Circulating diabetes biomarkers have been identified with proteomics measured at a single timepoint, but what is additionally provided by longitudinal repeated measurements in the same individuals, over many years, is unknown. We studied participants in the Multi-Ethnic Study of Atherosclerosis (MESA; N=5,322, mean baseline age 61.7 years) at exams 1 (2000-2002), 5 (2010-2012), and 6 (2016-2018) profiled with Olink 3K. Associations with incident diabetes, mostly of type 2, were modeled using Cox proportional hazards with exam 1 proteins (i.e., single timepoint) and time-updating Cox with proteins from all 3 exams (i.e., longitudinal repeated) adjusted for clinical risk factors. We identified 27 novel single-timepoint associations and up to a 4-fold increase in longitudinal associations (FDR<0.05) with a proportional increase in the number consistent with causality via cis-Mendelian Randomization (~5%) and a smaller overlap in MESA longitudinal versus single associations with UK Biobank single timepoint findings (42% versus 87%, respectively). Compared to small molecule metabolism pathway enrichment among the shared proteins, proteins unique to the longitudinal analyses enriched for protein and cellular processing pathways. We conclude that longitudinal repeated measurements identify a number of distinct disease biomarkers, in part by revealing the progression of relevant biological processes within an individual closer to clinical diabetes diagnosis versus single measurements.
ARTICLE HIGHLIGHTS:We investigated whether ketogenesis is required for the metabolic benefits of intermittent fasting (IF) and whether these effects differ between sexes. We specifically asked whether ketogenesis drives IF-mediated protection against obesity and fatty liver disease in male and female mice. We found that IF reduced adiposity independently of ketogenesis in both sexes, but its antisteatotic and antifibrotic effects were ketogenesis-dependent in male mice and minimal in female mice. These findings reveal a sex-dependent ketogenesis-inflammation-fibrosis axis and highlight the need to consider sex and ketone metabolism when designing dietary or therapeutic interventions.
ARTICLE HIGHLIGHTS:Childhood obesity shows large differences in body composition and health risk that are not well captured by BMI or simple metabolic classifications, prompting the need for more precise characterization. This study aimed to determine whether a data-driven framework integrating detailed body composition measures could better describe obesity-related phenotypic heterogeneity and its relationship with cardiometabolic risk in children. We delineated a continuous body composition manifold encompassing fat-dominant, lean-dominant, and concomitant high-mass phenotypes, which captured diverging cardiometabolic risk trajectories and yielded modest incremental improvements in risk prediction. These findings support more precise risk stratification and provide a practical tool to improve early identification and prevention of obesity-related health complications in children.
ARTICLE HIGHLIGHTS:A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.
ARTICLE HIGHLIGHTS:Obesity is associated with the enrichment of unsaturated triacylglycerol (TAG) species in adipose tissue, but the mechanism driving this selective lipid accumulation remains unclear. We investigated whether substrate-selective lipolysis contributes to the retention of unsaturated fatty acids (FAs) in obese adipose tissue. Lipidomic profiling revealed predominant enrichment of FA 18:1 and FA 18:2 in midlife-predominant obese adipose TAGs, and functional assays showed that adipose triglyceride lipase preferentially hydrolyzes saturated TAGs under conditions of sufficient substrate supply. These results identify lipase substrate selectivity as a mechanistic contributor to lipid remodeling in obesity and a potential target for modulating adipose lipid turnover.
ARTICLE HIGHLIGHTS:Accelerated brain aging has been reported in diabetes, but its links with diabetic peripheral neuropathy (DPN) and neuropathic pain remain unclear. We explored brain age gap (BAG) in type 1 diabetes to determine if it differs across neuropathic phenotypes, relates to clinical characteristics including DPN measures, and shows distinct regional patterns. Diabetes participants had 3.5 years of BAG, rising to 6-7 years in those with DPN. Diabetes duration was the main driver of BAG, whereas DPN had limited impact and neuropathic pain no clear contribution. BAG was widespread across the brain. Accelerated brain aging appears to affect people with diabetes regardless of neuropathic complications.
