Kim Sujin, Park Dong-Ho, Moon Sohee, Gu Bonsang, Mantik Keren Esther Kristina, Kwak Hyo-Bum, Ryu Ji-Kan, Kang Ju-Hee
Department of Pharmacology, College of Medicine, Inha University, Incheon, Republic of Korea.
Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, Republic of Korea.
Front Nutr. 2024 Aug 29;11:1443483. doi: 10.3389/fnut.2024.1443483. eCollection 2024.
Despite evidence suggesting that metabolic intermediates like β-HB influence white adipose tissue (WAT) metabolism, the precise molecular mechanisms remain unclear. The aim of this study was to investigate the impact of beta-hydroxybutyrate (β-HB) on the fat browning program and to explore the underlying molecular mechanisms using both and models. We assessed the effects of β-HB on fat browning in adipocytes using 3T3-L1 cells and rat models.
We evaluated the effects of β-HB on fat browning, thermogenesis, lipid accumulation, adipokine expression, and mitochondrial biogenesis by treating mature 3T3-L1 adipocytes with sodium β-HB for 24 h or by continuously exposing preadipocytes to β-HB during the 8-day differentiation process. Male Sprague Dawley rats were divided into control, exercise only (EX), ketogenic diet only (KD), and combined exercise and ketogenic diet (KE) groups for an 8-week intervention involving diet and/or exercise. After intervention, we evaluated WAT histology, plasma lipids and adipokines, and the expression of markers related to fat browning, thermogenesis and mitochondrial biogenesis in WAT of rats.
In our adipocyte culture experiments, β-HB reduced intracellular lipid accumulation by enhancing lipolysis and stimulated the expression of thermogenic and fat browning genes like uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), and adipokines such as fibroblast growth factor 21 (FGF21) and Fibronectin type III domain-containing protein 5 (FDNC5). Additionally, β-HB activated the AMPK-SIRT1-PGC-1α pathway, with UCP1 and PRDM16 upregulation mediated by β-HB intracellular action and SIRT1 activity. In animal experiments, KE group raised β-HB levels, decreasing body weight and blood lipids. KD with EX promoted WAT browning possibly via AMPK-SIRT1-PGC-1α, augmenting PRDM16, UCP1, FGF21, and FNDC5 expression.
β-HB induction via KD and/or EX shows potential in promoting WAT browning by activating mitochondrial biogenesis, lipolysis, and thermogenesis, suggesting that dietary and physical intervention inducing β-HB may benefit metabolic health.
尽管有证据表明像β-羟基丁酸（β-HB）这样的代谢中间产物会影响白色脂肪组织（WAT）的代谢，但其确切的分子机制仍不清楚。本研究的目的是研究β-羟基丁酸（β-HB）对脂肪褐变程序的影响，并使用细胞和动物模型探索其潜在的分子机制。我们使用3T3-L1细胞和大鼠模型评估了β-HB对脂肪细胞中脂肪褐变的影响。
我们通过用β-羟基丁酸钠处理成熟的3T3-L1脂肪细胞24小时，或在8天的分化过程中持续将前脂肪细胞暴露于β-HB，来评估β-HB对脂肪褐变、产热、脂质积累、脂肪因子表达和线粒体生物发生的影响。将雄性Sprague Dawley大鼠分为对照组、仅运动组（EX）、仅生酮饮食组（KD）和运动与生酮饮食联合组（KE），进行为期8周的饮食和/或运动干预。干预后，我们评估了大鼠白色脂肪组织的组织学、血浆脂质和脂肪因子，以及白色脂肪组织中与脂肪褐变、产热和线粒体生物发生相关标志物的表达。
在我们的脂肪细胞培养实验中，β-HB通过增强脂肪分解减少细胞内脂质积累，并刺激产热和脂肪褐变基因如解偶联蛋白1（UCP1）、含PR结构域蛋白16（PRDM16）的表达，以及脂肪因子如成纤维细胞生长因子21（FGF21）和含III型纤连蛋白结构域蛋白5（FDNC5）的表达。此外，β-HB激活了AMPK-SIRT1-PGC-1α通路，β-HB的细胞内作用和SIRT1活性介导了UCP1和PRDM16的上调。在动物实验中，KE组提高了β-HB水平，降低了体重和血脂。KD联合EX可能通过AMPK-SIRT1-PGC-1α促进白色脂肪组织褐变，增加PRDM16、UCP1、FGF21和FNDC5的表达。
通过KD和/或EX诱导β-HB在通过激活线粒体生物发生、脂肪分解和产热来促进白色脂肪组织褐变方面显示出潜力，这表明饮食和体育干预诱导β-HB可能有益于代谢健康。
