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Abstract
The role of Ahnak in obesity has been reported previously. Loss of Ahnak leads to decreased Bmp4/Smad1 signaling, resulting in the downregulation of adipocyte differentiation. However, the biological significance of Ahnak remains largely unknown. In this study, we demonstrate that Ahnak-mediated impaired adipogenesis results in decreased Bmpr1α transcriptional expression. To confirm this, Ahnak siRNA was used to knock-down Ahnak in C3H10T1/2 and primary stromal vascular fraction cells. Ahnak siRNA transfected cells showed suppression of Bmpr1α expression and decreased BMP4/ Bmpr1α signaling. The differential adipogenesis was further confirmed by knock-down of Bmpr1α in C3H10T1/2 cells, which resulted in reduced adipogenesis. Moreover, stable Ahnak knock-out C3H10T1/2 cells stably transfected with Ahnak CRISPR/Cas9 plasmid suppressed expression of Bmpr1α and prevented differentiation into adipocytes. Furthermore, we developed immortalized pre-adipocytes from wild-type or Ahnak Knock-out mice’s stromal vascular fraction (SVF) to confirm the function of Ahnak in pre-adipocyte transition. Immortalized Ahnak knock-out SVF cells showed lower level of Bmpr1α expression, evidence by their impaired BMP4/Bmpr1α signaling. Upon adipogenic induction, immortalized Ahnak knock-out SVF cells exhibited a marked decrease in adipocyte differentiation compared with immortalized wild-type pre-adipocytes. Furthermore, over-expression of Bmpr1α restored the adipogenic activity of Ahnak knock-out C3H10T1/2 cells and immortalized Ahnak knock-out SVF cells. Our data reveal the missing link in Ahnak-mediated adipose tissue remodeling and suggest that precise regulation of Ahnak in adipose tissue might have a therapeutic advantage for metabolic disease treatment.
Highlights
Obesity is characterized by the excessive adipocyte hypertrophy and hyperplasia caused by highly imbalance of energy expenditure vs. food intake[1]
Immortalized inguinal white adipose tissue (iWAT) stromal vascular fraction (SVF) cells showed different adipogenic differentiation capacity To obtain unbiased insight into putative Ahnakdependent molecular pathways impacting Bmpr1αmediated adipocyte differentiation, we developed immortalized pre-adipocytes derived from SVF of WT, Ahnak hetero zygote (He), and Ahnak knock-out mice iWAT (Im WT, Im He, and Immortalized Ahnak knock-out SVF cells (Im Ko), respectively)
We previously found that Ahnak functions in obesity resistance and insulin sensitivity by regulation of Smad1/ 5 signaling pathways
Summary
Obesity is characterized by the excessive adipocyte hypertrophy and hyperplasia caused by highly imbalance of energy expenditure vs. food intake[1]. Even though the clinical importance of obesity is growing, our understanding of the molecular mechanisms regulating the Adipose tissues play a major role in energy storage in mammals. Adipose tissues have been divided into two distinct types: white adipose tissues (WATs), which are the primary site of energy storage by accumulating lipids and brown adipose tissues (BATs)[3]. WAT primarily contributes to energy storage for the regulation of energy balance and serves as a Official journal of the Cell Death Differentiation Association. Woo et al Cell Death and Disease (2018)9:864 central endocrine organ playing key roles in metabolism[4]. The dysfunction of adipocytes causes a diverse range of diseases, including obesity, diabetes, and lipodystrophies[5], derived by adipogenesis from specific precursor cells. The pre-adipocyte to adipogenic differentiation (adipogenesis) is a key process in fat mass
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