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Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

Abstract : In mice, exercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders. White adipose tissue (WAT) plays a crucial role in energetic homeostasis regulation through the storage of excess energy in the large central vacuole of white adipocytes 1. WAT also performs metabolic functions and secretes several hormones such as Resistin (Retn) 1-3 and Leptin (Lep) which regulates body weight, lipid and glucose metabolism 4-6. WAT is located in diverse sites throughout the body, such as the subcutaneous inguinal (SC-WAT), perigonadal (GAT), mesenteric (MAT) and perirenal (PAT) depots 7,8. While these depots are collectively named white adipose tissue, they have different developmental origins: SC-WAT, GAT and MAT derive from lateral plate mesoderm in female mice whereas PAT derive from the somitic mesoderm 8. These different origins could contribute to differences in the physiology of fat depots. In contrast, brown adipose tissue (BAT) has a critical thermogenic function thanks to its property to dissipate excess energy through heat production 9. BAT depots are derived from the somitic mesoderm 8 and are located in the inter-scapular region in mice and in both neck and supraclavicular regions in humans 9. Brown adipocytes are smaller than white adipocytes. They exhibit multiple small lipid vacuoles and large number of mitochondria involved in heat production through the constitutive activation of the thermogenic uncoupling protein 1 (Ucp1) 10-12. A third type of adipocyte, called beige adipocyte, has been described within WAT 9,13. Morphological and transcriptomic analyses show that brown and beige adipocytes are remarkably similar and express the same thermogenic markers, including Ucp1 14. In mice, beige adipocytes differentiation occurs in response to long open
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Marianne Bléher, Berbang Meshko, Isabelle Cacciapuoti, Rachel Gergondey, Yoann Kovacs, et al.. Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue. Scientific Reports, Nature Publishing Group, 2020, 10 (1), ⟨10.1038/s41598-020-72698-w⟩. ⟨hal-02988104⟩

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