Absence of leptin signaling allows fat accretion in cystic fibrosis mice

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.

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion

“…However, this interpretation is complicated since activity levels of CF mice in both assays are reduced as determined by total distance traveled. CF mice display higher resting energy expenditure and can result in less active mice 33,34 . This reduction in total activity is not changed in anyway by the depletion of Hdac6 expression.…”

Small adipose stores in cystic fibrosis mice are characterized by reduced cell volume, not cell number

“…To overcome low de novo lipogenesis and following CF patient recommendation of high-fat diet feeding, we fed CF mice a high-fat diet. We recently reported that high-fat diet feeding failed to improve growth and adiposity in CF mice (2). These observations suggest that the paucity of adipose tissue might be a consequence of multiple factors, such as poor substrate availability either from de novo pathways (via VLDL delivery) or chylomicron origin from intestinal absorption and/or developmental or other endocrine factors.…”

Serum leptin and neuropeptide Y in patients with cystic fibrosis—A single center study

“…In the literature there are inconsistent data regarding the leptin concentration CF patients, which indicates that there is dysregulation of leptin synthesis among CF patients. Studies in mice model of CF revealed increasing caloric intake while disrupting a metabolic regulatory system, leptin signaling, led to enhanced growth and significant fat stores ( 14 ). Furthermore, leptin disturbances also contribute to abnormal immune response as well as susceptibility to infections that are common in CF ( 15 ).…”