SignificanceShortly after its appearance on the drug market, it was found out that thalidomide was highly teratogenic. Although thalidomide passed the safety check in pregnant mice, it was not safe among humans due to different actions of thalidomide among various species. Due to inactivity of immunomodulatory drugs (IMiDs) in mice, preclinical safety checks and clinical investigation of IMiDs is impossible in murine models. Here, we developed a murine model to study IMiDs in vivo and began to unravel the complex IMiD mechanism of action. This model may also permit investigation of the main safety concerns. We further investigated IMiD activity toward different substrates targeted by small molecules. Overall, our study provides an important insight into the study of IMiDs.

Immune cells infiltrate adipose tissues and provide a framework to regulate energy homeostasis. However, the precise underlying mechanisms and signaling by which the immune system regulates energy homeostasis in metabolic tissues remain poorly understood. Here, we show that the AT-rich interactive domain 5A (Arid5a), a cytokine-induced nucleic acid binding protein, is important for the maintenance of adipose tissue homeostasis. Long-term deficiency of Arid5a in mice results in adult-onset severe obesity. In contrast, transgenic mice overexpressing Arid5a are highly resistant to high-fat diet-induced obesity. Inhibition of Arid5a facilitates the in vitro differentiation of 3T3-L1 cells and fibroblasts to adipocytes, whereas its induction substantially inhibits their differentiation. Molecular studies reveal that Arid5a represses the transcription of peroxisome proliferator activated receptor gamma 2 (Ppar-γ2) due to which, in the absence of Arid5a, Ppar-γ2 is persistently expressed in fibroblasts. This phenomenon is accompanied by enhanced fatty acid uptake in Arid5a-deficient cells, which shifts metabolic homeostasis toward prolipid metabolism. Furthermore, we show that Arid5a and Ppar-γ2 are dynamically counterregulated by each other, hence maintaining adipogenic homeostasis. Thus, we show that Arid5a is an important negative regulator of energy metabolism and can be a potential target for metabolic disorders.

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