Angiotensin Receptor–Binding Protein ATRAP/ Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity

Abstract

BackgroundMetabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life‐threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity‐related metabolic disorders, moving the tissue toward a proinflammatory phenotype.Methods and ResultsHere we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of ATRAP/Agtrap, which is a specific binding modulator of the angiotensin II type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of ATRAP in the pathophysiology of metabolic disorders, we produced homozygous ATRAP deficient (Agtrap−/−) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading, Agtrap−/− mice displayed systemic metabolic dysfunction, characterized by an increased accumulation of pad fat, hypertension, dyslipidemia, and insulin resistance, along with adipose tissue inflammation. Conversely, subcutaneous transplantation of donor fat pads overexpressing ATRAP derived from Agtrap transgenic mice to Agtrap−/− recipient mice improved the systemic metabolic dysfunction.ConclusionsThese results demonstrate that Agtrap−/− mice are an effective model of metabolic disorders with visceral obesity and constitute evidence that ATRAP plays a protective role against insulin resistance, suggesting a new therapeutic target in metabolic disorders. Identification of ATRAP as a novel receptor binding modulator of adipose tissue inflammation not only has cardiovascular significance but may have generalized implication in the regulation of tissue function.

ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice

“…In Dahl salt-sensitive rats, high-salt diet loading decreased renal ATRAP expression and accelerated the progression of hypertensive kidney injury [27]. Expression of ATRAP in the WAT was decreased in KKAy mice, a diabetes mellitus model, compared with control C57BL/6N mice [16]. We also reported changes in tissue ATRAP expression in response to a pathological stimulus.…”

“…Because ATRAP does not modulate the physiological AT1R signaling pathway in the absence of pathological stimuli, no clear difference was expected between genotypes fed an LFD [16]. However, even dietary obesity induced by an HFD did not result in differences in glucose or lipid metabolism between ATRAP adipoq and ATRAP f1/f1 mice.…”

“…The GTT and ITT were performed as previously described with slight modifications [16]. Briefly, GTT and ITT were performed 4 days apart at the end of the experimental period between 10:00 a.m.–2:00 p.m. and 2:00 p.m.–4:00 p.m., respectively.…”

“…Angiotensin II type-1 receptor-associated protein and AT1R are endogenously expressed in many organs. Notably, adipose tissue shows high endogenous expression levels of ATRAP [14,15,16,17]. In our previous study, 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.…”

“…In our previous study, 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. Moreover, 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]. …”