👤 Smita Mall

The hypothalamus plays a central role in regulating metabolism by integrating hormonal and nutrient-derived signals to maintain energy homeostasis across the life span. Maternal nutritional status during critical windows of development is a major environmental factor that can permanently alter this regulation. Both maternal overnutrition and undernutrition have been shown to disturb circulating leptin, insulin, and glucagon-like peptide-1 (GLP-1), and to disrupt the normal development of hypothalamic nuclei implicated in energy balance. Experimental and clinical studies indicate that these insults miswire proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/AgRP) pathways, alter leptin and insulin receptor signaling, trigger neuroinflammation, glial and vascular changes, and are accompanied by enduring epigenetic alterations, including DNA methylation and chromatin remodeling at genes such as Pomc, Npy, Mc4r, Lepr, and Insr. Together, these adaptations establish new set points for appetite, energy expenditure, and glucose regulation, thereby increasing the lifelong risk of obesity and type 2 diabetes in the offspring. In this narrative review, we synthesize evidence from animal models and human studies linking maternal nutrition to hypothalamic programming via leptin, insulin, and GLP-1. We also highlight major gaps, including limited data on GLP-1 in maternal undernutrition, the specific role of individual micronutrients, and the timing and reversibility of hypothalamic programming, to inform future mechanistic, translational, and preventive research. Show less

The study aimed to assess the effectiveness of three clinical diagnostic criteria [Simon Broome (SB), MEDPED (MP), and guideline-derived (GL-EAS)] in identifying children with familial hypercholesterolaemia (FH) compared with genetic testing. The evaluation involved 1337 children with elevated LDL cholesterol (LDL-C) levels, focusing on the sensitivity and specificity of these clinical scores in detecting genetically confirmed FH cases. Clinical data were gathered by a self-reporting questionnaire. Clinical FH was defined in accordance with the tested FH score. Genetically confirmed heterozygous FH (HeFH) was defined by a (likely) pathogenic variant. Of the 1337 children undergoing genetic analysis, 211 showed a pathogenic FH mutation. Applying SB, MP, and GL-EAS criteria resulted in 210/1337, 125/1337, and 112/835 children being categorized to have FH clinically. The sensitivity of the clinical scores ranged from 0.44 to 0.54 with a positive predictive value (PPV) of 0.51-0.79. The specificity was 0.91-0.97 with a negative predictive value (NPV) of 0.89-0.91. Similar results were observed for the three clinical scores regarding sensitivity, specificity, PPV, and NPV in subgroup analyses defined by gender, age (<10 years vs. ≥10 years), or weight [≥90th BMI (body mass index) percentile vs. <90th BMI percentile]. Clinical FH scores offer a high degree of specificity for FH diagnosis in children, but at the expense of low sensitivity. Specifically, half of the mutation-positive children in this study would have been missed for early diagnosis and preventive treatment. Given the widespread availability of affordable genetic testing, such analysis should be performed at a lower threshold than that indicated by these clinical scores. Show less