inhibitor that selectively prevents excessive activation of the AT1R signaling pathway. Systemic ATRAP-knockout mice fed a high-fat diet (HFD) showed increased significant visceral fat, adipocyte hypertrophy, enhanced inflammation with macrophage infiltration of adipose tissue, and exacerbation of systemic insulin resistance compared with wild-type mice fed an HFD. The transplantation of epididymal white adipose tissue (WAT), which highly expresses exogenous ATRAP, to systemic ATRAP knockout mice, caused a reduction in visceral fat and insulin resistance [16]
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