ObjectiveFibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice.MethodsTo address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling. We also studied the ability of FAP to process FGF21 in vitro and TB to block FAP enzymatic activity.ResultsTB administration to diet-induced obese (DIO) animals led to profound decreases in body weight, reduced food consumption and adiposity, increased energy expenditure, improved glucose tolerance and insulin sensitivity, and lowered cholesterol levels. Total and intact plasma FGF21 were observed to be elevated in TB-treated DIO mice but not lean animals where the metabolic impact of TB was significantly attenuated. Furthermore, and in stark contrast to naïve DIO mice, the administration of TB to obese FGF21 knockout animals demonstrated no appreciable effect on body weight or any other measures of metabolism. In support of these results we observed no enzymatic degradation of human FGF21 at either end of the protein when FAP was inhibited in vitro by TB.ConclusionsWe conclude that pharmacological inhibition of FAP enhances levels of FGF21 in obese mice to provide robust metabolic benefits not observed in lean animals, thus validating this enzyme as a novel drug target for the treatment of obesity and diabetes.

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.

It is well known that chronic hypertension is associated with increased morbidity and mortality from stroke, coronary artery disease, congestive heart failure, renal disease, and so on.1,2 Arterial tone is persistently increased as a result of malfunction of vessel relaxation in chronic hypertension.2 It is well recognized that arterial tone is regulated by functional balance of the ion channels responsible for cellular depolarization and hyperpolarization. The increased arterial tone is mainly related to depolarization of smooth muscle, which may have resulted from dysfunction of ion channels responsible for cell membrane hyperpolarization. 3 The membrane depolarization activates voltage-dependent l-type Ca 2+ channels, induces an increase in Ca 2+ influx and global intracellular Ca 2+ level, and causes vessel constriction. 4,5 It is believed that large-conductance Ca 2+ -activated K + (BK Ca ) channels play an important role in hyperpolarization of vascular smooth muscle cells (VSMCs).6 BK Ca channels are activated by intracellular local Ca 2+ release events through ryanodine receptors (Ca 2+ sparks) from the sarcoplasmic reticulum and subsequently induce a hyperpolarization that opposes vasoconstriction. 6-8The Ca 2+ sparks are highly localized and short-lived Ca 2+ transients, which is a local Ca 2+ signaling to induce spontaneous transient outward currents (STOCs) in VSMCs and neurons, and mediate different physiological functions. 8,9 In VSMCs, functional coupling of sparks to STOCs hyperpolarizes the membrane potential, which in turn closes the voltage-dependent l-type Ca 2+ channels, decreases global [Ca 2+ ] i , and induces vascular relaxation. 7 Studies from animal models demonstrated that a reduced activity of Ca 2+ sparks and STOCs is involved in an increase of vascular tone in hypertension. [10][11][12] However, little information is available in literature regarding BK Ca channel activity in human arterial cells/tissue from patients with hypertension. The present study was therefore to investigate whether BK Ca activity is altered in VSMCs isolated from mesentery arterial tissues of Han Chinese patients with hypertension using approaches of electrophysiology and molecular biology.Abstract-Chronic hypertension is associated with an impaired vascular relaxation caused by an increased vascular tone; however, the underlying mechanisms are not fully understood in human patients. The present study was to investigate whether large-conductance Ca 2+-and voltage-activated K + (BK Ca ) channels are involved in dysfunctional relaxation of artery in Han Chinese patients with hypertension using the perforated patch clamp, inside-out single-channel, and macromembrane patch recording techniques to determine whole-cell current, spontaneous transient outward current, open probability, and Ca 2+ sensitivity and the reverse transcription polymerase chain reaction and Western blot analysis to examine the gene and protein expression of α-subunit (KCa1.1) and β1-subunit (KCNMB1) of BK Ca channels in isolated human ...

Based on the structure of FKBP12 complexed with FK506 or rapamycin, with computer-aided design, two neurotrophic ligands, (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leucine ethyl ester and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester, were designed and synthesized. Fluorescence experiments were used to detect the binding affinity between FKBP12 and these two ligands. Complex structures of FKBP12 with these two ligands were obtained by x-ray crystallography. In comparing FKBP12-rapamycin complex and FKBP12-FK506 complex as well as FKBP12-GPI-1046 solution structure with these new complexes, significant volume and surface area effects and obvious contact changes were detected which are expected to cause their different binding energies-showing these two novel ligands will become more effective neuron regeneration drugs than GPI-1046, which is currently undergoing phase II clinical trail as a neurotrophic drug. Analysis of volume and surface area effects also gives a new clue for structure-based drug design.

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