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<p>Obesity arises from disrupted energy homeostasis, yet the neural mechanisms linking transcriptional regulation to energy expenditure remain unclear. Here, we identify plant homeodomain finger protein 6 (Phf6), a gene mutated in Börjeson-Forssman-Lehmann syndrome (BFLS), as a pivotal regulator of energy balance. Phf6 is enriched in a subset of estrogen receptor 1 (Esr1)-expressing neurons within the hypothalamic medial preoptic area (MPOA). Knockout of <i>Phf6</i> in the MPOA leads to obesity in a sex-dependent manner by reducing physical activity and energy expenditure, independent of food intake. In female mice, <sup>MPOA</sup>Phf6 neurons respond to physical activity. Activation and inhibition of <sup>MPOA</sup>Phf6 neurons increases and decreases physical activity and energy expenditure, respectively. Phf6 sustains the intrinsic excitability of <sup>MPOA</sup>Phf6 neurons and their responsiveness to estrogen. Circuit mapping identified an <sup>MPOA</sup>Phf6-<sup>VMHvl</sup>Esr1 pathway mediating Phf6’s effect on metabolism. These findings reveal a neurobiological basis for BFLS-associated obesity and highlight potential therapeutic targets.</p>

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Regulation of physical activity and energy expenditure through Phf6 in the medial preoptic area

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Jingjie Wang,
  • Bing Liu,
  • Xiaohua Wu,
  • Jingjing Sun,
  • Yaxin Wang,
  • Liang He,
  • Linhua Gan,
  • Xiangfeng Du,
  • Jingyu Ruan,
  • Lingzhi Pi,
  • Qing-Feng Wu,
  • Ju Huang

摘要

Obesity arises from disrupted energy homeostasis, yet the neural mechanisms linking transcriptional regulation to energy expenditure remain unclear. Here, we identify plant homeodomain finger protein 6 (Phf6), a gene mutated in Börjeson-Forssman-Lehmann syndrome (BFLS), as a pivotal regulator of energy balance. Phf6 is enriched in a subset of estrogen receptor 1 (Esr1)-expressing neurons within the hypothalamic medial preoptic area (MPOA). Knockout of Phf6 in the MPOA leads to obesity in a sex-dependent manner by reducing physical activity and energy expenditure, independent of food intake. In female mice, MPOAPhf6 neurons respond to physical activity. Activation and inhibition of MPOAPhf6 neurons increases and decreases physical activity and energy expenditure, respectively. Phf6 sustains the intrinsic excitability of MPOAPhf6 neurons and their responsiveness to estrogen. Circuit mapping identified an MPOAPhf6-VMHvlEsr1 pathway mediating Phf6’s effect on metabolism. These findings reveal a neurobiological basis for BFLS-associated obesity and highlight potential therapeutic targets.