IMPROVE 2023: The 2nd International Meeting on Pathway-Related Obesity: Vision & Evidence.

A total of 150 clinicians and researchers representing 19 countries came together in person and online to participate in the highly anticipated 2nd International Meeting on Pathway-Related Obesity: Vision & Evidence (IMPROVE), held on 13-15 December 2023 in Paris, France. Building on the success of the inaugural event in 2022, this gathering served as a pivotal platform for attendees to delve into the latest scientific and clinical developments in hyperphagia and early-onset obesity caused by rare melanocortin-4 receptor (MC4R) pathway disease. The central objective of the meeting was to explore the complexities of MC4R pathway-related diseases and generate opportunities for collaborative dialogue among delegates for the advancement of this field.

Alteration of IGF-1 bioavailability due to PAPPA2 deficiency leads to sex-specific metabolic disturbances.

Background: The growth hormone (GH)/insulin-like growth factor (IGF-1) axis determines optimal growth and affects metabolism and energy homeostasis. Pregnancy-associated plasma protein-A2 (PAPPA2) regulates bioactive IGF-1 availability and patients with PAPPA2 deficiency have impaired growth and glucose metabolism. This axis is altered in metabolic disturbances such as obesity and anorexia nervosa in a sex-specific manner, but the mechanisms involved are not completely understood.

Hyperphagia in rare melanocortin-4 receptor pathway diseases: therapeutic options and assessing treatment response.

Hyperphagia is a hallmark of both congenital and acquired rare melanocortin-4 receptor (MC4R) pathway diseases. Currently, the medical community has no standard treatment guidelines or approach to establishing treatment benefit. This narrative review discusses current understandings of the pathophysiology, burden, and treatment of hyperphagia and summarizes findings from a systematic literature review of validated instruments for assessing the response to hyperphagia treatment.

Peripheral precocious puberty in girls with McCune-Albright syndrome: a case series.

Objective: To describe the follow-up of girls with peripheral precocious puberty (PPP) due to McCune-Albright syndrome (MAS).

Subjects And Methods: Data from 18 females, including anthropometric and reproductive outcomes, were evaluated. Genetic analysis was performed on DNA from peripheral leukocytes via digital PCR.

Early childhood height, weight, and BMI development in children with monogenic obesity: a European multicentre, retrospective, observational study.

Background: Monogenic defects in the leptin-melanocortin pathway are associated with hyperphagia and severe, early-onset obesity. Early childhood growth patterns in height, weight, and BMI, might serve as phenotypic markers for specific genetic disorders; however, reliable data are scarce. This study aimed to evaluate the natural history of height, weight, and BMI in early childhood in a large European group of individuals with monogenic obesity.

Impact of Setmelanotide on Metabolic Syndrome Risk in Patients With Bardet-Biedl Syndrome.

Context: Bardet-Biedl syndrome (BBS) is a rare genetic disease associated with disruptions in melanocortin-4 receptor pathway signaling that can contribute to increased risk for metabolic syndrome and obesity-related comorbidities.

Objective: Here, MetS-Z-BMI scores, a continuous measure based on body mass index, were calculated to determine metabolic syndrome severity and response to treatment with the melanocortin-4 receptor agonist setmelanotide in BBS.

Methods: All patients from a Phase 3 study (NCT03746522) of setmelanotide with data required for the calculation of MetS-Z-BMI scores were included.

A New Mediterranean Lifestyle Pyramid for Children and Youth: A Critical Lifestyle Tool for Preventing Obesity and Associated Cardiometabolic Diseases in a Sustainable Context.

Cardiovascular disease risk factors begin in childhood and track into adulthood, increasing the possibility of impaired cardiometabolic health. Adopting healthy dietary patterns can help curb childhood obesity, a worrisome epidemic problem at present. In the era of personalized nutrition, dietary recommendations should be adapted to different stages of life, including children (older than 3 y) and adolescents.

Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial.

Background: Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2-5 years with POMC or LEPR deficiency or BBS.

Hypothalamic obesity: from basic mechanisms to clinical perspectives.

Despite the diverse nature of obesity, there is compelling genetic, clinical, and experimental evidence that endorses the important contribution of brain circuits to this condition. The hypothalamus contains major regulatory circuits for bodyweight homoeostasis, the deregulation of which can lead to obesity. Although functional perturbation of hypothalamic pathways could lie at the basis of common forms of obesity, the term hypothalamic obesity has been created to define those rare forms of severe obesity where a clear hypothalamic substrate can be identified, either of genetic or acquired origin.

Palmitic Acid Modulation of the Insulin-Like Growth Factor System in Hypothalamic Astrocytes and Neurons.

Introduction: Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here, we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally.

Methods: Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both.

Reduction in Hippocampal Amyloid-β Peptide (Aβ) Content during Glycine-Proline-Glutamate (Gly-Pro-Glu) Co-Administration Is Associated with Changes in Inflammation and Insulin-like Growth Factor (IGF)-I Signaling.

Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-β peptides (Aβs) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE), has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 for 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects.

Kisspeptin signaling in astrocytes modulates the reproductive axis.

Reproduction is safeguarded by multiple, often cooperative, regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation.

The differential effects of palmitic acid and oleic acid on the metabolic response of hypothalamic astrocytes from male and female mice.

Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid β-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets.

Implication of Pappalysins and Stanniocalcins in the Bioavailability of IGF-I in Children With Type 1 Diabetes Mellitus.

Context: Anomalies in the growth hormone (GH)/insulin-like growth factor (IGF) axis, are common in children with type 1 diabetes mellitus (T1DM), even in those reaching a normal or near-normal final height. However, concentrations of the IGF bioavailability regulatory factors (pappalysins [PAPP-As] and stanniocalcins [STCs]) have not been reported in children with T1DM.

Objective: To determine serum concentrations of PAPP-As and STCs in children at diagnosis of T1DM and after insulin treatment and the correlation of these factors with other members of the GH/IGF axis, beta-cell insulin reserve, auxology, and nutritional status.

Prepubertal Children With Obesity Have High Free IGF-1 Levels and Accelerated Growth Despite Reduced Pappalysin Levels.

Background: Prepubertal children with obesity frequently have enhanced growth, accelerated skeletal maturation, and changes in the growth hormone-insulin-like growth factor (GH-IGF) axis. However, the involvement of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF bioavailability has not been studied in obesity.

Objective: We aimed to determine the effects of childhood obesity and weight reduction on serum levels of PAPP-A, PAPP-A2, STC1, and STC2 and their relationship with IGF bioavailability, growth, and other components of the GH-IGF system.

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments.

Background: Children with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways.

Methods: Plasma, hypothalamus, pituitary gland and liver of Pappa2 mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.

Synergism Between Hypothalamic Astrocytes and Neurons in Metabolic Control.

Astrocytes are no longer considered as passive support cells. In the hypothalamus, these glial cells actively participate in the control of appetite, energy expenditure, and the processes leading to obesity and its secondary complications. Here we briefly review studies supporting this conclusion and the advances made in understanding the underlying mechanisms.

Identifying subgroups of childhood obesity by using multiplatform metabotyping.

Obesity results from an interplay between genetic predisposition and environmental factors such as diet, physical activity, culture, and socioeconomic status. Personalized treatments for obesity would be optimal, thus necessitating the identification of individual characteristics to improve the effectiveness of therapies. For example, genetic impairment of the leptin-melanocortin pathway can result in rare cases of severe early-onset obesity.

Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.

Purpose: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.

Methods: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.

Increased IGFBP Proteolysis, IGF-I Bioavailability, and Pappalysin Levels in Children With Prader-Willi Syndrome.

Context: Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown.

Objective: We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment.