37 posts

Exposure of adipocytes to bisphenol-A in vitro interferes with insulin action without enhancing adipogenesis

De Filippis E, Li T, Rosen ED

Bisphenol-A (BPA) is a lipophilic compound widely used in the manufacture of plastic items and thought to play a role in the growing obesity epidemic. Recent publications suggest that BPA may have a pro-adipogenic effect. Here we explore the effect of low, but environmentally relevant, concentrations of BPA on adipogenesis using a variety of cellular models. Mouse 3T3-L1, C3H10T1/2 and human adipose-derived stromal cells (hADSCs) were cultured with BPA concentrations ranging from 0.1nM to 100μM. We failed to observe positive effects on differentiation at any dose or in any model. 3T3-L1 adipocytes differentiated with high concentrations of BPA showed decreased mRNA expression of several adipocyte markers. Mature adipocytes differentiated in the presence of BPA were insulin resistant, with an approximate 25% reduction in insulin-stimulated glucose uptake. This was accompanied by a significant decrease in insulin-stimulated Akt phosphorylation, and an increase in mRNA levels of inflammatory markers (i.e. IL-6, TNFα). In conclusion, low, but environmentally relevant, doses of BPA may contribute to the development of a chronic, low-grade inflammatory state in exposed adipocytes, which in turn may affect adipose tissue insulin sensitivity, independent of adipogenesis. These studies suggest an alternative mechanism by which BPA may contribute to the development of obesity.

PLoS One. 2018 Aug 22;13(8):e0201122. doi: 10.1371/journal.pone.0201122. eCollection 2018



Brown Adipose Tissue Controls Skeletal Muscle Function via the Secretion of Myostatin

Kong X, Yao T, Zhou P, Kazak L, Tenen D, Lyubetskaya A, Dawes BA, Tsai L, Kahn BB, Spiegelman BM, Liu T, Rosen ED

Skeletal muscle and brown adipose tissue (BAT) are functionally linked, as exercise increases browning via secretion of myokines. It is unknown whether BAT affects muscle function. Here, we find that loss of the transcription factor IRF4 in BAT (BATI4KO) reduces exercise capacity, mitochondrial function, ribosomal protein synthesis, and mTOR signaling in muscle and causes tubular aggregate formation. Loss of IRF4 induces myogenic gene expression in BAT, including the secreted factor myostatin, a known inhibitor of muscle function. Reducing myostatin via neutralizing antibodies or soluble receptor rescues the exercise capacity of BATI4KO mice. In addition, overexpression of IRF4 in brown adipocytes reduces serum myostatin and increases exercise capacity in muscle. Finally, mice housed at thermoneutrality have reduced IRF4 in BAT, lower exercise capacity, and elevated serum myostatin; these abnormalities are corrected by excising BAT. Collectively, our data point to an unsuspected level of BAT-muscle crosstalk driven by IRF4 and myostatin.

Cell Metab. 2018 Oct 2;28(4):631-643.e3. doi: 10.1016/j.cmet.2018.07.004. Epub 2018 Aug 2



Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity

Roh HC, Tsai LTY, Shao M, Tenen D, Shen Y, Kumari M, Lyubetskaya A, Jacobs C, Dawes B, Gupta RK, Rosen ED

Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological “whitening,” but it is unknown whether or to what extent this represents a true shift in cellular identity. Using cell-type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure. We further show that a transcriptional cascade involving glucocorticoid receptor and Zfp423 can drive warm-induced whitening of beige adipocytes. These studies identify the epigenomic and transcriptional bases of an extraordinary example of cellular plasticity in response to environmental signals.

Cell Metab. 2018 May 1;27(5):1121-1137.e5. doi: 10.1016/j.cmet.2018.03.005. Epub 2018 Apr 12