Department of Pediatrics, Case Western Reserve University , Cleveland, Ohio.
Department of Nutrition, Case Western Reserve University , Cleveland, Ohio.
Am J Physiol Gastrointest Liver Physiol. 2018 Nov 1;315(5):G685-G698. doi: 10.1152/ajpgi.00344.2017. Epub 2018 Aug 17.
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.
负能量平衡是囊性纤维化（CF）的一个普遍特征。胰腺功能不全、能量消耗增加、肺部疾病和营养不良都是 CF 的特征，导致负能量平衡，从而导致低生长表型。由于低体重和体重指数与 CF 患者的肺部健康和生存密切相关，因此改善能量平衡是一个重要的临床目标（例如，高脂肪饮食）。CF 小鼠模型也表现出负能量平衡（生长迟缓和能量消耗增加），与外分泌胰腺功能不全、肺部疾病和营养不良无关。为了通过增加热量摄入和减少能量消耗来改善能量平衡，我们通过将 db/db 瘦素受体等位基因与携带 R117H Cftr 突变的小鼠杂交来破坏瘦素信号。与 db/db 小鼠相比，CF 小鼠（CF db/db）中瘦素信号的缺失导致延迟和适度的过度进食，新合成的脂肪生成和脂肪沉积较低，仅产生中度肥胖的 CF 小鼠。db/db 小鼠的体长较大，但 CF db/db 小鼠的体长没有增加，表明 CF 对骨生长有依赖性影响。无论 Cftr 基因型如何，db/db 基因型都会导致较低的能量消耗，从而导致肥胖。尽管存在 db/db 基因型，但 CF 基因型表现出较高的呼吸商，表明碳水化合物氧化增加，从而限制了用于脂肪生成的碳水化合物。总之，CFTR 活性降低部分抑制了 db/db 相关的过度进食、脂肪生成增加和病态肥胖。CF 小鼠仍然积累了大量的脂肪组织，与高脂肪饮食喂养的小鼠相比，这突出了饮食碳水化合物而不仅仅是脂肪对 CF 能量平衡的重要性。新的和值得注意的是，我们表明 CF 小鼠能够在碳水化合物过度喂养、脂肪生成增加和能量消耗减少的情况下积累脂肪，尽管长度不受影响。高脂肪饮食喂养不能改善 CF 小鼠的生长。通过降低 CFTR 活性，CF 双突变小鼠中病态的 db/db 样肥胖减轻。
