TY - JOUR
T1 - Human Paneth cell α-defensin-5 treatment reverses dyslipidemia and improves glucoregulatory capacity in diet-induced obese mice
AU - Larsen, Ida Søgaard
AU - Fritzen, Andreas Mæchel
AU - Carl, Christian Strini
AU - Agerholm, Marianne
AU - Damgaard, Mads Thue Fejerskov
AU - Holm, Jacob Bak
AU - Marette, Andre
AU - Nordkild, Peter
AU - Kiens, Bente
AU - Kristiansen, Karsten
AU - Wehkamp, Jan
AU - Jensen, Benjamin Anderschou Holbech
N1 - CURIS 2019 NEXS 221
PY - 2019
Y1 - 2019
N2 - Objective: Overnutrition is the principal cause of insulin resistance (IR) and dyslipidemia, which drive non-alcoholic fatty liver disease (NAFLD). Overnutrition is further linked to disrupted bowel function, microbiota alterations and change-of-function in gut-lining cell populations including Paneth cells of the small intestine. Paneth cells regulate microbial diversity through expression of antimicrobial peptides, particularly human alpha-defensin-5 (HD-5), and have shown repressed secretory capacity in human obesity.Methods: Mice were fed a 60%HFD for 13 weeks and subsequently treated with physiologically relevant amounts of HD-5 (0,001%) or vehicle for 10 weeks. The glucoregulatory capacity was determined by glucose tolerance tests and measurements of corresponding insulin concentrations both before and during intervention. Gut microbiome composition was examined by 16S rRNA gene amplicon sequencing. Fresh fecal samples were collected immediately before and after intervention. Small intestine samples were harvested at necropsy. Plasma and liver lipid and protein profiles were determined by biochemical analyses.Results: HD-5 treated mice exhibited improved glucoregulatory capacity along with an ameliorated plasma- and liver lipid profile. This was accompanied by specific decrease in jejunal inflammation and gut microbiota alterations including increased Bifidobacterium abundances, whichcorrelated inversely with metabolic dysfunctions.Conclusion: This study provides proof-of-concept for the use of human defensins to improve host metabolism by mitigating the triad cluster of dyslipidemia, IR and NAFLD.
AB - Objective: Overnutrition is the principal cause of insulin resistance (IR) and dyslipidemia, which drive non-alcoholic fatty liver disease (NAFLD). Overnutrition is further linked to disrupted bowel function, microbiota alterations and change-of-function in gut-lining cell populations including Paneth cells of the small intestine. Paneth cells regulate microbial diversity through expression of antimicrobial peptides, particularly human alpha-defensin-5 (HD-5), and have shown repressed secretory capacity in human obesity.Methods: Mice were fed a 60%HFD for 13 weeks and subsequently treated with physiologically relevant amounts of HD-5 (0,001%) or vehicle for 10 weeks. The glucoregulatory capacity was determined by glucose tolerance tests and measurements of corresponding insulin concentrations both before and during intervention. Gut microbiome composition was examined by 16S rRNA gene amplicon sequencing. Fresh fecal samples were collected immediately before and after intervention. Small intestine samples were harvested at necropsy. Plasma and liver lipid and protein profiles were determined by biochemical analyses.Results: HD-5 treated mice exhibited improved glucoregulatory capacity along with an ameliorated plasma- and liver lipid profile. This was accompanied by specific decrease in jejunal inflammation and gut microbiota alterations including increased Bifidobacterium abundances, whichcorrelated inversely with metabolic dysfunctions.Conclusion: This study provides proof-of-concept for the use of human defensins to improve host metabolism by mitigating the triad cluster of dyslipidemia, IR and NAFLD.
KW - Faculty of Science
KW - Human defensins
KW - Diet induced obesity
KW - Insulin resistance
KW - NAFLD
KW - Host-microbe interactions
U2 - 10.1152/ajpendo.00019.2019
DO - 10.1152/ajpendo.00019.2019
M3 - Journal article
C2 - 30860877
VL - 317
SP - E42-E52
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 1
ER -