Thyroid hormone (TH) production is a tightly regulated process controlled by a classic negative feedback loop involving the hypothalamus, the pituitary, and the thyroid, which has led to the common name hypothalamus-pituitary-thyroid axis (Figure 1). The thyrotropin-releasing hormone (TRH) is produced in the hypothalamus. Once released, TRH reaches the pituitary gland and binds to the TRH receptor and stimulates the production and secretion of thyroid-stimulating hormone (TSH), also known as thyrotropin (Liu et al., 2019). In the thyroid, TSH binds to the TSH receptor (TSHR) and induces TH production. When needed,

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

No abstract

No abstract