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Rimonabant (SR-141716A) clinical trials demonstrate that antagonism of the CB1 cannabinoid receptor can result in better glucose control as indicated by a reduction in HbA[sub 1c] levels and an improvement in insulin sensitization in treated patients. These effects may be mediated in part through regulation of white adipose tissue lipolysis, the catabolic process whereby triglyceride stores are hydrolyzed to fatty acids and glycerol. In adipose tissue, catecholamine binding to β-adrenergic receptors activates adenylate cyclase through a G[sub s]-coupled mechanism, thereby increasing intracellular cAMP levels. Subsequent activation of protein kinase A by cAMP results in phosphorylation and activation of hormone-sensitive lipase, the rate-limiting enzyme in lipolysis. To explore the effect of cannabinoid modulation of adenlyate cyclase activity, an HTRF (Homogenous Time-Resolved Fluorescence) assay was established to measure the concentration of intracellular cAMP. The CB1 receptor agonist, R(+)-WIN55, 212-2, inhibited forskolin-stimulated cAMP production in CHO cells expressing the CB1 receptor, and SR-141716A blocked this effect in a dose-dependent manner. Consistent with a G[sub i]-coupling mechanism, pertussis toxin attenuated the CB1 receptor agonist-mediated inhibition but not the stimulation of cAMP production. Similar to the in vitro results, CB1 receptor agonist treatment of ob/ob mice acutely inhibited fasting-induced levels of plasma FFAs, an effect that was blocked by SR-141716A administration. Together, these data provide additional evidence that CB1 receptor antagonism regulates adipose tissue lipid metabolism. [ABSTRACT FROM AUTHOR]

The secretin-like, class B1 sub-family of seven transmembrane-spanning G protein coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and utilize a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via a large N-terminal extracellular domain that forms a hydrophobic ligand binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogues of several class B1 ligands for therapeutic use. Among the most successful of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multi-functional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of poly-pharmacologic ligands. Further, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complex with either native ligands or multi-functional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

Glucagon-like peptide 1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1 receptor (GLP-1R) expression in α-cells using both antibody-dependent and antibody-independent strategies. A novel α-cell-specific GLP-1R knockout (αGLP-1R -/- ) mouse model was created and used to investigate its effects on glucagon secretion and glucose metabolism. Male and female αGLP-1R -/- mice both showed higher nonfasting glucagon levels than their wild-type littermates, whereas insulin and GLP-1 levels remained similar. Female αGLP-1R -/- mice exhibited mild glucose intolerance after an intraperitoneal glucose administration and showed increased glucagon secretion in response to a glucose injection compared with the wild-type animals. Furthermore, using isolated islets, we confirmed that αGLP-1R deletion did not interfere with β-cell function but affected glucagon secretion in a glucose-dependent bidirectional manner: the αGLP-1R -/- islets failed to inhibit glucagon secretion at high glucose and failed to stimulate glucagon secretion at very low glucose condition. More interestingly, the same phenomenon was recapitulated in vivo under hypoglycemic and postprandial (fed) conditions. Taken together, this study demonstrates that GLP-1 (via GLP-1R in α-cells) plays a bidirectional role, either stimulatory or inhibitory, in glucagon secretion depending on glucose levels., (© 2018 by the American Diabetes Association.)

FSH is a critical hormone regulator of gonadal function that is secreted from the pituitary gonadotrope cell. Human patients and animal models with mutations in the LHX3 LIM-homeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH. We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH beta-subunit promoter, but not the proximal LHbeta promoter. The related LHX4 mammalian transcription factor can also induce FSHbeta promoter transcription, but the homologous Drosophila protein LIM3 cannot. The actions of LHX3 are specifically blocked by a dominant negative LHX3 protein containing a Kruppel-associated box domain. Six LHX3-binding sites were characterized within the FSHbeta promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin. Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHbeta promoter and basal promoter activity in gonadotrope cells. Using quantitative methods, we show that the responses of the FSHbeta promoter to activin do not require induction of the LHX3 gene. By comparative genomics using the human FSHbeta promoter, we demonstrate structural and functional conservation of promoter induction by LHX3. We conclude that the LHX3 LIM homeodomain transcription factor is involved in activation of the FSH beta-subunit gene in the pituitary gonadotrope cell.