Abstract
Adipose tissue dynamically changes its mass in response to external nutritional status, which plays an important role in maintaining the lipid homeostasis. Physiologically, feeding events are associated with the expansion of adipose tissue, but little is known about the detailed molecular mechanisms of this expansion. Here, using comprehensive transcriptome analysis, we found that levels of transforming growth factor β1 (TGF-β1), a key regulator of extracellular matrix (ECM) remodeling, were increased in adipose tissue under feeding conditions and associated with the lipogenic pathway. In addition, TGF-β receptors are highly expressed in adipose tissue, and pharmacological inhibition of TGF-β1 reduced adipose tissue mass and caused ectopic lipid accumulation in the liver. This reduced fat mass was associated with decreased gene expression in ECM remodeling and lipogenesis. Furthermore, similar results were observed in the adipose tissue of SMAD family member 3 knockout mice or upon systemic TGF-β neutralization, with significant reductions in both ECM remodeling and lipogenesis-related genes. Mechanistically, we found that insulin-induced TGF-β1 and cell-autonomous action remodels the ECM of adipocytes, which controls the downstream focal adhesion kinase–AKT signaling cascades and enhances the lipogenic pathway. Of note, destruction of collagens or matrix metalloproteinase/a disintegrin and metalloprotease activities, critical components of ECM remodeling, blocked TGF-β1-mediated focal adhesion kinase–AKT signaling and the lipogenic pathway. Taken together, this study identifies a previously unknown lipogenic role of TGF-β1 by which adipocytes can expand to adapt to physiological feeding events.
Highlights
Lipid storage is an important characteristic of living organisms, and proper regulation plays a critical role in energy homeostasis [1,2,3]
Feeding events increase circulating insulin levels, which trigger TGFβ1 induction in adipocytes
We showed a significant linkage between the extracellular matrix and the intracellular lipogenic pathway, in which the focal adhesion kinase (FAK)/AKT signaling cascade mediated the feeding-related adaptational process in adipocytes
Summary
Lipid storage is an important characteristic of living organisms, and proper regulation plays a critical role in energy homeostasis [1,2,3]. Insulin activity is associated with alterations in several intracellular signaling cascades [17], among which the AKT pathway induces the expression of downstream genes, such as SREBP1, ChREBP, ACC, ACLY, FASN and SCD [1,18,19] These lipogenic molecules enhance enzymatic processes to convert dietary carbohydrates into fat, called de novo lipogenesis (DNL), and the energy source is accumulated in specialized intracellular structures and lipid droplets of adipocytes [1,18,19]. Adipocyte-derived bioactive cytokines or hormones, called adipocytokines, play important roles in the control of energy homeostasis in an endocrine or autocrine/paracrine manner [2,4]. Little is known about adipocytokines that control feeding-linked lipid storage of adipocytes in an autocrine/paracrine manner. We showed how adiposederived TGFβ1 controls the feeding-linked lipogenic process of adipocytes via a series of in silico, in vivo and in vitro experiments
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