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Publication
Absence of leptin signaling allows fat accretion in cystic fibrosis mice.
Authors Bederman IR, Pora G, O'Reilly M, Poleman J, Spoonhower K, Puchowicz M, Perez A,
Erokwu BO, Rodriguez-Palacios A, Flask CA, Drumm ML
Submitted By Submitted Externally on 1/2/2019
Status Published
Journal American journal of physiology. Gastrointestinal and liver physiology
Year 2018
Date Published 11/1/2018
Volume : Pages 315 : G685 - G698
PubMed Reference 30118352
Abstract Negative energy balance is a prevalent feature of cystic fibrosis (CF).
Pancreatic insufficiency, elevated energy expenditure, lung disease, and
malnutrition, all characteristic of CF, contribute to the negative energy
balance causing low body-growth phenotype. As low body weight and body mass
index strongly correlate with poor lung health and survival of patients with CF,
improving energy balance is an important clinical goal (e.g., high-fat diet). CF
mouse models also exhibit negative energy balance (growth retardation and high
energy expenditure), independent from exocrine pancreatic insufficiency, lung
disease, and malnutrition. To improve energy balance through increased caloric
intake and reduced energy expenditure, we disrupted leptin signaling by crossing
the db/db leptin receptor allele with mice carrying the R117H Cftr mutation.
Compared with db/db mice, absence of leptin signaling in CF mice (CF db/db)
resulted in delayed and moderate hyperphagia with lower de novo lipogenesis and
lipid deposition, producing only moderately obese CF mice. Greater body length
was found in db/db mice but not in CF db/db, suggesting CF-dependent effect on
bone growth. The db/db genotype resulted in lower energy expenditure regardless
of Cftr genotype leading to obesity. Despite the db/db genotype, the CF genotype
exhibited high respiratory quotient indicating elevated carbohydrate oxidation,
thus limiting carbohydrates for lipogenesis. In summary, db/db-linked
hyperphagia, elevated lipogenesis, and morbid obesity were partially suppressed
by reduced CFTR activity. CF mice still accrued large amounts of adipose tissue
in contrast to mice fed a high-fat diet, thus highlighting the importance of
dietary carbohydrates and not simply fat for energy balance in CF. NEW &
NOTEWORTHY We show that cystic fibrosis (CF) mice are able to accrue fat under
conditions of carbohydrate overfeeding, increased lipogenesis, and decreased
energy expenditure, although length was unaffected. High-fat diet feeding failed
to improve growth in CF mice. Morbid db/db-like obesity was reduced in CF
double-mutant mice by reduced CFTR activity.




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