Adipocyte‐Specific Enhancement of Angiotensin II Type 1 Receptor‐Associated Protein Ameliorates Diet‐Induced Visceral Obesity and Insulin Resistance

Abstract

BackgroundThe renin–angiotensin system has a pivotal role in the pathophysiology of visceral obesity. Angiotensin II type 1 receptor (AT1R) is a major player in the signal transduction of the renin–angiotensin system, and the overactivation of this signaling contributes to the progression of visceral obesity. We have shown that the AT1R‐associated protein (ATRAP) promotes AT1R internalization from the cell surface into cytoplasm along with the suppression of overactivation of tissue AT1R signaling. In this study, we examined whether the enhancement of adipose ATRAP expression could efficiently prevent diet‐induced visceral obesity and insulin resistance.Methods and ResultsWe generated adipocyte‐specific ATRAP transgenic mice using a 5.4‐kb adiponectin promoter, and transgenic mice and littermate control mice were fed either a low‐ or high‐fat diet for 10 weeks. Although the physiological phenotypes of the transgenic and control mice fed a low‐fat diet were comparable, the transgenic mice exhibited significant protection against high‐fat diet–induced adiposity, adipocyte hypertrophy, and insulin resistance concomitant with an attenuation of adipose inflammation, macrophage infiltration, and adipokine dysregulation. In addition, when mice were fed a high‐fat diet, the adipose expression of glucose transporter type 4 was significantly elevated and the level of adipose phospho‐p38 mitogen‐activated protein kinase was significantly attenuated in the transgenic mice compared with control mice.ConclusionsResults presented in this study suggested that the enhancement in adipose ATRAP plays a protective role against the development of diet‐induced visceral obesity and insulin resistance through improvement of adipose inflammation and function via the suppression of overactivation of adipose AT1R signaling. Consequently, adipose tissue ATRAP is suggested to be an effective therapeutic target for the treatment of visceral obesity.

Angiotensin II Type 1 Receptor‐Associated Protein Regulates Kidney Aging and Lifespan Independent of Angiotensin

“…However, ATRAP exerts no evident influence on the physiological AT1R signaling pathway. For example, the phenotype of ATRAP transgenic mice with overexpression of ATRAP in cardiovascular tissue is similar to that of their littermate WT control mice under nonstimulating conditions . In the current study, there were no significant differences in blood pressure, cardiovascular injury, and glucose/fat metabolism profiles between aged ATRAP‐KO and WT mice (Figure ; Table).…”

“…ATRAP in cardiovascular and adipose tissue can inhibit hyperactivation of tissue AT1R signaling caused by certain pathological stimuli, such as chronic Ang II infusion or dietary loading, and improve cardiovascular disturbances and insulin resistance . However, ATRAP exerts no evident influence on the physiological AT1R signaling pathway.…”

Transcripto‐based network analysis reveals a model of gene activation in tongue squamous cell carcinomas

“…Ang II type 1 receptor (AT1R)‐associated protein (ATRAP/Agtrap) is a transmembrane protein localized to the plasma membrane and perinuclear vesicular structures and was originally identified as a low‐molecular‐weight protein that binds to the carboxyl‐terminal domain of AT1R . The strongest expression of ATRAP was found in renal tubules of kidneys, and it also was found in the heart, kidneys, vascular smooth muscle cells, and adipose tissues . Previous studies showed us that ATRAP could enhance the constitutive internalization of AT1R and suppress the activation of angiotensin II in order to negatively regulate angiotensin II signaling and selectively suppress Ang II‐mediated pathological responses .…”

Angiotensin receptor subtypes regulate adipose tissue renewal and remodelling

“…ATRAP‐dependent signalling can suppress the overactivation of adipose AT 1 R signalling, mediated by G protein and β‐arrestin. This action can prevent hypertrophy, diet‐induced visceral obesity and insulin resistance and, hence, play a compensatory role .…”