Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.

PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T(3) during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-kappaB, growth factors, bile acids, hypoxia-inducible factor-1alpha, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.