Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.

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This review outlines challenges faced in recognition and detection of dicarboxylic acids and dicarboxylates and strategies used to obtain effective and observable interactions in the period from 2014 to 2020.

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This chapter outlines the development of small-molecule fluorescent chemosensors for phosphate species. Phosphate species are ubiquitous in nature, play diverse roles in biological systems, and display extensive variation in the functionality attached to the phosphate group. These molecules have a diffuse negative charge, are highly solvated, and are all linked by a common phosphate group. Together, these features present a significant challenge for the development of species-selective chemosensors that function in aqueous media with appropriate binding affinities. This challenge has been tackled via a variety of approaches, including chemosensors that bind the phosphate group via charge–charge, hydrogen-bonding, and metal–cation interactions. Key examples of each of these interaction types, varied approaches to chemosensor design, and fluorescence response mechanisms are highlighted.