polyunsaturated fatty acids (pufas)  (Koppers Inc)

Journal: Obesity (Silver Spring, Md.)

Article Title: The NLRP3 inhibitor NT ‐0796 enhances and sustains GLP ‐ 1R agonist‐mediated weight loss in a murine diet‐induced obesity model

doi: 10.1002/oby.24305

Figure Lengend Snippet: Effects of NT‐0796, semaglutide, or combinations in mice with DIO switched to a PUFA diet. Mice with DIO fed a HFD were dosed therapeutically with NT‐0796 (100 mg/kg, po, tid), semaglutide (0.005 mg/kg, sc, q.d), or a combination from day 0 to 28. On day 29, diet was switched to a PUFA diet, and the respective treatment continued (over days 29–56). An additional group of mice served as calorie‐restricted controls, body weight of which were maintained as closely to NT‐0796‐dosed mice as possible by controlling the degree of calorie restriction throughout the experiment. (A) Experimental schematic. (B) Percentage body weight change over time. An overnight fast into day 55 (dashed line) was performed for assessment of further exploratory endpoints. (C) Body weight over time. (D) Perirenal, (E) inguinal, (F) epididymal, and (G) total fat mass was assessed at study end (day 56). (H) Average daily food intake and (I) average daily calorie (kilocalories) intake during PUFA diet exposure (days 29–56). (J) Plasma IL‐1RA levels at study end (day 56). Data are expressed as mean ± SEM or as box and whisker plots and analyzed by one‐ or two‐way ANOVA with Tukey multiple comparisons test and significance calculated using GraphPad Prism version 10.2.2. **** p < 0.0001; *** p < 0.001; ** p < 0.01; and * p < 0.05. DIO, diet‐induced obesity; HFD, high‐fat diet; IL‐1RA, interleukin‐1 receptor antagonist; po, orally; PUFA, polyunsaturated fatty acid; qd, 1 time/day; sc, subcutaneously; tid, 3 times/day.

Article Snippet: Additional mouse cohorts were fed a diet enriched in polyunsaturated fatty acids (PUFA; 40% of kilocalories from fat; Dyets, Inc., category #D240510) [ ], which bears greater resemblance to the composition of a typical human diet.

Techniques: Clinical Proteomics, Whisker Assay

Journal: bioRxiv

Article Title: Binding of PUFA stabilizes a conductive state of the selectivity filter in IKs channels

doi: 10.1101/2024.01.11.575247

Figure Lengend Snippet: A) (black) Prolonged QT interval in the ECG is due to for example loss-of-function mutations of KCNQ1/KCNE1 channels that generate the IKs current that normally contributes to the repolarizing phase of the ventricular AP. (red) PUFAs are potent activators of KCNQ1/KCNE1 channels that can restore the normal functioning of the channel and restore the AP duration and the QT interval. B) Representative current traces of KCNQ1/KCNE1 in 0 μM and 20 μM of Lin-Glycine. Voltage protocol on top. C) Conductance versus voltage curves from tail currents in B (at arrows). Channel activation by PUFA results in two main effects: a shift of the voltage-dependence of activation (ΔV0.5) and an increase in the channel maximum conductance (ΔGmax). D ) KCNQ1 transmembrane topology. Residues mutated in this study are labeled. E ) KCNQ1 top view (PDB: 6UZZ) with PUFA binding sites: Site I, at the VSD; and Site II, at the pore domain. The four subunits are shown in four different colors. F ) Cartoon of PUFA mechanism of action. Site I, top panel. Electrostatic interactions between PUFA head groups and positively charged residues in S4 facilitate channel activation by stabilizing the outward state of S4. Site II, bottom panel. PUFA interaction with residues in the pore domain facilitates the increase in the maximum channel conductance.

Article Snippet: The polyunsaturated fatty acid (PUFA) Lin-Glycine was purchased from Cayman Chemicals (Ann Arbor, MI), kept in stock of 100 mM with ethanol at - 20 ° C and diluted in ND96 solution the day of the experiments.

Techniques: Activation Assay, Labeling, Binding Assay