Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis.

Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed "committed pre-adipocytes" from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling, and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.

Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth.

Tumorigenesis is associated with elevated glucose and glutamine consumption, but how cancer cells can sense their levels to activate lipid synthesis is unknown. Here, we reveal that ammonia, released from glutamine, promotes lipogenesis via activation of sterol regulatory element-binding proteins (SREBPs), endoplasmic reticulum-bound transcription factors that play a central role in lipid metabolism. Ammonia activates the dissociation of glucose-regulated, N-glycosylated SREBP-cleavage-activating protein (SCAP) from insulin-inducible gene protein (Insig), an endoplasmic reticulum-retention protein, leading to SREBP translocation and lipogenic gene expression. Notably, 25-hydroxycholesterol blocks ammonia to access its binding site on SCAP. Mutating aspartate D428 to alanine prevents ammonia binding to SCAP, abolishes SREBP-1 activation and suppresses tumour growth. Our study characterizes the unknown role, opposite to sterols, of ammonia as a key activator that stimulates SCAP-Insig dissociation and SREBP-1 activation to promote tumour growth and demonstrates that SCAP is a critical sensor of glutamine, glucose and sterol levels to precisely control lipid synthesis.

Genomic Analysis of an Obesity Paradox: A Microarray Study of the Aortas of Morbidly Obese Decedents With Mild and Severe Atherosclerosis.

BACKGROUND: Atherosclerosis of the aorta and coronary arteries is still one of the major causes of death. We recently reported obesity paradox between body mass index and atherosclerosis of the aortas (AA) in morbidly obese decedent patients. The cause of this obesity paradox is unknown. The aim of the present study was to carry out genomic microarray analysis to determine gene expression profiles in the aortas of morbidly obese decedents with either mild or severe atherosclerosis of the aorta. METHODS: Microarray studies using Affymetrix GeneChips Clariom D Human array chips were performed on the aortas obtained from 6 morbidly obese decedents, 3 of whom had minimal AA and 3 who had severe disease. RESULTS: Group 1 (severe AA) and group 2 (mild AA) included 3 patients each. The patients were matched by age and body mass index. There were significant (P<0.005) differences in the expressions of 1067 genes between groups 1 and 2, including 602 upregulated and 465 downregulated genes. CONCLUSIONS: Our data show significantly different gene signatures between morbidly obese decedents who have mild or severe AA, suggesting that genetic factors may be important contributors to the obesity paradox as it relates to aortic atherosclerosis. Further studies are warranted to define differences in protein expression in the aortas of these 2 groups to further elucidate the cause of this obesity paradox.

MicroRNA Biomarkers for Patients With Muscle-Invasive Bladder Cancer Undergoing Selective Bladder-Sparing Trimodality Treatment.

PURPOSE: Trimodality therapy with maximal transurethral resection of bladder tumor and definitive chemoradiation reserving cystectomy for salvage of local recurrence is an accepted treatment alternative to upfront cystectomy for selected patients with muscle-invasive bladder cancer. There is a need for molecular biomarkers to predict which patients will respond to bladder preservation therapy. METHODS AND MATERIALS: We sought to identify biomarkers with the ability to predict response to chemoradiation and survival after selective bladder preservation therapy in a cohort of 40 patients using a microRNA profiling approach. In vitro experiments were performed using transitional cell carcinoma lines CRL1749, HTB5, and HTB4. RESULTS: We identified a panel of microRNAs associated with overall survival in our bladder preservation cohort and in the TCGA cohort. We also identified several microRNAs, including miR-23a and miR-27a, microRNAs of the miR-23a cluster, to be suggestively associated with complete response to chemoradiation therapy. The microRNAs were significantly associated with overall survival in The Cancer Genome Atlas cohort. In vitro studies suggest that the functional roles of miR-23a and miR-27a involve targeting the SFRP1 protein, a negative regulator of the Wnt signaling pathway. The upregulation of ß-catenin in the Wnt signaling pathway mediated proliferation, migration, invasion, and sensitivity to radiation and cisplatin treatment in bladder cancer cells. CONCLUSIONS: Our results indicate that miR-23a and miR-27a act as oncomirs, and once independently validated, they may help appropriately triage selected bladder cancer patients to individualize treatment.