Sphingolipid signatures at the extremes of energy balance: a comparative study of obesity and anorexia nervosa in women
5 affiliations
- 1Department of Clinical Sciences and Community Health, Dipartimento di Eccellenza 2023–2027, University of Milan
- 2Department of Health Sciences, University of Milan
- 3Experimental Laboratory for Auxo-Endocrinological Research, Istituto Auxologico Italiano, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico)
- 4Division of Auxology, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
- 5Division of Eating and Nutrition Disorders, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Abstract
Background: Anorexia nervosa (AN) and obesity (OB) represent opposite extremes of energy balance and are both associated with profound metabolic alterations. Increasing evidence suggests that sphingolipids play a central role in cardiometabolic regulation, inflammation, and insulin signaling; however, clinical sphingolipidomic studies have largely investigated AN and OB separately. Direct comparative studies using a harmonized analytical framework are currently lacking.
Objectives: The primary objective of this study was to determine whether women with AN or OB exhibit distinct plasma sphingolipidomic signatures compared with a normal-weight healthy (NWH) group and with each other. Secondary objectives included identifying multivariate sphingolipid patterns associated with nutritional phenotype and evaluating associations between plasma sphingolipids and cardiometabolic parameters.
Methods: In this cross-sectional study, 114 women were enrolled (28 with AN, 37 with OB, and 49 NWH controls). Plasma sphingolipidomics was assessed using targeted liquid chromatography–tandem mass spectrometry (LC–MS/MS). Clinical, anthropometric, biochemical, inflammatory, and hemodynamic variables were collected in all participants. Group comparisons were performed using non-parametric statistics with Benjamini–Hochberg false discovery rate (FDR) correction. Multivariate analyses included principal component analysis (PCA), hierarchical clustering analysis (HCA), partial least squares discriminant analysis (PLS-DA), and variable importance in projection (VIP) analysis. Age-adjusted regression analyses were performed to investigate associations between sphingolipid variables and cardiometabolic predictors.
Results: Clinical and metabolic variables differed among the AN, NWH, and OB groups. After FDR correction, 38 of 45 sphingolipid variables differed significantly among groups, involving ceramides, dihydroceramides, sphingomyelins, glycosphingolipids, sphingoid-base-related metabolites, and ceramide ratio indices. AN was characterized by increased levels of several sphingomyelins, lactosylceramides, GM3 species, S1P, and DhS1P. In contrast, OB showed enrichment of selected dihydroceramides and ceramide ratio indices together with lower levels of several very-long-chain glycosphingolipids. The direct OB-versus-AN comparison yielded the largest number of FDR-significant variables among the three pairwise comparisons. PCA, hierarchical clustering, and PLS-DA consistently demonstrated structured multivariate separation among groups. The supervised PLS-DA model achieved an overall accuracy of 0.851 and identified DHCer 24:1, DHCer 18, HexCer 22, Cer 24:1, SM 24:1, and DHCer 18:1 among the variables with the highest VIP scores. Age-adjusted analyses revealed significant associations between sphingolipid variables and BMI, HOMA-IR, blood pressure, CRP, triglycerides, and HDL-cholesterol.
Conclusions: Women with AN and OB exhibit distinct but partially overlapping plasma sphingolipidomic signatures, characterized by coordinated remodeling across multiple sphingolipid pathways. AN was predominantly associated with sphingomyelin- and glycosphingolipid-enriched patterns, whereas OB was characterized by dihydroceramide- and ceramide-ratio-associated remodeling. These findings support the concept that severe undernutrition and obesity represent biologically distinct states of sphingolipid dysregulation and suggest that plasma sphingolipid signatures may serve as candidate biomarkers of metabolic remodeling and cardiometabolic risk across the extremes of energy balance.
