Novel Fat Taste Receptor Agonists Curtail Progressive Weight Gain in Obese Male Mice.

BACKGROUND & AIMS: The spontaneous preference for dietary lipids is principally regulated by 2 lingual fat taste receptors, CD36 and GPR120. Obese animals and most of human subjects exhibit low orosensory perception of dietary fat because of malfunctioning of these taste receptors. Our aim was to target the 2 fat taste receptors by newly synthesized high affinity fatty acid agonists to decrease fat-rich food intake and obesity. METHODS: We synthesized 2 fat taste receptor agonists (FTA), NKS-3 (CD36 agonist) and NKS-5 (CD36 and GPR120 agonist). We determined their molecular dynamic interactions with fat taste receptors and the effect on Ca2+ signaling in mouse and human taste bud cells (TBC). In C57Bl/6 male mice, we assessed their gustatory perception and effects of their lingual application on activation of tongue-gut loop. We elucidated their effects on obesity and its related parameters in male mice fed a high-fat diet. RESULTS: The two FTA, NKS-3 and NKS-5, triggered higher Ca2+ signaling than a dietary long-chain fatty acid in human and mouse TBC. Mice exhibited a gustatory attraction for these compounds. In conscious mice, the application of FTA onto the tongue papillae induced activation of tongue-gut loop, marked by the release of pancreato-bile juice into collecting duct and cholecystokinin and peptide YY into blood stream. Daily intake of NKS-3 or NKS-5 via feeding bottles decreased food intake and progressive weight gain in obese mice but not in control mice. CONCLUSIONS: Our results show that targeting fat sensors in the tongue by novel chemical fat taste agonists might represent a new strategy to reduce obesity.

Mechanism of the Dehydrogenative Phenothiazination of Phenols.

The straightforward capture of oxidized phenothiazines with phenols under aerobic conditions represents a unique cross-dehydrogenative C-N bond-forming reaction in terms of operational simplicity. The mechanism of this cross-dehydrogenative N-arylation of phenothiazines with phenols has been the object of debate, particularly regarding the order in which the substrates are oxidized and their potentially radical or cationic nature. Understanding the selective reactivity of phenols for oxidized phenothiazines is one of the key objectives of this study. The reaction mechanism is investigated in detail by utilizing electron paramagnetic resonance spectroscopy, cyclic voltammetry, radical trap experiments, kinetic isotope effects, and solvent effects. Finally, the key reaction steps are calculated by using density functional theory (DFT) and broken-symmetry open-shell singlet DFT methods to unravel a unique biradical mechanism for the oxidative phenothiazination of phenols.

Ru-Catalyzed Dehydrogenative C-O Bond Formation with Anilines and Phenols.

The Ru catalyzed cross-dehydrogenative C-O bond formation between anilines and phenols is described and discussed. The exclusive C-O versus C-N bond-formation selectivity, moreover in the absence of chelating-assisting directing groups and while leaving the N-H position untouched, is a remarkable feature of this metal-catalyzed radical cross-dehydrogenative coupling.

O2 -mediated dehydrogenative amination of phenols.

A method was developed for the direct dehydrogenative construction of CN bonds between unprotected phenols and a series of cyclic anilines without resorting to any kind of metal activation of either substrate and without the use of halides. The resulting process relies on the exclusively organic activation of molecular oxygen and the subsequent oxidation of the aniline substrate. This allows the coupling of ubiquitous phenols, thus furnishing aminophenols through an atom-economical and most sustainable dehydrogenative amination method. This new reactivity, which relies on the intrinsic organic reactivity of cumene in what can be seen as a modified Hock activation process of oxygen, is expected to have a large impact on the formation of CN bonds in organic synthesis.