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PubMed2025

Divergence of Leptin Receptor and Interleukin-6 Receptor Subunit b in Early Vertebrate Evolution and Physiological Insights from the Sea Lamprey.

Current knowledge of class-I cytokine receptors comes primarily from studies in jawed vertebrates (gnathostomes), and their origin and evolution remain unresolved. In this study, we identified a leptin receptor-like sequence (LepRL) and three interleukin-6 receptor subunit b-like sequences (IL6RBL) from a jawless vertebrate (cyclostome), the sea lamprey (Petromyzon marinus). Based on structural, phylogenetic, and syntenic analyses, we deduced that these lamprey receptors are likely distinct ohnologs to gnathostome LepR and IL6RB-related receptors, respectively, that arose in the two rounds of vertebrate whole-genome duplication (1R and 2R). Notably, lamprey LepRL likely originated from a different 1R progenitor than the one giving rise to gnathostome LepR during cyclostome hexaploidization. Differential patterns in mRNA expression of LepRL and IL6RBLs were observed among adult tissues, during larval metamorphosis, and in response to juvenile feeding. Feeding stimulated hepatic expression of LepRL and IL6RBL (namely, IL6RBL1) mRNAs in correlation with upregulation of insulin-like growth factor mRNA, whereas brain LepRL and IL6RBL1 mRNA expression was correlated positively with neuropeptide Y but inversely with intestinal content in fed juveniles. Notably, these observations along with immunolocalization of LepRL in the hypothalamus suggest a role of leptin signaling in regulating energy balance that is conserved among vertebrates. Additionally, seawater exposure stimulated branchial LepRL expression coincident with increased expression of ion transporters in ionocytes, indicating a role of leptin signaling in osmoregulation. These findings provide new insight into the early evolution of class-I cytokine receptors and reveal diverse functions of the leptin signaling system in jawless vertebrate.

Animals↗
PubMed2026

Exploration of body mass index and circulating metabolic factors as predictors of metformin benefit in the Canadian Cancer Trials Group MA.32.

BACKGROUND: In the MA.32 randomized adjuvant breast cancer trial, metformin (vs placebo) did not impact invasive disease-free survival or overall survival in estrogen and/or progesterone receptor-positive or -negative breast cancer; exploratory analyses suggested a benefit in HER2-positive breast cancer. We investigated whether body mass index (BMI) and obesity-associated blood variables predicted metformin benefit in immunohistochemically defined breast cancer subtypes (luminal [estrogen/progesterone receptor positive, HER2 negative], triple-negative breast cancer [estrogen receptor, progesterone receptor, HER2 negative], HER2 positive). METHODS: A total of 3649 nondiabetic patients with high risk T1-3, N0-3, M0 breast cancer were randomly assigned. Baseline fasting plasma was assayed for insulin, glucose, leptin, and C-reactive protein; Homeostasis Model Assessment was calculated. For each breast cancer subtype and each outcome (distant recurrence free survival, overall survival, invasive disease-free survival), Cox models examined interactions of BMI and blood variables with metformin vs placebo outcomes. RESULTS: Mean age was 51.1-53.0 years; mean BMI was 27.3-27.5 kg/m2. Most cancers were T2, N0, or N1 and grade 2-3; 2104 (57.7%) were luminal, 925 (25.3%) TN, and 620 (17.0%) HER2 positive. Median follow-up was 95.9 months. In luminal breast cancer, statistically significant interactions were identified for leptin, insulin, and Homeostasis Model Assessment on distant recurrence-free survival, and in triple-negative breast cancer, a statistically significant interaction was identified for glucose on distant recurrence-free survival, with potential adverse effects of metformin at lower levels of each variable. In those with HER2-positive breast cancer, there was no variable that predicted metformin benefit. CONCLUSIONS: Body mass index and blood variables did not identify subgroups with luminal or triple-negative breast cancer who benefited from metformin or those with HER2-positive breast cancer who did not benefit. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01101438: 2010-04-09.

Female↗
PubMed2026

Whole-exome sequencing-centered genetic evaluation for early-onset obesity in Chinese children: a retrospective single-center cohort.

BACKGROUND: Genetic causes of early-onset obesity remain undercharacterized in East Asian children. This study evaluated a whole-exome sequencing (WES)-centered diagnostic workflow in Chinese children with obesity onset before 5 years. METHODS: Consecutive children with body mass index above the 95th percentile and obesity onset before 5 years who completed structured inpatient assessment at a single center between February 2022 and December 2023 were retrospectively analyzed. Phenotyping included clinical, biochemical, oral glucose tolerance, cortisol rhythm, and liver assessments. Genetic testing combined WES, mitochondrial DNA analysis, multiplex ligation-dependent probe amplification (MLPA) for obesity-related imprinting loci, WES-based copy-number variant and runs-of-homozygosity analyses, and Sanger validation. Variants were interpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. RESULTS: Among 23 children, clinically relevant genetic findings were identified in 6 (26.1%): melanocortin-4 receptor (MC4R) c.831T>A (p.C277*), maternal uniparental disomy of 15q11-13, and four phenotype-correlated variants of uncertain significance in UCP3, BBS1, NCOA1, and SH2B1. The definitive/likely diagnostic yield, restricted to pathogenic or confirmed imprinting findings, was 8.7% (2/23). Findings involved leptin-MC4R signaling, BBSome function, fatty-acid oxidation, and chromosomal imprinting. Genetically positive children showed numerically higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but differences were not statistically significant. BBS1 p.T374S was relatively enriched in East Asian reference data. CONCLUSIONS: A WES-centered integrated workflow detected heterogeneous genetic mechanisms in Chinese children with early-onset obesity, but variant of uncertain significance (VUS)-associated findings should be distinguished from confirmed diagnoses. Orthogonal methylation/MLPA and runs of homozygosity (ROH) analyses were necessary for imprinting diagnosis. Larger multicenter studies and functional validation are needed.

Chinese children↗