A high-fat diet induces changes in mesenteric adipose tissue accelerating early-stage pancreatic carcinogenesis in mice

IF 4.8 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Aya S. Ead , Joanna Wirkus , Karen Matsukuma , Gerardo G. Mackenzie
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Abstract

Increased adiposity is a significant risk factor for pancreatic cancer development. Multiple preclinical studies have documented that high-fat, high calorie diets, rich in omega-6 fatty acids (FA) accelerate pancreatic cancer development. However, the effect of a high-fat, low sucrose diet (HFD), on pancreatic carcinogenesis remains unclear. We evaluated the impact of a HFD on early-stage pancreatic carcinogenesis in the clinically relevant KrasLSL-G12D/+; Ptf1aCre/+ (KC) genetically engineered mouse model, and characterized the role of the mesenteric adipose tissue (MAT). Cohorts of male and female KC mice were randomly assigned to a control diet (CD) or a HFD, matched for FA composition (9:1 of omega-6 FA: omega-3 FA), and fed their diets for 8 weeks. After 8 weeks on a HFD, KC mice had significantly higher body weight, fat mass, and serum leptin compared to CD-fed KC mice. Furthermore, a HFD accelerated pancreatic acinar-to-ductal metaplasia (ADM) and proliferation, associated with increased activation of ERK and STAT3, and macrophage infiltration in the pancreas, compared to CD-fed KC mice. Metabolomics analysis of the MAT revealed sex differences between diet groups. In females, a HFD altered metabolites related to FA (α-linolenic acid and linoleic acid) and amino acid metabolism (alanine, aspartate, glutamate). In males, a HFD significantly affected pathways related to alanine, aspartate, glutamate, linoleic acid, and the citric acid cycle. A HFD accelerates early pancreatic ADM through multifaceted mechanisms, including effects at the tumor and surrounding MAT. The sex-dependent changes in MAT metabolites could explain some of the sex differences in HFD-induced pancreatic ADM.

Abstract Image

高脂饮食诱导肠系膜脂肪组织发生变化,加速小鼠早期胰腺癌的发生。
背景:脂肪增加是胰腺癌发病的一个重要风险因素。多项临床前研究表明,富含欧米伽-6 脂肪酸(FA)的高脂肪、高热量饮食会加速胰腺癌的发展。然而,高脂肪、低蔗糖饮食(HFD)对胰腺癌发生的影响仍不清楚。我们在临床相关的 KrasLSL-G12D/+; Ptf1aCre/+ (KC) 基因工程小鼠模型中评估了高脂低蔗糖饮食对早期胰腺癌发生的影响,并确定了肠系膜脂肪组织 (MAT) 的作用:方法:将一组雄性和雌性 KC 小鼠随机分配到对照组饮食(CD)或高脂饮食(HFD)中,两种饮食的脂肪酸组成(ω-6 脂肪酸:ω-3 脂肪酸的比例为 9:1)相匹配,并喂食它们八周:结果:摄入 HFD 八周后,KC 小鼠的体重、脂肪量和血清瘦素明显高于摄入 CD 的 KC 小鼠。此外,与喂食 CD 的 KC 小鼠相比,高密度脂蛋白膳食加速了胰腺渐变(ADM)和增殖,与 ERK 和 STAT3 的活化增加以及胰腺中巨噬细胞的浸润有关。MAT的代谢组学分析显示了不同饮食组之间的性别差异。在雌性小鼠中,高纤维食物改变了与脂肪酸(α-亚麻酸和亚油酸)和氨基酸代谢(丙氨酸、天门冬氨酸、谷氨酸)有关的代谢物。在男性中,高纤维食物会显著影响与丙氨酸、天门冬氨酸、谷氨酸、亚油酸和柠檬酸循环有关的途径:结论:高脂饮食通过多方面的机制加速早期胰腺ADM,包括对肿瘤和周围MAT的影响。MAT代谢物的性别依赖性变化可以解释HFD诱导的胰腺ADM的部分性别差异。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Nutritional Biochemistry
Journal of Nutritional Biochemistry 医学-生化与分子生物学
CiteScore
9.50
自引率
3.60%
发文量
237
审稿时长
68 days
期刊介绍: Devoted to advancements in nutritional sciences, The Journal of Nutritional Biochemistry presents experimental nutrition research as it relates to: biochemistry, molecular biology, toxicology, or physiology. Rigorous reviews by an international editorial board of distinguished scientists ensure publication of the most current and key research being conducted in nutrition at the cellular, animal and human level. In addition to its monthly features of critical reviews and research articles, The Journal of Nutritional Biochemistry also periodically publishes emerging issues, experimental methods, and other types of articles.
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