Structures of active melanocortin-4 receptor−Gs-protein complexes with NDP-α-MSH and setmelanotide

The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R–Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor–Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs

Chronic depression: development and evaluation of the luebeck questionnaire for recording preoperational thinking (LQPT)

<p>Abstract</p> <p>Background</p> <p>A standardized instrument for recording the specific cognitive psychopathology of chronically depressed patients has not yet been developed. Up until now, preoperational thinking of chronically depressed patients has only been described in case studies, or through the external observations of therapists. The aim of this study was to develop and evaluate a standardized self-assessment instrument for measuring preoperational thinking that sufficiently conforms to the quality criteria for test theory.</p> <p>Methods</p> <p>The "Luebeck Questionnaire for Recording Preoperational Thinking (LQPT)" was developed and evaluated using a german sample consisting of 30 episodically depressed, 30 chronically depressed and 30 healthy volunteers. As an initial step the questionnaire was subjected to an item analysis and a final test form was compiled. In a second step, reliability and validity tests were performed.</p> <p>Results</p> <p>Overall, the results of this study showed that the LQPT is a useful, reliable and valid instrument. The reliability (split-half reliability 0.885; internal consistency 0.901) and the correlations with other instruments for measuring related constructs (control beliefs, interpersonal problems, stress management) proved to be satisfactory. Chronically depressed patients, episodically depressed patients and healthy volunteers could be distinguished from one another in a statistically significant manner (p < 0.001).</p> <p>Conclusion</p> <p>The questionnaire fulfilled the classical test quality criteria. With the LQPT there is an opportunity to test the theory underlying the CBASP model.</p

Evaluation of a rare glucose-dependent insulinotropic polypeptide receptor variant in a patient with diabetes

AIMS: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that augments insulin secretion in pancreatic β-cells via its glucose-dependent insulinotropic polypeptide receptor (GIPR). Recent genome-wide association studies identified a single nucleotide variant (SNV) in the GIPR encoding gene (GIPR), rs1800437, that is associated with obesity and insulin resistance. In the present study, we tested whether GIPR variants contribute to obesity and disturb glucose homeostasis or diabetes in specific patient populations. MATERIALS AND METHODS: Exon sequencing of GIPR was performed in 164 children with obesity and insulin resistance and in 80 children with paediatric-onset diabetes of unknown origin. The Study of Health in Pomerania (SHIP) cohort, comprising 8320 adults, was screened for the GIPR variant Arg217Leu. GIPR variants were expressed in COS-7 cells and cAMP production was measured upon stimulation with GIP. Cell surface expression was determined by ELISA. Protein homology modelling of the GIPR variants was performed to extract three-dimensional information of the receptor. RESULTS: A heterozygous missense GIPR variant Arg217Leu (rs200485112) was identified in a patient of Asian ancestry. Functional characterization of Arg217Leu revealed reduced surface expression and signalling after GIP challenge. The homology model of the GIPR structure supports the observed functional relevance of Arg217Leu. CONCLUSION: In vitro functional studies and protein homology modelling indicate a potential relevance of the GIPR variant Arg217Leu in receptor function. The heterozygous variant displayed partial co-segregation with diabetes. Based on these findings, we suggest that GIPR variants may play a role in disturbed glucose homeostasis and may be of clinical relevance in homozygous patients

Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide.

CONTEXT: Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity. In pivotal Phase 3 clinical trials, treatment with the MC4R agonist setmelanotide reduced hunger and weight in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. OBJECTIVE: To characterize the historical weight trajectory in these patients. METHODS: This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). These were multicenter trials. Patients had obesity due to POMC/PCSK1 or LEPR deficiency. During the trial, patients were treated with setmelanotide. Historical data on measured weight and height were obtained during screening. RESULTS: A total of 17 patients (POMC, n = 8; PCSK1, n = 1; LEPR, n = 8) with historical weight and height data were included in this analysis. Before setmelanotide treatment, patients with obesity due to POMC/PCSK1 or LEPR deficiency were above the 95th percentile for weight throughout childhood, demonstrated continuous weight gain, and did not show long-term weight loss upon interventions (eg, diet, surgery, exercise). Setmelanotide treatment attenuated weight and body mass index trajectories over the observation period of 1 year. CONCLUSION: In patients with POMC, PCSK1, or LEPR deficiency, traditional interventions for weight loss had limited impact on the trajectory of severe early-onset obesity. However, setmelanotide treatment attenuated weight and body mass index trajectories and led to weight loss associated with health benefits in most individuals

Supplementary Material for: Long-Term Lanreotide Treatment in Six Patients with Congenital Hyperinsulinism

<b><i>Background:</i></b> Medical treatment is a substantial therapeutic measure to achieve glycemic control and prevent hypoglycemic brain damage without surgery in patients with congenital hyperinsulinism (CHI). However, only few drugs are available and even fewer are approved as a medical therapy to maintain normal blood glucose levels. The established therapies are demanding for caregivers and complicated by different side effects such as gastrointestinal symptoms, hypertrichosis, and obesity. Therefore, it is important to develop new strategies to improve blood glucose control. <b><i>Methods:</i></b> We report the use of the very-long-acting somatostatin analogue lanreotide autogel in 6 patients with CHI over a mean duration of 40.8 months. Blood glucose levels before and after the start and dosage titration of lanreotide in these patients are compared. <b><i>Results:</i></b> In 3 of 6 patients, switching to lanreotide raised mean blood glucose levels and reduced individually as well as overall the risk for hypoglycemic episodes (odds ratio 0.38) significantly. <b><i>Conclusion:</i></b> Lanreotide autogel can be used as an alternative pharmacological treatment and may be beneficial in conservatively treated patients with CHI