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Gao, Yun
Publications (2 of 2) Show all publications
Gao, Y., Shabalina, I. G., Braz, G. R., Cannon, B., Yang, G. & Nedergaard, J. (2022). Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues. Biochimica et Biophysica Acta - Bioenergetics, 1863(4), Article ID 148542.
Open this publication in new window or tab >>Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues
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2022 (English)In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1863, no 4, article id 148542Article in journal (Refereed) Published
Abstract [en]

The possibility that N-acyl amino acids could function as brown or brite/beige adipose tissue-derived lipokines that could induce UCP1-independent thermogenesis by uncoupling mitochondrial respiration in several peripheral tissues is of significant physiological interest. To quantify the potency of N-acyl amino acids versus conventional fatty acids as thermogenic inducers, we have examined the affinity and efficacy of two pairs of such compounds: oleate versus N-oleoyl-leucine and arachidonate versus N-arachidonoyl-glycine in cells and mitochondria from different tissues. We found that in cultures of the muscle-derived L6 cell line, as well as in primary cultures of murine white, brite/beige and brown adipocytes, the N-acyl amino acids were proficient uncouplers but that they did not systematically display higher affinity or potency than the conventional fatty acids, and they were not as efficient uncouplers as classical protonophores (FCCP). Higher concentrations of the N-acyl amino acids (as well as of conventional fatty acids) were associated with signs of deleterious effects on the cells. In liver mitochondria, we found that the N-acyl amino acids uncoupled similarly to conventional fatty acids, thus apparently via activation of the adenine nucleotide transporter-2. In brown adipose tissue mitochondria, the N-acyl amino acids were able to activate UCP1, again similarly to conventional fatty acids. We thus conclude that the formation of the acyl-amino acid derivatives does not confer upon the corresponding fatty acids an enhanced ability to induce thermogenesis in peripheral tissues, and it is therefore unlikely that the N-acyl amino acids are of specific physiological relevance as UCP1-independent thermogenic compounds.

Keywords
Adenine nucleotide transporter, Fatty acids, N-acyl amino acids, Nonshivering thermogenesis, Uncoupling protein-1, N-oleoyl-leu, N-arachidonoyl-gly
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-204413 (URN)10.1016/j.bbabio.2022.148542 (DOI)000781771000002 ()35192808 (PubMedID)
Available from: 2022-05-04 Created: 2022-05-04 Last updated: 2022-05-04Bibliographically approved
Luijten, I., Jaiprakash, A., Hettinga, L., Gao, Y., Cannon, B. & Nedergaard, J.Ucp1 transcription is regulated by glucocorticoid receptor binding at Ucp1 regulatory regions.
Open this publication in new window or tab >>Ucp1 transcription is regulated by glucocorticoid receptor binding at Ucp1 regulatory regions
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Glucocorticoids suppress Ucp1gene expression in brown adipocytes (BA) and brite/beige adipocytes (WA) in a cell-autonomous manner. The intracellular mechanism through which this suppression is mediated is not known. In in vitrodifferentiated primary cultures of murine brown and brite pre-adipocytes, the presence of dexamethasone (DEX) significantly reduced adrenergically-induced Ucp1mRNA levels, but upregulated the expression of other adrenergically-regulated genes. Additionally, DEX treatment increased NE-induced cAMP accumulation in BA. We thus conclude that the glucocorticoid-induced downregulation of Ucp1transcription occurs independently of a glucocorticoid-induced upregulation of the adrenergic signaling pathway. Using chromatin immunoprecipitation in combination with DNA sequencing in brown adipose tissue isolated from C57Bl/6 and BALB/c mice, we identified 6 glucocorticoid receptor binding sites in Ucp1active enhancer regions marked by H3K27ac. Luciferase reporter gene assays in the BA WT1 cell line indicated that the liganded GR binds to a regulatory region 0-4 kb upstream of the Ucp1transcription start site and thereby suppresses transcription. Thus, our study has identified a direct regulation of Ucp1transcription by the glucocorticoid receptor that occurs independently of the effects of glucocorticoids on adrenergic signaling. 

Keywords
Glucocorticoids, UCP1, transcription, adrenergic signaling, brown adipocyte, glucocorticoid response element
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-163988 (URN)
Funder
The Royal Swedish Academy of Sciences
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2022-02-26Bibliographically approved
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