Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

The expansion of subcutaneous (SC) white adipose tissue (WAT) has beneficial effects on metabolic health. Our previous work showed an increased number of bone morphogenetic protein 4 (BMP4)-activated beige adipocytes in SC WAT, indicating a potential role of BMP4 in adipocyte recruitment. It was also demonstrated that BMP4 committed multipotent mesodermal C3H10T1/2 stem cells to the adipocyte lineage ex vivo . However, the mechanism by which BMP4 regulates adipogenesis in vivo has not been clarified. In this study, we found that BMP4 stimulated de novo adipogenesis in SC WAT concomitant with enhanced blood vessel formation, thus promoting adipose tissue angiogenesis. Platelet-derived growth factor receptor-β-positive (PDGFRβ ⁺ ) multipotent stem cells within the neoangiogenic vessels were found to be adipocyte progenitors. Moreover, BMP4 downregulated PDGFRβ by stimulating the lysosome-dependent degradation, which efficiently initiated adipogenic differentiation. These results suggest how BMP4 regulates adipocyte recruitment in SC WAT, and thus promote its beneficial metabolic effects.

Adipose tissues, including white, beige and brown adipose tissue, have evolved to be highly dynamic organs. Adipose tissues undergo profound changes during development and regeneration and readily undergo remodeling to meet the demands of an ever-changing metabolic landscape. The dynamics are determined by the high plasticity of adipose tissues, which contain various cell types: adipocytes, immune cells, endothelial cells, nerves and fibroblasts. There are numerous proteins that participate in regulating the plasticity of adipose tissues. Among these, bone morphogenetic proteins (BMPs) were initially found to regulate the differentiation of adipocytes, and they are being reported to have pleiotropic functions by emerging studies. Here, in the first half of the paper, we summarize the plasticity of adipocytes and macrophages, which are two groups of cells targeted by BMP signaling in adipose tissues. We then review how BMPs regulate the differentiation, death and lipid metabolism of adipocytes. In addition, the potential role of BMPs in regulating adipose tissue macrophages (ATMs) is considered. Finally, the expression of BMPs in adipose tissues and their metabolic relevance are discussed.

Ying Zou, Yi-Na Wang, Hong Ma, Zhi-Hui He, Yan Tang, Liang Guo, Yang Liu, Meng Ding, Shu-Wen Qian, Qi-Qun Tang

Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4^fl/fl and Tlr4^LoxTB) that allow ablation of TLR4 only in hepatocytes (Tlr4^LKO) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4^LoxTB × Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4^LKO) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3β (GSK3β) was observed in the liver of Tlr4^LKO mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4^LoxTB × Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4^LoxTB). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4^LoxTB × Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4^LoxTB × Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.