Lack of TRPV1 aggravates obesity-associated hypertension through the disturbance of mitochondrial Ca2+ homeostasis in brown adipose tissue

Li Li,Zongshi Lu,Lijuan Wang,Liqun Ma,Mei You,Zhiming Zhu,Huan Ma,Cui Zhou,Chengkang He,Qing Zhou,Tingbing Cao,Aidi Mou,Zhidan Luo,Yu Zhao,Peng Gao,Yucun Gu,Xiao Wei

doi:10.1038/s41440-021-00842-8

Li Li, Zongshi Lu + Show 15 more

Open Access

https://doi.org/10.1038/s41440-021-00842-8

Copy DOI

Abstract

The combination of obesity and hypertension is associated with high morbidity and mortality; however, the mechanism underlying obesity-induced hypertension remains unclear. In this study, we detected the possible effects of TRPV1, a previously identified antihypertensive calcium (Ca2+) channel in adipose tissue, on the occurrence of obesity and hypertension in mice lacking UCP1, a spontaneously genetically manipulated obesity model, by generating TRPV1 and UCP1 double knockout mice. In these mice, obesity and hypertension appeared earlier and were more severe than in mice with the knockout of UCP1 or TRPV1 alone. The knockout of TRPV1 in UCP1 knockout mice further reduced functional brown adipose tissue (BAT) generation; decreased resting oxygen consumption, heat production, and locomotor activities; and was accompanied by severe mitochondrial respiratory dysfunction in BAT. Mechanistically, TRPV1, UCP1, and LETM1 acted as a complex to maintain an appropriate mitochondrial Ca2+ level, and TRPV1 knockout caused a compensatory increase in mitochondrial Ca2+ uptake via LETM1 activation. However, the compensatory response was blocked in UCP1−/− mice, resulting in dramatically reduced mitochondrial Ca2+ uptake and higher production of ATP and oxidative stress. This study provides in vivo evidence for the critical role of BAT mitochondrial Ca2+ homeostasis in obesity-associated hypertension and indicates that the TRPV1/UCP1/LETM1 complex may be an alternative intervention target.

Highlights

Obesity has become a major public health problem
We found that the regulatory effect of Transient receptor potential vanilloid-1 (TRPV1) on Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) was critical to restrain obesity and related hypertension, and the knockout of TRPV1 further exacerbated obesity in uncoupling protein 1 (UCP1) knockout mice, resulting in more severe hypertension
Western blot results indicated that the expression of TRPV1 or UCP1 could not be detected in the brown adipose tissue (BAT) of the double knockout mice (Supplementary Fig. 1A, B)

Summary

Introduction

Obesity has become a major public health problem. The World Health Organization (WHO) pointed out that with the prevalence of obesity, the double burden of communicable and noncommunicable diseases is imminent [1]. Obesity-associated hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular diseases (CVDs) [2]. The etiology of obesity-associated hypertension is extremely heterogeneous, as it is the result of increased sodium reabsorption, the activation of the renin–angiotensin–aldosterone system, endothelial dysfunction and decreased sensitivity to natriuretic peptides, as well as oxidative and inflammatory stress [2]. The abnormal production of reactive oxygen species (ROS) has been considered a common pathogenetic mechanism of cardiovascular diseases resulting from diverse risk factors, such as chronic smoking, diabetes mellitus, and metabolic syndrome [3]

Methods

Results

Discussion

Conclusion