Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity.

Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle.

Growth differentiation factor 15 neutralization does not impact anorexia or survival in lipopolysaccharide-induced inflammation.

Growth differentiation factor 15 (GDF15) causes anorexia and weight loss in animal models, and higher circulating levels are associated with cachexia and reduced survival in cancer and other chronic diseases such as sepsis. To investigate the role of sepsis-induced GDF15, we examined whether GDF15 neutralization via a validated and highly potent monoclonal antibody, mAB2, modulates lipopolysaccharide (LPS)-induced anorexia, weight loss, and mortality in rodents. LPS injection transiently increased circulating GDF15 in wild-type mice, decreased food intake and body weight, and increased illness behavior and mortality at a high dose.

Structure-function relationships of the soluble form of the antiaging protein Klotho have therapeutic implications for managing kidney disease.

The fortuitously discovered antiaging membrane protein αKlotho (Klotho) is highly expressed in the kidney, and deletion of the gene in mice causes a phenotype strikingly similar to that of chronic kidney disease (CKD). Klotho functions as a co-receptor for fibroblast growth factor 23 (FGF23) signaling, whereas its shed extracellular domain, soluble Klotho (sKlotho), carrying glycosidase activity, is a humoral factor that regulates renal health. Low sKlotho in CKD is associated with disease progression, and sKlotho supplementation has emerged as a potential therapeutic strategy for managing CKD.

Complex assembly on the human CYP17 promoter.

Optimal steroid hormone biosynthesis occurs via the integration of multiple regulatory processes, one of which entails a coordinate increase in the transcription of all genes required for steroidogenesis. In the human adrenal cortex adrenocorticotropin (ACTH) activates a signaling cascade that promotes the dynamic assembly of protein complexes on the promoters of steroidogenic genes. For CYP17, multiple transcription factors, including steroidogenic factor-1 (SF-1), GATA-6, and sterol regulatory binding protein 1 (SREBP1), are recruited to the promoter during activated transcription.

Multiple Signaling Pathways Coordinate CYP17 Gene Expression in the Human Adrenal Cortex.

Optimal levels of steroid hormone biosynthesis are assured by the integration of several regulatory mechanisms, including substrate delivery, enzymatic activity, and gene transcription. In the human adrenal cortex, optimal glucocorticoid secretion is achieved by the actions of adrenocorticotropin (ACTH), which exerts transcriptional pressure on all genes involved in steroidogenesis. One of these genes is CYP17, which encodes P450 17alpha-hydroxylase-17,20 lyase, a key enzyme in the production of cortisol and adrenal androgens.

Transcriptional regulation of adrenocortical steroidogenic gene expression.

By serving as ligands for nuclear and plasma membrane receptors, steroid hormones are key regulators of a diverse array of physiological processes. These hormones are synthesized from cholesterol in tissues such as the adrenal cortex, ovaries, testes, and placenta. Because steroid hormones control the expression of numerous genes, steroidogenic cells utilize multiple mechanisms that ensure tight control of the synthesis of these molecules.