RESUMEN
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.
Asunto(s)
Tejido Adiposo/patología , Fibrosis Quística/complicaciones , Leptina/metabolismo , Lipogénesis , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Animales , Dieta de Carga de Carbohidratos/efectos adversos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/genética , Transducción de SeñalRESUMEN
Cystic fibrosis (CF) mouse models exhibit exocrine pancreatic function, yet they do not develop adipose stores to the levels of non-CF mice. CF mice homozygous for the Cftr mutation (F508del) at 3 wk (postweaning) and 6 wk (young adult) of age had markedly less adipose tissue than non-CF mice. Food intake was markedly lower in 3-wk-old CF mice but normalized by 6 wk of age. Both 3- and 6-wk-old mice had dietary lipid absorption and fecal lipid excretion comparable to non-CF mice. Hepatic de novo lipogenesis (DNL), determined by (2)H incorporation, was reduced in CF mice. At 3 wk, F508del mice had significantly decreased DNL of palmitate and stearate, by 83% and 80%, respectively. By 6 wk, DNL rates in non-CF mice remained unchanged compared with 3-wk-old mice, while DNL rates of F508del mice were still reduced, by 33% and 40%, respectively. Adipose tissue fatty acid (FA) profiles were comparable in CF and non-CF mice, indicating that adipose differences are quantitative, not qualitative. A correspondingly lower content of (2)H-labeled FA was found in CF adipose tissue, consistent with reduced deposition of newly made hepatic triglycerides and/or decreased adipose tissue lipogenesis. Hepatic transcriptome analysis revealed lower mRNA expression from several genes involved in FA biosynthesis, suggesting downregulation of this pathway as a mechanism for the reduced lipogenesis. These novel data provide a model for altered lipid metabolism in CF, independent of malabsorption, and may partly explain the inability of pancreatic enzyme replacement therapy to completely restore normal body mass to CF patients.