Intra-abdominal adipose depot variation in adipogenesis, lipogenesis, angiogenesis, and fibrosis gene expression and relationships with insulin resistance and inflammation in premenopausal women with severe obesity.

Although severe obesity is associated with insulin resistance (IR) and inflammation, secretory function of intra-abdominal adipose tissues and their relationships with IR and inflammation markers remain poorly understood. Aims were to measure gene expression of adipogenic (C/EBPα/ß, PPARγ-1/2, SREBP-1c, LXRα), lipogenic (SCD1, DGAT-1/2), angiogenic (VEGFα, leptin), and fibrotic (LOX, COL6A3) factors in the round ligament (RL), omental (OM), and mesenteric (ME) fat depots and to evaluate their relationships with IR and inflammation markers in 48 women with severe obesity undergoing bariatric surgery. Gene expression was assessed by RT-qPCR, and plasma glucose and insulin (HOMA-IR calculated), PAI-1, IL-6, TNFα, adiponectin, and leptin levels were determined. C/EBPß and PPARγ-1/2 mRNA levels were more expressed in the OM (0.001

Elevated Expression of Glycerol-3-Phosphate Phosphatase as a Biomarker of Poor Prognosis and Aggressive Prostate Cancer.

The limitations of the biomarker prostate-specific antigen (PSA) necessitate the pursuit of biomarkers capable of better identifying high-risk prostate cancer (PC) patients in order to improve their therapeutic management and outcomes. Aggressive prostate tumors characteristically exhibit high rates of glycolysis and lipogenesis. Glycerol 3-phosphate phosphatase (G3PP), also known as phosphoglycolate phosphatase (PGP), is a recently identified mammalian enzyme, shown to play a role in the regulation of glucose metabolism, lipogenesis, lipolysis, and cellular nutrient-excess detoxification. We hypothesized that G3PP may relieve metabolic stress in cancer cells and assessed the association of its expression with PC patient prognosis. Using immunohistochemical staining, we assessed the epithelial expression of G3PP in two different radical prostatectomy (RP) cohorts with a total of 1797 patients, for whom information on biochemical recurrence (BCR), metastasis, and mortality was available. The association between biomarker expression, biochemical recurrence (BCR), bone metastasis, and prostate cancer-specific survival was established using log-rank and multivariable Cox regression analyses. High expression of G3PP in PC epithelial cells is associated with an increased risk of BCR, bone metastasis, and PC-specific mortality. Multivariate analysis revealed high G3PP expression in tumors as an independent predictor of BCR and bone metastasis development. High G3PP expression in tumors from patients eligible for prostatectomies is a new and independent prognostic biomarker of poor prognosis and aggressive PC for recurrence, bone metastasis, and mortality.

Modulation of de Novo Lipogenesis Improves Response to Enzalutamide Treatment in Prostate Cancer.

De novo lipogenesis (DNL) is now considered as a hallmark of cancer. The overexpression of key enzymes of DNL is characteristic of both primary and advanced disease and may play an important role in resistance to therapies. Here, we showed that DNL is highly enhanced in castrate resistant prostate cancer (CRPC) cells compared to hormone sensitive and enzalutamide resistant cells. This observation suggests that this pathway plays an important role in the initiation of aggressive prostate cancer and in the development of enzalutamide resistance. Importantly, here we show that both prostate cancer cells sensitive and resistant to enzalutamide are dependent on DNL to proliferate. We next combined enzalutamide with an inhibitor of Stearoyl CoA Desaturase 1 (SCD1), an important enzyme in DNL, and observed significantly reduced tumor growth caused by the important change in tumoral lipid desaturation. Our findings suggest that the equilibrium between monounsaturated fatty acids and saturated fatty acids is essential in the establishment of the more aggressive prostate cancer phenotype and that the combination therapy induces a disruption of this equilibrium leading to an important decrease of cell proliferation. These findings provide new insights into the role of DNL in the progression of prostate cancer cells. The study also provides the rationale for the use of an inhibitor of SCD1 in combination with enzalutamide to improve response, delay enzalutamide resistance and improve disease free progression.

Hepatic BSCL2 (Seipin) Deficiency Disrupts Lipid Droplet Homeostasis and Increases Lipid Metabolism via SCD1 Activity.

Berardinelli-Seip congenital lipodystrophy (BSCL) is an autosomal recessive disorder. The more severe form, designated BSCL2, arises due to mutations in the BSCL2 gene. Patients with BSCL2, as well as Bscl2 -/- mice, have a near total absence of body fat, an organomegaly, and develop metabolic disorders including insulin resistance and hepatic steatosis. The function of the Seipin (BSCL2) protein remains poorly understood. Several lines of evidence have indicated that Seipin may have distinct functions in adipose versus non-adipose cells. Here we present evidence that BSCL2/Bscl2 plays a role in lipid droplet (LD) biogenesis and homeostasis in primary and cultured hepatocytes. Our results show that decreasing BSCL2/Bscl2 expression in hepatocytes increases the number and size of LD, as well as the expression of genes implicated in their formation and stability. We also show that knocking down SCD1 expression reverses the phenotype associated with Seipin deficiency. Interestingly, BSCL2 knockdown induces SCD1 expression and activity, potentially leading to increased basal phosphorylation of proteins involved in the insulin signaling cascade, as well as further increasing fatty acid uptake and de novo lipogenesis. In conclusion, our results suggest that a hepatic BSCL2/Bscl2 deficiency induces the increase and expansion of LD, potentially via increased SCD1 activity.