TY - JOUR

T1 - Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids

AU - Fiorenza, Matteo

AU - Checa, Antonio

AU - Sandsdal, Rasmus M.

AU - Jensen, Simon B.K.

AU - Juhl, Christian R.

AU - Noer, Mikkel H.

AU - Bogh, Nicolai P.

AU - Lundgren, Julie R.

AU - Janus, Charlotte

AU - Stallknecht, Bente M.

AU - Holst, Jens Juul

AU - Madsbad, Sten

AU - Wheelock, Craig E.

AU - Torekov, Signe S.

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024

Y1 - 2024

N2 - Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.

AB - Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.

KW - adiponectin

KW - ceramide

KW - cytokines

KW - exercise

KW - FGF21

KW - GDF15

KW - GLP-1 receptor agonist

KW - leptin

KW - obesity

KW - sphingolipids

U2 - 10.1016/j.xcrm.2024.101629

DO - 10.1016/j.xcrm.2024.101629

M3 - Journal article

C2 - 38959886

AN - SCOPUS:85197238748

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

SN - 2666-3791

IS - 7

M1 - 101629

ER -