Journal of Lipid Research Volume 56, 2015 423Adipose tissue is an endocrine organ whose products orchestrate the metabolic functions of various tissues, including brain, pancreas, and liver, to maintain systemic homeostasis. Adipocytes respond to metabolic and immune cues by mobilizing their fat stores through lipolysis and by secreting a variety of hormones and cytokines ( 1, 2 ). Such signals converge on target tissues, for example on liver to regulate glucose production, and on ␤ cells to modulate insulin production. A critical molecule for the integration of adipocyte biology with systemic metabolic regulation is aP2 [fatty acid binding protein (FABP) 4], a lipid binding protein that is upregulated during differentiation of adipocytes and upon macrophage activation ( 3, 4 ). Since its identifi cation, aP2 has been studied primarily for its intracellular functions in lipid metabolism and infl ammation ( 3,4 ). Genetic deletion models demonstrated that this FABP plays a critical role in the pathogenesis of several chronic metabolic diseases, including diabetes, atherosclerosis, and fatty liver. Mice defi cient in aP2 or aP2 and the related protein FABP5/mal1 together have improved adipose and liver function, increased insulin sensitivity, and reduced fatty liver and cardiovascular disease in the context of high-fat diet and genetic mouse models of obesity and atherosclerosis ( 5-12 ). The link between aP2 and metabolic disease is also supported by genetic association studies in multiple populations demonstrating metabolic and cardiovascular benefi ts in individuals carrying a rare haploinsuffi ciency mutation in the aP2 locus, validating the relevance of this pathway in human disease ( 13,14 ).

Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.

Six transmembrane protein of prostate (Stamp) proteins play an important role in prostate cancer cell growth. Recently, we found that Stamp2 has a critical role in the integration of inflammatory and metabolic signals in adipose tissue where it is highly expressed and regulated by nutritional and metabolic cues. In this study, we show that all Stamp family members are differentially regulated during adipogenesis: whereas Stamp1 expression is significantly decreased upon differentiation, Stamp2 expression is increased. In contrast, Stamp3 expression is modestly changed in adipocytes compared to preadipocytes, and has a biphasic expression pattern during the course of differentiation. Suppression of Stamp1 or Stamp2 expression both led to inhibition of 3T3-L1 differentiation in concert with diminished expression of the key regulators of adipogenesis - CCAAT/enhancer binding protein alpha (C/ebpα) and peroxisome proliferator-activated receptor gamma (Pparγ). Upon Stamp1 knockdown, mitotic clonal expansion was also inhibited. In contrast, Stamp2 knockdown did not affect mitotic clonal expansion, but resulted in a marked decrease in superoxide production that is known to affect adipogenesis. These results suggest that Stamp1 and Stamp2 play critical roles in adipogenesis, but through different mechanisms.

No abstract

Background: Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obese mice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress. Methods: 3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNFα. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays. Results: ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNFα had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBPαmediated STAMP2 expression. Conclusion: These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.

Six Transmembrane Protein of Prostate 2 (STAMP2) has been implicated in both prostate cancer (PCa) and metabolic disease. STAMP2 has unique anti-inflammatory and pro-metabolic properties in mouse adipose tissue, but there is limited information on its role in human metabolic tissues. Using human adipose-derived stem cells (ASCs), we report that STAMP2 expression is dramatically upregulated during adipogenesis. shRNA-mediated STAMP2 knockdown in ASCs significantly suppresses adipogenesis and interferes with optimal expression of adipogenic genes and adipocyte metabolic function. Furthermore, ASC-derived adipocyte-mediated stimulation of prostate tumor growth in nude mice is significantly reduced upon STAMP2 knockdown in ASC adipocytes. These results suggest that STAMP2 is crucial for normal ASC conversion into adipocytes and their metabolic function, as well as their ability to facilitate PCa growth in vivo.

Increased metabolic activity is a hallmark of proliferating cancer cells. One common deregulated metabolic pathway in prostate cancer is de novo lipogenesis which is highly increased in prostate cancer and is linked to poor prognosis and metastasis. Male sex hormones play an essential role in prostate cancer growth and have been shown to increase the expression and activity of several lipogenic factors, such as fatty acid synthase (FASN) and sterol regulatory element-binding proteins (SREBPs), leading to accumulation of neutral lipids in prostate cancer cells. These factors are being evaluated as potential prognostic markers and therapeutic targets in prostate cancer. Here we describe methods to directly detect and quantify accumulation of neutral lipids and assess concomitant changes in lipogenic gene expression in LNCaP prostate cancer cells.

No abstract