LETMD1 is required for mitochondrial structure and thermogenic function of brown adipocytes

Obesity and metabolic disorders caused by energy surplus pose an increasing concern within the global population. Brown adipose tissue (BAT) dissipates energy through mitochondrial non‐shivering thermogenesis, thus representing a powerful agent against obesity. Here we explore the novel role of a mi...

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Bibliographic Details
Published in:The FASEB journal 2021-11, Vol.35 (11), p.e21965-n/a
Main Authors: Snyder, Madigan M., Yue, Feng, Zhang, Lijia, Shang, Renjie, Qiu, Jiamin, Chen, Jingjuan, Kim, Kun Ho, Peng, Ying, Oprescu, Stephanie N., Donkin, Shawn S., Bi, Pengpeng, Kuang, Shihuan
Format: Article
Language:English
Subjects:
Adipocytes, Brown - cytology
Adipocytes, Brown - metabolism
Adipose Tissue, Brown - cytology
Adipose Tissue, Brown - metabolism
Animals
brown adipose tissue
cold intolerance
LETM1 domain containing 1
Mice
Mice, Inbred C57BL
Mice, Knockout
mitochondria
Mitochondria - metabolism
Obesity - metabolism
Oncogene Proteins - physiology
Receptors, Cell Surface - physiology
Thermogenesis
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Summary:Obesity and metabolic disorders caused by energy surplus pose an increasing concern within the global population. Brown adipose tissue (BAT) dissipates energy through mitochondrial non‐shivering thermogenesis, thus representing a powerful agent against obesity. Here we explore the novel role of a mitochondrial outer membrane protein, LETM1‐domain containing 1 (LETMD1), in BAT. We generated a knockout (Letmd1KO) mouse model and analyzed BAT morphology, function and gene expression under various physiological conditions. While the Letmd1KO mice are born normally and have normal morphology and body weight, they lose multilocular brown adipocytes completely and have diminished mitochondrial abundance, DNA copy number, cristae structure, and thermogenic gene expression in the intrascapular BAT, associated with elevated reactive oxidative stress. In consequence, the Letmd1KO mice fail to maintain body temperature in response to acute cold exposure without food and become hypothermic within 4 h. Although the cold‐exposed Letmd1KO mice can maintain body temperature in the presence of food, they cannot upregulate expression of uncoupling protein 1 (UCP1) and convert white to beige adipocytes, nor can they respond to adrenergic stimulation. These results demonstrate that LETMD1 is essential for mitochondrial structure and function, and thermogenesis of brown adipocytes.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202100597R