Uncovering the function of Wisp1 in whole-body glucose homeostasis: insights from Wisp1 knockout mice

WNT1-inducible signaling pathway protein 1 (Wisp1/CCN4) is a matricellular protein implicated in inflammation and metabolic dysfunction in obesity, yet its role in whole-body glucose metabolism remains unclear. In this study, Wisp1 knockout (KO) mice were analysed under physiological and high-fat (HF) diet conditions to define its impact on metabolic regulation. Neither physiological nor HF diet conditions revealed an effect of Wisp1 deficiency on whole-body glucose tolerance. However, male KO mice on a HF diet exhibited enhanced insulin sensitivity, lower insulin levels, and a marked reduction in adipose tissue inflammation, as evidenced by diminished macrophage infiltration and decreased pro-inflammatory cytokine expression in visceral fat. Additionally, beta cell mass expansion was attenuated in KO mice under HF diet, aligning with lower macrophage infiltration in islets. These findings suggest that improved insulin sensitivity in KO mice occurs independently of changes in glucose tolerance, likely due to mitigated adipose tissue inflammation. Thus, Wisp1 primarily modulates local adipose inflammatory responses, indirectly affecting islet adaptation to metabolic stress, rather than serving as a direct regulator of systemic glucose homeostasis.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-01-15
DOI
https://doi.org/10.64898/2026.01.15.699691
Primary Topic
Connective Tissue Growth Factor Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Uncovering the function of Wisp1 in whole-body glucose homeostasis: insights from Wisp1 knockout mice

Colleen K. Hadley, Zeran Lin, Marta Fontcuberta-PiSunyer, Paul A. Cohen et al.
bioRxiv (Cold Spring Harbor Laboratory)
Connective Tissue Growth Factor Research
article

Uncovering the function of Wisp1 in whole-body glucose homeostasis: insights from Wisp1 knockout mice

Colleen K. Hadley, Zeran Lin, Marta Fontcuberta-PiSunyer, Paul A. Cohen, Rosa Gasa, Jessica Angulo-Capel, Fernandez-Ruiz Rebeca, Josep Vidal, Marta Perea-Atienzar, Ainhoa Garcia-Alaman
article en

Abstract

WNT1-inducible signaling pathway protein 1 (Wisp1/CCN4) is a matricellular protein implicated in inflammation and metabolic dysfunction in obesity, yet its role in whole-body glucose metabolism remains unclear. In this study, Wisp1 knockout (KO) mice were analysed under physiological and high-fat (HF) diet conditions to define its impact on metabolic regulation. Neither physiological nor HF diet conditions revealed an effect of Wisp1 deficiency on whole-body glucose tolerance. However, male KO mice on a HF diet exhibited enhanced insulin sensitivity, lower insulin levels, and a marked reduction in adipose tissue inflammation, as evidenced by diminished macrophage infiltration and decreased pro-inflammatory cytokine expression in visceral fat. Additionally, beta cell mass expansion was attenuated in KO mice under HF diet, aligning with lower macrophage infiltration in islets. These findings suggest that improved insulin sensitivity in KO mice occurs independently of changes in glucose tolerance, likely due to mitigated adipose tissue inflammation. Thus, Wisp1 primarily modulates local adipose inflammatory responses, indirectly affecting islet adaptation to metabolic stress, rather than serving as a direct regulator of systemic glucose homeostasis.

bioRxiv (Cold Spring Harbor Laboratory)
Cornell University (US), Instituto de Salud Carlos III (ES), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Tri-Institutional PhD Program in Chemical Biology (US), Hospital Clínic de Barcelona (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Universitat de Barcelona (ES), Rockefeller University (US)
Ministerio de Ciencia, Innovación y Universidades, Universitat de Barcelona, Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, National Institutes of Health, Weill Cornell Medical College, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 86%
Connective Tissue Growth Factor Research
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