Absence of leptin signaling allows fat accretion in cystic fibrosis mice

Ilya R. Bederman, Gavriella Pora, Maureen O’reilly, James Poleman, Kimberly Spoonhower, Michelle Puchowicz, Aura Perez, Bernadette O. Erokwu, Alex Rodriguez-Palacios, Chris A. Flask, Mitchell L. Drumm

Research output: Contribution to journalArticle

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 doublemutant mice by reduced CFTR activity.

LanguageEnglish (US)
PagesG685-G698
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume315
Issue number5
DOIs
StatePublished - Nov 1 2018
Externally publishedYes

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Leptin
Cystic Fibrosis
Fats
Lipogenesis
Energy Metabolism
High Fat Diet
Genotype
Exocrine Pancreatic Insufficiency
Hyperphagia
Carbohydrates
Malnutrition
Inbred CFTR Mouse
Lung Diseases
Growth
Obesity
Dietary Carbohydrates
Leptin Receptors
Morbid Obesity
Bone Development
Energy Intake

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Absence of leptin signaling allows fat accretion in cystic fibrosis mice. / Bederman, Ilya R.; Pora, Gavriella; O’reilly, Maureen; Poleman, James; Spoonhower, Kimberly; Puchowicz, Michelle; Perez, Aura; Erokwu, Bernadette O.; Rodriguez-Palacios, Alex; Flask, Chris A.; Drumm, Mitchell L.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 315, No. 5, 01.11.2018, p. G685-G698.

Research output: Contribution to journalArticle

Bederman, IR, Pora, G, O’reilly, M, Poleman, J, Spoonhower, K, Puchowicz, M, Perez, A, Erokwu, BO, Rodriguez-Palacios, A, Flask, CA & Drumm, ML 2018, 'Absence of leptin signaling allows fat accretion in cystic fibrosis mice' American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 315, no. 5, pp. G685-G698. https://doi.org/10.1152/ajpgi.00344.2017
Bederman, Ilya R. ; Pora, Gavriella ; O’reilly, Maureen ; Poleman, James ; Spoonhower, Kimberly ; Puchowicz, Michelle ; Perez, Aura ; Erokwu, Bernadette O. ; Rodriguez-Palacios, Alex ; Flask, Chris A. ; Drumm, Mitchell L. / Absence of leptin signaling allows fat accretion in cystic fibrosis mice. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2018 ; Vol. 315, No. 5. pp. G685-G698.
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AU - Spoonhower, Kimberly

AU - Puchowicz, Michelle

AU - Perez, Aura

AU - Erokwu, Bernadette O.

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AU - Drumm, Mitchell L.

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