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PPARγ regulates glucose and lipid metabolism, yet safer PPARγ-targeted insulin sensitizers are needed to treat metabolic disorders. Here, Kuang-Ting et al. elucidate structure–function relationships of non-covalent inverse agonists that enhance receptor binding and improve insulin sensitivity, providing a framework for next-generation drug design.

Dysregulated protein levels can cause disease. The authors present a scalable platform capable of identifying small molecules that alter disease-linked target protein levels, and report >40 that increase SynGAP protein abundance, with SR1815 restoring neuronal function in Syngap1 deficient neurons.

PPARγ nuclear receptor ligand activities can span agonism to inverse agonism. Here, the authors use NMR to show how chemical changes within a ligand series shift the receptor’s dynamic conformational ensemble between active and repressive states.

Central to the lineage commitment of multipotent mesenchymal stem cells is the nuclear receptor PPARγ, the master regulator of adipogenesis. Here the authors use a variety of structural approaches to rationally design PPARγ inverse agonist SR2595, and demonstrate its ability to promote osteogenesis.

A systems-based approach to profile glucocorticoid (GC) receptor ligands in a broad range of assays representing different phenotypic responses linked these to transcriptional profiles and led to separation of GC therapeutic effects from side effects.

The repressive states of peroxisome proliferator-activated receptor γ (PPARγ) are ill-defined, despite nuclear receptors being a major drug target. Here authors demonstrate multiple structurally distinct repressive states, providing a structural rationale for ligand bias in a nuclear receptor.

The transcription factor TCF7L2 mediates two important responses to nicotine in the medial habenula region of the rodent brain: aversion to nicotine, and regulation of blood sugar levels through a polysynaptic habenula–pancreas circuit.

Unlike RORα, which has been thought to be somewhat redundant, RORγt has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that RORα is important in Th17 differentiation and that RORα deletion or a small molecule inhibitor of RORα can reduce disease in EAE and colitis mouse models.

Synthetic compounds that alter circadian rhythms have been shown to modulate energy expenditure and systemic metabolism in rodents. Here, the authors study the psychological effects of such compounds, and find synthetic REV-ERB agonists increase wakefulness and reduce anxiety-like behaviour in mice.

Synthetic REV-ERB agonists can alter the circadian expression of core clock genes in the hypothalami of mice, which changes the expression of metabolic genes in liver, skeletal muscle and adipose tissue, and results in increased energy expenditure.

PPARγ ligands are used to control diabetes, but their anti-diabetic actions are puzzling. Here the authors show that phosphorylation of PPARγ by cyclin-dependent kinase 5 (Cdk5) in mice is linked to obesity induced by high-fat feeding, and that inhibition of the effect in humans by the drug rosiglitazone is closely associated with its anti-diabetic effects. Several anti-diabetic PPARγ ligands directly inhibit the effect, and thus support a more normal non-diabetic pattern of gene expression.

Some nuclear receptors dimerize with retinoid X receptor to allow ligand-dependent signalling. Here, Kojetin et al.use structural and biophysical techniques to identify structural changes that guide these complex signalling networks.

The nuclear receptor PPARγ regulates insulin sensitivity and is the molecular target of anti-diabetic drugs. Here, Hughes et al. show demonstrate binding of synthetic PPARγ agonists to a previously unknown binding site within PPARγ and show this affects structure and function of the receptor.

Using mouse and human plasma, Carver et al. identify factors that are altered with age and test which are reverted by a panel of genetic and pharmacological senolytic interventions in aged mice. They identify IL-23R as a senescence-associated, age-increased circulating biomarker.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a target for insulin sensitizing drugs. Here the authors combine NMR, X-ray crystallography and MD simulations and report a structural mechanism for eliciting PPARγ inverse agonism, where coactivator binding is inhibited and corepressor binding promoted, which causes PPARγ repression.

Bart Staels and his colleagues show that the transcription factor Rev-erb-α is highly expressed in oxidative muscle and, via loss- and gain-of-function experiments, including pharmacological activation, that it plays a key partin regulating the oxidative capacity of the muscle and exercise endurance.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor. Here the authors provide insights into PPARγ activation by combining fluorine (¹⁹F) NMR and molecular dynamics simulations to characterize the nuclear receptor conformational ensemble in solution and the response of this ensemble to ligand and coregulatory peptide binding.

Nicotine has rewarding effects that motivate its consumption. In addition to these rewarding effects, nicotine also has aversive properties that motivate its avoidance. Here the authors identify a pathway in the brain that regulates nicotine avoidance. Adaptive responses in this and other aversion-related pathways may contribute to the development of tobacco addiction.