Sirtuin 3-mediated pyruvate dehydrogenase activity determines brown adipocytes phenotype under high-salt conditions

Tong Wei,Chenglin Huang,Mengwei Sun,Penghao Liu,Gaojian Huang,Jing Gao,Weili Shen

doi:10.1038/s41419-019-1834-4

Tong Wei, Chenglin Huang + Show 5 more

Open Access

https://doi.org/10.1038/s41419-019-1834-4

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Abstract

Previous study indicated that Sirtuin 3 (SIRT3) is a central regulator of adaptive thermogenesis in brown adipose tissue (BAT). Here we investigate the role of SIRT3 in the modulation of cellular phenotype in BAT under high salt intake (HS). HS downregulated SIRT3 level in BAT, accompanied by decreased oxygen consumption rate, and caused a severe loss of BAT characteristics. Mechanically, SIRT3 interacted with pyruvate dehydrogenase E1α (PDHA1) and deacetylated Lys-83 both in vitro and in vivo under HS. In parallel, HS suppressed salt-induced kinase (Sik) 2 phosphorylation. Silencing Sik2 further diminished SIRT3 activity and enhanced acetylation of PDHA1 K83 level. Reconstruction of SIRT3 restored PDH activity and thermogenic markers expression in differentiated brown adipocytes from SIRT3 knockout (KO) mice. In addition, loss of SIRT3 induced selective remodelling of phospholipids and glycerolipids in BAT exposure to HS. These data indicate that SIRT3 is an essential enzymatic switch that controls brown adipose cell phenotype.

Highlights

Adipose tissue is an important metabolic regulator of energy balance, which has two functionally distinct types of adipocytes
Sirtuin 3 (SIRT3) level is reduced in beige adipose tissue (BAT) after 6 weeks of High salt (HS) intake To examine the effects of HS on SIRT3 expression, C57BL/6 mice were subjected to HS (1% NaCl in tap water) intake for 6 weeks
The results showed that SIRT3 is abundantly expressed in BAT compared with subcutaneous (SAT) and epididymis (EAT) white adipose tissue (WAT) (Fig. 1a, b)

Summary

Introduction

Adipose tissue is an important metabolic regulator of energy balance, which has two functionally distinct types of adipocytes. Those in white adipose tissue (WAT) store excess energy and contain a single large lipid vesicle and few mitochondria, whereas those in brown and brite/beige adipose tissue (BAT) burn excess energy and have multilocular lipid droplets and abundant mitochondria that produce heat by uncoupled respiration[1]. The role of HS in lipid metabolism and fat deposition is debated[10] Both human and animal studies have shown that a HS diet increases WAT mass, adipocyte size and leptin production[11,12]. Others have demonstrated that salt restriction increased WAT mass, whereas a low-

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