Background: PPARγ agonists improve insulin sensitivity but also evoke weight gain.Results: GQ-16 is a PPARγ partial agonist that blocks receptor phosphorylation by Cdk5 and improves insulin sensitivity in diabetic mice in the absence of weight gain.Conclusion: The unique binding mode of GQ-16 appears to be responsible for the compound's advantageous pharmacological profile.Significance: Similar compounds could have promise as anti-diabetic therapeutics.

BackgroundBeige adipocytes comprise a unique thermogenic cell type in the white adipose tissue (WAT) of rodents and humans, and play a critical role in energy homeostasis. In this scenario, recruitment of beige cells has been an important focus of interest for the development of novel therapeutic strategies to treat obesity. PPARγ activation by full agonists (thiazolidinediones, TZDs) drives the appearance of beige cells, a process so-called browning of WAT. However, this does not translate into increased energy expenditure, and TZDs are associated with weight gain. Partial PPARγ agonists, on the other hand, do not induce weight gain, but have not been shown to drive WAT browning. The present study was designed to investigate the effects of GQ-16 on BAT and on browning of WAT in obese mice.MethodsMale Swiss mice with obesity and hyperglycemia induced by high fat diet were treated with vehicle, rosiglitazone (4 mg/kg/d) or the TZD-derived partial PPARγ agonist GQ-16 (40 mg/kg/d) for 14 days. Fasting blood glucose, aspartate aminotransferase, alanine aminotransferase and lipid profile were measured. WAT and brown adipose tissue (BAT) depots were excised for determination of adiposity, relative expression of Ucp-1, Cidea, Prdm16, Cd40 and Tmem26 by RT-qPCR, histological analysis, and UCP-1 protein expression analysis by immunohistochemistry. Liver samples were also removed for histological analysis and determination of hepatic triglyceride content.ResultsGQ-16 treatment reduced high fat diet-induced weight gain in mice despite increasing energy intake. This was accompanied by reduced epididymal fat mass, reduced liver triglyceride content, morphological signs of increased BAT activity, increased expression of thermogenesis-related genes in interscapular BAT and epididymal WAT, and increased UCP-1 protein expression in interscapular BAT and in epididymal and inguinal WAT.ConclusionThis study suggests for the first time that a partial PPARγ agonist may increase BAT activity and induce the expression of thermogenesis-related genes in visceral WAT.General SignificanceThese findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity.

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A theoretical study is presented with the aim to investigate the molecular properties of intermolecular complexes formed by the monomeric units of polyvinylpyrrolidone (PVP) or polyethyleneglycol (PEG) polymers and a set of four imidazolidine (hydantoine) derivatives. The substitution of the carbonyl groups for thiocarbonyl in the hydantoin scaffold was taken into account when analyzing the effect of the hydrogen bonds on imidazolidine derivatives. B3LYP/6-31G(d,p) calculations and topological integrations derived from the quantum theory of atoms in molecules (QTAIM) were applied with the purpose of examining the N-H···O hydrogen bond strengths formed between the amide group of the hydantoine ring and the oxygen atoms of PVP and PEG polymers. The effects caused by the N-H···O interaction fit the typical evidence for hydrogen bonds, which includes a variation in the stretch frequencies of the N-H bonds. These frequencies were identified as being vibrational red-shifts because their values decreased. Although the values of such calculated interaction energies are between 12 and 33 kJ mol(-1), secondary intermolecular interactions were also identified. One of these secondary interactions is formed through the interaction of the benzyl hydrogen atoms with the oxygen atoms of the PVP and PEG structures. As such, we have analyzed the stretch frequencies on the C-H bonds of the benzyl groups, and blue-shifts were identified on these bonds. In this sense, the intermolecular systems formed by hydantoine derivatives and PVP/PEG monomers were characterized as a mix of red-shifting and blue-shifting hydrogen-bonded complexes.

In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03μM. The 8c derivative showed the highest potency against cruzain (IC50=2.4μM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.