ABSTRACT
The commitment of mesenchymal stem cells (MSCs) to preadipocytes and the termination of differentiation to adipocytes are critical for maintaining systemic energy homeostasis. However, our knowledge of the molecular mechanisms governing the commitment of MSCs to preadipocytes and the subsequent termination of their differentiation into adipocytes remain limited. Additionally, the role of Sox6 sex-determining region Y (SRY)-box6 (Sox6), a transcription factor that regulates gene transcription, is reportedly involved in various cellular processes, including adipogenesis; however, its function in regulating preadipocyte development and the factors involved in the termination of adipogenic differentiation remain unexplored. Therefore, we investigated the role of Sox6 in regulating the differentiation of adipocytes by monitoring the effects of its overexpression in C3H10T1/2 cells (in vitro) and C57BL/6J mouse (in vivo) models of adipogenesis. We observed lower Sox6 expression in the adipose tissue of obese mice than that in control mice. Sox6 overexpression inhibited the differentiation of MSC by directly binding to the lysyl oxidase (Lox) and preadipocyte factor 1 (Pref1) promoters, which was potentiated by histone deacetylase-1(HDAC1). Our findings suggest that Sox6 is a key regulator of MSC commitment to adipocytes; therefore, targeting the Sox6-mediated regulation of this process could offer potential therapeutic avenues for addressing obesity and related metabolic disorders.
Subject(s)
Adipogenesis , Mesenchymal Stem Cells , Animals , Mice , Adipogenesis/genetics , Cell Differentiation/genetics , Mice, Inbred C57BL , Protein-Lysine 6-Oxidase/genetics , Protein-Lysine 6-Oxidase/metabolism , SOXD Transcription Factors/genetics , SOXD Transcription Factors/metabolismABSTRACT
Polycystic ovary syndrome is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive age. Most patients with polycystic ovary syndrome have hyperandrogenism, caused by excess androgen synthesis. Bone morphogenetic protein 4 (BMP4) is an essential regulator of embryonic development and organ formation, and recent studies have also shown that BMP4 may be involved in female steroidogenesis process. However, the effect of BMP4 on hyperandrogenism remains unknown. Here, using a female mouse model of hyperandrogenism, we found that ovarian BMP4 levels were significantly decreased in hyperandrogenism. Elevated androgens inhibited BMP4 expression via activation of androgen receptors. Moreover, BMP4 treatment suppressed androgen synthesis in theca cells and promoted estrogen production in granulosa cells by regulating the expression of steroidogenic enzymes, including CYP11A, HSD3B2, CYP17A1, and CYP19A1 Consistently, knockdown of BMP4 augmented androgen levels and inhibited estrogen levels. Mechanistically, Smad signaling rather than the p38 MAPK pathway regulated androgen and estrogen formation, thereby mediating the effect of BMP4. Of note, BMP4-transgenic mice were protected against hyperandrogenism. Our observations clarify a vital role of BMP4 in controlling sex hormone levels and offer new insights into intervention for managing hyperandrogenism by targeting the BMP4-Smad signaling pathway.
Subject(s)
Bone Morphogenetic Protein 4/metabolism , Disease Models, Animal , Hyperandrogenism/etiology , Ovary/metabolism , Polycystic Ovary Syndrome/physiopathology , Signal Transduction , Smad4 Protein/metabolism , Androgens/metabolism , Androgens/pharmacology , Animals , Bone Morphogenetic Protein 4/antagonists & inhibitors , Bone Morphogenetic Protein 4/genetics , Cells, Cultured , Dehydroepiandrosterone , Down-Regulation/drug effects , Estrogens/metabolism , Female , Gene Expression Regulation, Enzymologic , Gene Knockdown Techniques , Granulosa Cells/drug effects , Granulosa Cells/metabolism , Granulosa Cells/pathology , Mice, Inbred C57BL , Mice, Transgenic , Ovary/drug effects , Ovary/pathology , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , RNA Interference , Receptors, Androgen/chemistry , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Signal Transduction/drug effects , Smad4 Protein/antagonists & inhibitors , Smad4 Protein/genetics , Theca Cells/drug effects , Theca Cells/metabolism , Theca Cells/pathologyABSTRACT
Dysregulation of insulin signaling leads to type 2 diabetes mellitus (T2DM) and other metabolic disorders. Obesity is an important contributor to insulin resistance, and although the understanding of this relationship has improved in recent years, the mechanism of obesity-induced insulin resistance is not completely understood. Disorders of copper metabolism tend to accompany the development of obesity, which increases the risk of insulin resistance. Synthesis of cytochrome c oxidase 1 (SCO1) functions in the assembly of cytochrome c oxidase (COX) and cellular copper homeostasis. However, the role of SCO1 in the regulation of metabolism remains unknown. Here, we found that obese mice had higher expression of SCO1 and lower levels of copper in white adipose tissue (WAT) than did the control mice. Overexpression of SCO1 in adipocytes was associated with copper deficiency. Copper increased insulin sensitivity by decreasing the level of phosphatase and tensin homolog (PTEN) protein. Ectopic expression of SCO1 led to insulin resistance and was accompanied by a decrease in intracellular copper level, and addition of copper abolished the inhibitory effect of SCO1 on insulin sensitivity. Our results demonstrated a novel role of SCO1 in modulating insulin sensitivity via the regulation of copper concentration in WAT and suggested a potential therapeutic target for T2DM.
