Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.

Brown and beige adipose tissues are specialized for thermogenesis and are important for energy balance in mice. Mounting evidence suggests chromatin modifying enzymes are integral for the development, maintenance, and functioning of thermogenic adipocytes. p300 and CREB-binding protein (CBP) are histone acetyltransferases (HATs) responsible for writing the transcriptionally activating mark H3K27ac. Despite their homology, p300 and CBP do have unique tissue and context-dependent roles, which have yet to be examined in brown and beige adipocytes specifically. We assessed the requirement of p300 or CBP in thermogenic fat using Ucp1-Cre mediated knockdown in mice to determine if their loss impacted tissue development, susceptibility to diet-induced obesity, and response to pharmacological induction via b3-agonism. Despite successful knockdown, brown adipose tissue mass and expression of thermogenic markers were unaffected by loss of either HAT. As such, knockout mice developed a comparable degree of diet-induced obesity and glucose intolerance to that of floxed controls. Furthermore, "browning" of white adipose tissue by the b3-adrenergic agonist CL-316,243remained largely intact in knockout mice. Although p300 and CBP have non-overlapping roles in other tissues, our results indicate they are individually dispensable within thermogenic fats specifically, possibly due to functional compensation by one another.

Pharmacological inhibition of neuropeptide Y receptors Y1 and Y5 reduces hypoxic breast cancer migration, proliferation, and signaling.

BACKGROUND: Neuropeptide Y (NPY) is an abundant neurohormone in human breast carcinomas that acts on a class of G-protein coupled receptors, of which NPY1R and NPY5R are the most highly expressed. This abundance is exploited for cancer imaging, but there is interest in pharmacological inhibition of the NPYRs to interrogate their functional relevance in breast cancer. We previously reported that NPY1R and NPY5R mRNA abundance is increased by hypoxia inducible factors, which sensitizes these receptors to NPY stimulation leading to enhanced migration and proliferation. METHODS/RESULTS: Here, we measured the effects of NPY1R and NPY5R antagonists in normoxia and hypoxia on migration, proliferation, invasion, and signaling in 2D and 3D models of breast cancer cell lines MDA-MB-231 and MCF7. Antagonizing NPY1R and/or NPY5R in hypoxia compared to normoxia more greatly reduced MAPK signaling, cell proliferation, cell migration and invasion, and spheroid growth and invasion. The estrogen receptor positive MCF7 cells were significantly less invasive in 3D spheres when NPY5R was specifically inhibited. There were some discrepancies in the responses of each cell line to the isoform-specific antagonists and oxygen availability, therefore further investigations are required to dissect the intricacies of NPYR signaling dynamics. In human breast tumor tissue, we show via immunofluorescence that NPY5R protein levels and colocalization with hypoxia correlate with advanced cancer, and NPY1R protein correlates with adverse outcomes. CONCLUSIONS: Antagonizing the NPYRs has been implicated as a treatment for a wide variety of diseases. Therefore, these antagonists may aid in the development of novel cancer therapeutics and patient-based treatment plans.