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BibTeX
@article{rigamonti2026sphingolipid,
title = {{Sphingolipid signatures at the extremes of energy balance: a comparative study of obesity and anorexia nervosa in women}},
author = {Antonello E. Rigamonti and Camillo Morano and Michele Dei Cas and Aldijana Sadikovic and Adele Bondesan and Diana Caroli and Francesca Frigerio and Laura Abbruzzese and Sandra Savino and Silvano G. Cella and Rita Paroni and Alessandro Sartorio},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1890712},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1890712/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sphingolipid signatures at the extremes of energy balance: a comparative study of obesity and anorexia nervosa in women
AU - Antonello E. Rigamonti
AU - Camillo Morano
AU - Michele Dei Cas
AU - Aldijana Sadikovic
AU - Adele Bondesan
AU - Diana Caroli
AU - Francesca Frigerio
AU - Laura Abbruzzese
AU - Sandra Savino
AU - Silvano G. Cella
AU - Rita Paroni
AU - Alessandro Sartorio
PY - 2026
DA - 2026/10/08
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1890712
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1890712/full
AB - Background: Anorexia nervosa (AN) and obesity (OB) represent opposite extremes of energy balance and are both associated with profound metabolic alterations. Increasing evidence suggests that sphingolipids play a central role in cardiometabolic regulation, inflammation, and insulin signaling; however, clinical sphingolipidomic studies have largely investigated AN and OB separately. Direct comparative studies using a harmonized analytical framework are currently lacking. Objectives: The primary objective of this study was to determine whether women with AN or OB exhibit distinct plasma sphingolipidomic signatures compared with a normal-weight healthy (NWH) group and with each other. Secondary objectives included identifying multivariate sphingolipid patterns associated with nutritional phenotype and evaluating associations between plasma sphingolipids and cardiometabolic parameters. Methods: In this cross-sectional study, 114 women were enrolled (28 with AN, 37 with OB, and 49 NWH controls). Plasma sphingolipidomics was assessed using targeted liquid chromatography–tandem mass spectrometry (LC–MS/MS). Clinical, anthropometric, biochemical, inflammatory, and hemodynamic variables were collected in all participants. Group comparisons were performed using non-parametric statistics with Benjamini–Hochberg false discovery rate (FDR) correction. Multivariate analyses included principal component analysis (PCA), hierarchical clustering analysis (HCA), partial least squares discriminant analysis (PLS-DA), and variable importance in projection (VIP) analysis. Age-adjusted regression analyses were performed to investigate associations between sphingolipid variables and cardiometabolic predictors. Results: Clinical and metabolic variables differed among the AN, NWH, and OB groups. After FDR correction, 38 of 45 sphingolipid variables differed significantly among groups, involving ceramides, dihydroceramides, sphingomyelins, glycosphingolipids, sphingoid-base-related metabolites, and ceramide ratio indices. AN was characterized by increased levels of several sphingomyelins, lactosylceramides, GM3 species, S1P, and DhS1P. In contrast, OB showed enrichment of selected dihydroceramides and ceramide ratio indices together with lower levels of several very-long-chain glycosphingolipids. The direct OB-versus-AN comparison yielded the largest number of FDR-significant variables among the three pairwise comparisons. PCA, hierarchical clustering, and PLS-DA consistently demonstrated structured multivariate separation among groups. The supervised PLS-DA model achieved an overall accuracy of 0.851 and identified DHCer 24:1, DHCer 18, HexCer 22, Cer 24:1, SM 24:1, and DHCer 18:1 among the variables with the highest VIP scores. Age-adjusted analyses revealed significant associations between sphingolipid variables and BMI, HOMA-IR, blood pressure, CRP, triglycerides, and HDL-cholesterol. Conclusions: Women with AN and OB exhibit distinct but partially overlapping plasma sphingolipidomic signatures, characterized by coordinated remodeling across multiple sphingolipid pathways. AN was predominantly associated with sphingomyelin- and glycosphingolipid-enriched patterns, whereas OB was characterized by dihydroceramide- and ceramide-ratio-associated remodeling. These findings support the concept that severe undernutrition and obesity represent biologically distinct states of sphingolipid dysregulation and suggest that plasma sphingolipid signatures may serve as candidate biomarkers of metabolic remodeling and cardiometabolic risk across the extremes of energy balance.
SN - 1664-2392
ER -