Nuclear receptors (NRs) play central roles in metabolic syndrome, making them attractive drug targets despite the challenge of achieving functional selectivity. For instance, members of the thiazolidinedione class of insulin sensitizers offer robust efficacy but have been limited due to adverse effects linked to activation of genes not involved in insulin sensitization. Studies reviewed here provide strategies for targeting subsets of PPARγ target genes, enabling development of next-generation modulators with improved therapeutic index. Additionally, emerging evidence suggests that targeting the NRs ROR and Rev-erb holds promise for treating metabolic syndrome based on their involvement in circadian rhythm and metabolism.
