Leptin: Master Regulator of Biological Functions that Affects Breathing.

Obesity is a global epidemic in developed countries accounting for many of the metabolic and cardiorespiratory morbidities that occur in adults. These morbidities include type 2 diabetes, sleep-disordered breathing (SDB), obstructive sleep apnea, chronic intermittent hypoxia, and hypertension. Leptin, produced by adipocytes, is a master regulator of metabolism and of many other biological functions including central and peripheral circuits that control breathing. By binding to receptors on cells and neurons in the brainstem, hypothalamus, and carotid body, leptin links energy and metabolism to breathing. In this comprehensive article, we review the central and peripheral locations of leptin's actions that affect cardiorespiratory responses during health and disease, with a particular focus on obesity, SDB, and its effects during early development. Obesity-induced hyperleptinemia is associated with centrally mediated hypoventilation with decrease CO2 sensitivity. On the other hand, hyperleptinemia augments peripheral chemoreflexes to hypoxia and induces sympathoexcitation. Thus, "leptin resistance" in obesity is relative. We delineate the circuits responsible for these divergent effects, including signaling pathways. We review the unique effects of leptin during development on organogenesis, feeding behavior, and cardiorespiratory responses, and how undernutrition and overnutrition during critical periods of development can lead to cardiorespiratory comorbidities in adulthood. We conclude with suggestions for future directions to improve our understanding of leptin dysregulation and associated clinical diseases and possible therapeutic targets. Lastly, we briefly discuss the yin and the yang, specifically the contribution of relative adiponectin deficiency in adults with hyperleptinemia to the development of metabolic and cardiovascular disease. © 2020 American Physiological Society. Compr Physiol 10:1047-1083, 2020.

18F-Labeled PET Probe Targeting Enhancer of Zeste Homologue 2 (EZH2) for Cancer Imaging.

The enzyme enhancer of zeste homologue 2 (EZH2) plays a catalytic role in histone methylation (H3K27me3), one of the epigenetic modifications that is dysregulated in cancer. The development of a positron emission tomography (PET) imaging agent targeting EZH2 has the potential to provide a method of stratifying patients for epigenetic therapies. In this study, we designed and synthesized a series of fluoroethyl analogs based upon the structure of EZH2 inhibitors UNC1999 and EPZ6438. Among the candidate compounds, 20b exhibited a high binding affinity to EZH2 (IC50 = 6 nM) with selectivity versus EZH1 (IC50 = 200 nM) by SAM competition assay, and furthermore, EZH2 inhibition was demonstrated in the pancreatic cancer cell line PANC-1 (IC50 = 9.8 nM). [18F]20b was synthesized successfully and showed 5-fold higher uptake in PANC-1 cells than in MCF-7 cells. MicroPET imaging in a PANC-1 cell xenograft mouse model indicates that [18F]20b has specific binding to EZH2, which was identified by ex vivo Western blot analysis of the tumor tissue.