White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models
Liang Li, Brian J. Feldman
Liang Li, Brian J. Feldman
Published July 1, 2024
Citation Information: J Clin Invest. 2024;134(13):e172360. https://doi.org/10.1172/JCI172360.
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White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models

Abstract

Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15’s direct regulation of Adrb1 is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.

Authors

Liang Li, Brian J. Feldman

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Figure 1

Acute modulation of Klf15 expression in white adipocytes induces a beige fat expression profile.

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Acute modulation of Klf15 expression in white adipocytes induces a beige...
(A) RT-qPCR quantifying the expression levels of Klf15 in adipocytes isolated from distinct fat pads. 1-way ANOVA, n = 3. (B) RT-qPCR quantifying the expression levels of Klf15 in adipocytes after isoproterenol (Iso) treatment for 4 hours. Student’s t test, n = 6. (C) RT-qPCR quantifying the expression levels of Klf15 in iWAT isolated from mice after they were injected with CL316243 (CL) (1 mg/kg/day) for 7 days. Student’s t test, n = 4. (D) RT-qPCR quantifying the relative expression levels of Adrb1, Adrb2, and Adrb3 in iWAT, gWAT, and BAT with iWAT set to 1 for each litter. 1-way ANOVA, n = 5. (E) Light phase microscopy images of adipocytes from differentiated SVF harvested from the iWAT of Klf15-fl/fl mice and infected with adenovirus expressing Cre (Ad-Cre) or adenovirus control (Ad-control). Scale bar: 25 μm. (F) RT-qPCR quantifying the expression levels of thermogenic genes and panadipocyte marker Adipoq. Student’s t test, n = 4. (G) RT-qPCR quantifying the expression levels. Student’s t tests followed by Holm-Šidák correction, n = 7. (H) Immunoblots detecting and quantifying the relative levels of β1AR following acute Klf15 deletion in adipocytes. Student’s t test, n = 3. (I) Immunoblots detecting and quantifying the relative levels of phosphorylation of p38 MAPK following acute Klf15 deletion in adipocytes. Student’s t test, n = 3. (J) RT-qPCR quantifying the change in Ucp1 expression levels with SB202190 pretreatment. Student’s t test, n = 3–4. (K) RT-qPCR quantifying the expression levels of Ucp1 following acute Klf15 deletion in adipocytes treated with Isoproterenol. 2-way ANOVA, n = 3. *P < 0.05, **P < 0.01, ***P < 0.001.