(P20-066-25) LETM-Domain Containing 1 (LETMD1) Enhances Energy Expenditure in Human Beige Adipocytes

Objectives: Brown and beige adipocytes are specialized fat cells that dissipate energy in the form of heat, and hold therapeutic potential for obesity and metabolic diseases. Leucine zipper-, EF-hand-containing transmembrane protein 1 domain containing 1 (LETMD1) was recently identified as a key protein in maintaining the thermogenic activity of brown adipocytes in animal models. In this study, we investigated the functional role of LETMD1 in human beige adipocytes and its utility to combat obesity and its associated metabolic disorders.

Methods: We tested the function of LETMD1 in human induced pluripotent stem cell (iPSCs)-derived beige adipocytes in vitro and the function of LETMD1 in human beige adipocytes were evaluated in the in vivo setting. RNA-Seq was conducted in normal and LETMD1-overexpressing human beige adipocytes. Using a LETMD1 knock-in human iPSC reporter line, a small molecule compound library was screened for compounds that increase LETMD1 expression in human beige adipocytes. The effect of the compound in inducing LETMD1 in beige adipocytes was examined in vitro and in animal models.

Results: LETMD1 plays an essential role in engaging energy dissipation in human beige adipocytes. Transplantation of LETMD1-overexpressing human beige adipocytes improved whole-body metabolism of the recipient mice. Mechanistically LETMD1 enhances the transcription of PGC1a, a key regulator of mitochondria biogenesis. Using LETMD1 reporter human beige adipocytes, SP-8356 was identified as a compound significantly increasing LETMD1 expression. Oral administration of SP-8356 induced genes related to UCP1-independent energy expenditure in beige adipocytes, and counteracted body weight gain and metabolic disorders in mice.

Conclusions: In summary, increased LETMD1 action, either genetically or pharmacologically, enhances the non-canonical UCP1-independent energy expenditure in beige adipocytes.

Funding Sources: This work is supported in part by the National Key Research and Development Plan of China (2022YFE021600), Science and Technology Planning Project of Guangdong Province (2022A0505090006 and 2023B12120009) and RGC general research fund (#14109622).