Downregulation of peripheral lipopolysaccharide binding protein impacts on perigonadal adipose tissue only in female mice.

Abstract

BACKGROUND AND AIMS:

The sexual dimorphism in fat-mass distribution and circulating leptin and insulin levels is well known, influencing the progression of obesity-associated metabolic disease. Here, we aimed to investigate the possible role of lipopolysaccharide-binding protein (LBP) in this sexual dimorphism.

METHODS:

The relationship between plasma LBP and fat mass was evaluated in 145 subjects. The effects of Lbp downregulation, using lipid encapsulated unlocked nucleomonomer agent containing chemically modified-siRNA delivery system, were evaluated in mice.

RESULTS:

Plasma LBP levels were associated with fat mass and leptin levels in women with obesity, but not in men with obesity. In mice, plasma LBP downregulation led to reduced weight, fat mass and leptin gain after a high-fat and high-sucrose diet (HFHS) in females, in parallel to increased expression of adipogenic and thermogenic genes in visceral adipose tissue. This was not observed in males. Plasma LBP downregulation avoided the increase in serum LPS levels in HFHS-fed male and female mice. Serum LPS levels were positively correlated with body weight and fat mass gain, and negatively with markers of adipose tissue function only in female mice. The sexually dimorphic effects were replicated in mice with established obesity. Of note, LBP downregulation led to recovery of estrogen receptor alpha (Esr1) mRNA levels in females but not in males.

CONCLUSION:

LBP seems to exert a negative feedback on ERα-mediated estrogen action, impacting on genes involved in thermogenesis. The known decreased estrogen action and negative effects of metabolic endotoxemia may be targeted through LBP downregulation.

• Authors: Ferran Comas, Ramon Díaz-Trelles, Aleix Gavaldà-Navarro, Edward Milbank, Nathalia Dragano, Samantha Morón-Ros, Rajesh Mukthavaram, Jessica Latorre, Francisco Ortega, Maria Arnoriaga-Rodriguez, Núria Oliveras-Cañellas, Wifredo Ricart, Priya P Karmali, Kiyoshi Tachikawa, Pad Chivukula, Francesc Villarroya, Marta Giralt, Miguel López, José Manuel Fernández-Real, José María Moreno-Navarrete
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 151 Pg. 113156 (Jul 2022) ISSN: 1950-6007 [Electronic] France
• PMID: 35643066 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Acute-Phase Proteins
• Carrier Proteins
• Estrogens
• Leptin
• Lipopolysaccharides
• Membrane Glycoproteins
• lipopolysaccharide-binding protein

Topics

• Acute-Phase Proteins
• Adipose Tissue
• Animals
• Carrier Proteins
• Diet, High-Fat
• Down-Regulation
• Estrogens (metabolism)
• Female
• Humans
• Leptin (metabolism)
• Lipopolysaccharides (metabolism, pharmacology)
• Male
• Membrane Glycoproteins
• Mice
• Mice, Inbred C57BL
• Obesity (metabolism)