Beta-cell injury in Ncb5or-null mice is exacerbated by consumption of a high-fat diet

• Published in: European journal of lipid science and technology 2012-03, Vol.114 (3), p.233-243
• Main Authors: Guo, Ying, Xu, Ming, Deng, Bin, Frontera, Jennifer R., Kover, Karen L., Aires, Daniel, Ding, Helin, Carlson, Susan E., Turk, John, Wang, WenFang, Zhu, Hao
• Format: Article
• Language: English
• Subjects: Beta-cells; Biological and medical sciences; body weight; Diabetes; diabetes mellitus; endoplasmic reticulum; enzymes; ER stress; etiology; Fat industries; fat intake; Feeding. Feeding behavior; Food industries; Fundamental and applied biological sciences. Psychology; High-fat diet; hyperglycemia; Lipotoxicity; metabolism; mice; mothers; oxidative stress; saturated fatty acids; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 1438-7697; 1438-9312
• DOI: 10.1002/ejlt.201100309

NADH‐cytochrome b5 oxidoreductase (Ncb5or) in endoplasmic reticulum (ER) is involved in fatty acid metabolism, and Ncb5or−/− mice fed standard chow (SC) are insulin‐sensitive but weigh less than wild‐type (WT) littermates. Ncb5or−/− mice develop hyperglycemia at about age 7 wk due to β‐cell dysfunction and loss in association with saturated fatty acid (SFA) accumulation and manifestations of ER and oxidative stress. Here we report that when Ncb5or−/− mice born to heterozygous mothers fed a high fat (HF) diet continue to ingest HF, they weigh as much as SC‐fed WT at age 5 wk. By age 7 wk, diabetes mellitus develops in all HF‐fed versus 68% of SC‐fed Ncb5or−/− mice. Islet β‐cell content in age 5‐wk Ncb5or−/− mice fed HF for 7 days is lower (53%) than for those fed SC (63%), and both are lower than for WT (75%, SC, vs. 69%, HF). Islet transcript levels for markers of mitochondrial biogenesis (PGC‐1α) and ER stress (ATF6α) are higher in Ncb5or−/− than WT mice but not significantly affected by diet. Consuming a HF diet exacerbates Ncb5or−/− β‐cell accumulation of intracellular SFA and increases the frequency of ER distention from 11% (SC) to 47% (HF), thus accelerates β‐cell injury in Ncb5or−/− mice. Practical applications: Lipid‐induced beta‐cell injury plays a key role in the etiology of diabetes but its mechanism is poorly understood. We have established a lean diabetes mouse model lacking Ncb5or, a redox enzyme that functions in cellular fatty acid metabolism. Ncb5or‐null mice develop early‐onset diabetes as a result of beta‐cell dysfunction and loss, which is associated with intracellular accumulation of saturated free fatty acids and elevated markers of ER and oxidative stress in beta‐cells. Consumption of a high fat diet partially restores body weight of Ncb5or‐null mice but accelerates onset of diabetes by exacerbating beta‐cell lipid overload and ER stress. This mouse model allows us to elucidate the role of fatty acid metabolism in beta‐cell function and maintenance. Histologic and immunohistochem ical staining for insulin and glucagon in pancreata of 5‐wk‐old WT and Ncb5or S/S mice after consuming a high fat (HF) diet for 7 days. A ‐ hematoxylin and eosin (H&E) staining; B ‐ insulin; C ‐ glucagon.