2. Academic Validation
  3. Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1

Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1

  • Mol Metab. 2023 Jun 4;101747. doi: 10.1016/j.molmet.2023.101747.
Fan Li 1,  Fenglin Zhang 1,  Xin Yi 1,  Lu Lu Quan 1,  Xiaohua Yang 1,  Cong Yin 1,  Zewei Ma 1,  Ruifan Wu 1,  Weijie Zhao 1,  Mingfa Ling 1,  Limin Lang 1,  Abdelaziz Hussein 1,  Shengchun Feng 1,  Yiming Fu 1,  Junfeng Wang 1,  Shuyi Liang 1,  Canjun Zhu 1,  Lina Wang 1,  Xiaotong Zhu 1,  Ping Gao 1,  Qianyun Xi 1,  Yongliang Zhang 1,  Lin Zhang 1,  Gang Shu 1,  Qingyan Jiang 2,  Songbo Wang 3
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Animal Nutrition Control and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China.
  • 2 Guangdong Provincial Key Laboratory of Animal Nutrition Control and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. Electronic address: qyjiang@scau.edu.cn.
  • 3 Guangdong Provincial Key Laboratory of Animal Nutrition Control and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China; Yunfu Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Wen's Foodstuffs Group Co., Ltd, Yunfu 527400, P. R. China. Electronic address: songbowang@scau.edu.cn.
PMID: 37279828 DOI: 10.1016/j.molmet.2023.101747
Abstract

Objective: Brown adipose tissue (BAT) plays a crucial role in regulating non-shivering thermogenesis under cold exposure. Proline hydroxylases (PHDs) were found to be involved in adipocyte differentiation and lipid deposition. However, the effects of PHDs on regulatory mechanisms of BAT thermogenesis are not fully understood.

Methods: We detected the expression of PHDs in different adipose tissues by using immunoblotting and Real-Time PCR. Further, immunoblotting, Real-Time PCR, and immunostaining were performed to determine the correlation between proline hydroxylase 2 (PHD2) and UCP1 expression. Inhibitor of PHDs and PHD2-sgRNA viruses were used to construct the PHD2-deficiency model in vivo and in vitro to investigate the impacts of PHD2 on BAT thermogenesis. Afterward, the interaction between UCP1 and PHD2 and the hydroxylation modification level of UCP1 were verified by Co-IP assays and immunoblotting. Finally, the effect of specific proline hydroxylation on the expression/activity of UCP1 was further confirmed by site-directed mutation of UCP1 and mass spectrometry analysis.

Results: PHD2, but not PHD1 and PHD3, was highly enriched in BAT, colocalized, and positively correlated with UCP1. Inhibition or knockdown of PHD2 significantly suppressed BAT thermogenesis under cold exposure and aggravated obesity of mice fed HFD. Mechanistically, mitochondrial PHD2 bound to UCP1 and regulated the hydroxylation level of UCP1, which was enhanced by thermogenic activation and attenuated by PHD2 knockdown. Furthermore, PHD2-dependent hydroxylation of UCP1 promoted the expression and stability of UCP1 protein. Mutation of the specific prolines (Pro-33, 133, and 232) in UCP1 significantly mitigated the PHD2-elevated UCP1 hydroxylation level and reversed the PHD2-increased UCP1 stability.

Conclusions: This study suggested an important role for PHD2 in BAT thermogenesis regulation by enhancing the hydroxylation of UCP1.

Keywords

BAT thermogenesis; Hydroxylation; PHD2; UCP1.

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