Research output: Contribution to journal › Article › Academic › peer-review
Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression marks human obesity. / Clemente-Olivo, Maria P.; Habibe, Jayron J.; Vos, Mariska et al.
In: Metabolism: clinical and experimental, Vol. 121, 154815, 01.08.2021.Research output: Contribution to journal › Article › Academic › peer-review
}
TY - JOUR
T1 - Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression marks human obesity
AU - Clemente-Olivo, Maria P.
AU - Habibe, Jayron J.
AU - Vos, Mariska
AU - Ottenhoff, Roelof
AU - Jongejan, Aldo
AU - Herrema, Hilde
AU - Zelcer, Noam
AU - Kooijman, Sander
AU - Rensen, Patrick C. N.
AU - van Raalte, Daniël H.
AU - Nieuwdorp, Max
AU - Eringa, Etto C.
AU - de Vries, Carlie J.
N1 - Funding Information: This research was supported by a grant from Rembrandt Institute of Cardiovascular Sciences and Research Institute Cardiovascular Sciences of Amsterdam UMC (C.J.dV.) and the Netherlands CardioVascular Research Initiative CVON-GENIUS-2 (P.C.N.R.). N.Z. is supported by a European Research Council Consolidator grant (617376). The graphical abstract was created with BioRender.com. Funding Information: This research was supported by a grant from Rembrandt Institute of Cardiovascular Sciences and Research Institute Cardiovascular Sciences of Amsterdam UMC (C.J.dV.) and the Netherlands CardioVascular Research Initiative CVON-GENIUS-2 (P.C.N.R.). N.Z. is supported by a European Research Council Consolidator grant ( 617376 ). The graphical abstract was created with BioRender.com . Publisher Copyright: © 2021 The Authors
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Objective: Four-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and expression of the FHL2 gene increases with age, and high FHL2 expression is associated with increased body weight in humans and mice. This led us to hypothesize that FHL2 is a determinant of diet-induced obesity. Methods: FHL2-deficient (FHL2−/−) and wild type male mice were fed a high-fat diet. Metabolic phenotyping of these mice, as well as transcriptional analysis of key metabolic tissues was performed. Correlation of the expression of FHL2 and relevant genes was assessed in datasets from white adipose tissue of individuals with and without obesity. Results: FHL2 Deficiency protects mice from high-fat diet-induced weight gain, whereas glucose handling is normal. We observed enhanced energy expenditure, which may be explained by a combination of changes in multiple tissues; mild activation of brown adipose tissue with increased fatty acid uptake, increased cardiac glucose uptake and browning of white adipose tissue. Corroborating our findings in mice, expression of FHL2 in human white adipose tissue positively correlates with obesity and negatively with expression of browning-associated genes. Conclusion: Our results position FHL2 as a novel regulator of obesity and energy expenditure in mice and human. Given that FHL2 expression increases during aging, we now show that low FHL2 expression associates with a healthy metabolic state.
AB - Objective: Four-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and expression of the FHL2 gene increases with age, and high FHL2 expression is associated with increased body weight in humans and mice. This led us to hypothesize that FHL2 is a determinant of diet-induced obesity. Methods: FHL2-deficient (FHL2−/−) and wild type male mice were fed a high-fat diet. Metabolic phenotyping of these mice, as well as transcriptional analysis of key metabolic tissues was performed. Correlation of the expression of FHL2 and relevant genes was assessed in datasets from white adipose tissue of individuals with and without obesity. Results: FHL2 Deficiency protects mice from high-fat diet-induced weight gain, whereas glucose handling is normal. We observed enhanced energy expenditure, which may be explained by a combination of changes in multiple tissues; mild activation of brown adipose tissue with increased fatty acid uptake, increased cardiac glucose uptake and browning of white adipose tissue. Corroborating our findings in mice, expression of FHL2 in human white adipose tissue positively correlates with obesity and negatively with expression of browning-associated genes. Conclusion: Our results position FHL2 as a novel regulator of obesity and energy expenditure in mice and human. Given that FHL2 expression increases during aging, we now show that low FHL2 expression associates with a healthy metabolic state.
KW - Browning of WAT
KW - Diet-induced obese mice
KW - Energy expenditure
KW - Energy metabolism
KW - Four-and-a-half LIM domain protein 2 (FHL2)
KW - Glucose uptake
KW - Lipid uptake
KW - White adipose tissue (WAT)
UR - http://www.scopus.com/inward/record.url?scp=85108999772&partnerID=8YFLogxK
U2 - 10.1016/j.metabol.2021.154815
DO - 10.1016/j.metabol.2021.154815
M3 - Article
C2 - 34119536
VL - 121
JO - Metabolism: clinical and experimental
JF - Metabolism: clinical and experimental
SN - 0026-0495
M1 - 154815
ER -
ID: 18920217