Erica L T van den Akker

Context The melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity. Objective We have identified 17 MC4R variants in adult and pediatric patients with obesity. Here we aimed to functionally characterize these variants by analyzing 4 different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants. Materials and Methods Cell surface expression and α-melanocyte stimulating hormone (α-MSH)- or setmelanotide-induced cAMP response, β-arrestin-2 recruitment, and ERK activation were measured in cells expressing either wild type or variant MC4R. Results We found a large heterogeneity in the function of these variants. We identified variants with a loss of response for all studied MC4R signaling, variants with no cAMP accumulation or ERK activation but normal β-arrestin-2 recruitment, and variants with normal cAMP accumulation and ERK activation but decreased β-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms. Setmelanotide displayed a greater potency and similar efficacy as α-MSH and induced significantly increased maximal cAMP responses of several variants compared to α-MSH. Despite the heterogeneity in functional response, there was no apparent difference in the obesity phenotype in our patients. Conclusion We show that these obesity-associated MC4R variants affect MC4R signaling differently yet lead to a comparable clinical phenotype. Our results demonstrate the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity, which may aid in improving personalized treatment.

Context Due to ethical considerations, antenatal dose finding for prednisolone and dexamethasone in pregnant women is limited, leading to a knowledge gap. Objective In order to guide the clinician in weighing benefits vs risks, the aim is to systematically review the current literature on the side effects of antenatal predniso(lo)ne and dexamethasone use on the fetus, newborn, and (pre)pubertal child. Evidence Acquisition The search was performed in PubMed/MEDLINE and Embase using prespecified keywords and Medical Subject Headings. This systematic review investigated studies published until August 2022, with the following inclusion criteria: studies were conducted in humans and assessed side effects of long-term antenatal predniso(lo)ne and dexamethasone use during at least one of the trimesters on the child during the fetal period, neonatal phase, and during childhood. Evidence Synthesis In total, 328 papers in PubMed and 193 in Embase were identified. Fifteen studies were eligible for inclusion. Seven records were added through references. Antenatal predniso(lo)ne use may be associated with lower gestational age, but was not associated with miscarriages and stillbirths, congenital abnormalities, differences in blood pressure or low blood glucose levels at birth, or with low bone mass, long-term elevated cortisol and cortisone, or high blood pressure at prepubertal age. Increased risks of antenatal dexamethasone use include association with miscarriages and stillbirths, and from age 16 years, associations with disturbed insulin secretion and higher glucose and cholesterol levels. Conclusions Based on the limited evidence found, predniso(lo)ne may have less side effects compared with dexamethasone in short- and long-term outcomes. Current literature shows minimal risk of side effects in the newborn from administration of a prenatal predniso(lo)ne dose of up to 10 mg per day.