Wada Eri, Hosono Hirotaka, Tanaka Miyako, Miyakawa Fumi, Ochi Kozue, Kohda Hiro, Tanno Shogo, Shimano Reon, Ito Ayaka, Kitaura Yasuyuki, Ichihara Kazuya, Matsumoto Akinobu, Ogi Tomoo, Satoh-Asahara Noriko, Murohara Toyoaki, Suganami Takayoshi
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
FASEB J. 2025 Jul 31;39(14):e70847. doi: 10.1096/fj.202501121R.
As obesity progresses, dynamic tissue remodeling of adipose tissue occurs over time, that is, adipocyte hypertrophy, chronic inflammation, and interstitial fibrosis. Some obese individuals exhibit healthy adipose tissue expansion, characterized by modest inflammation and fibrosis despite adipocyte hypertrophy, resulting in "Metabolically Healthy Obesity (MHO)". In this study, we investigated the effects of transient weight loss on adipose tissue remodeling during the development of obesity. Male C57BL6/J mice received various types of transient weight loss treatments during diet-induced obesity. A 2-week weight loss intervention during the inflammatory phase promoted healthy adipose tissue expansion, reduced ectopic lipid accumulation, and improved glucose metabolism. In contrast, protocols with shorter duration and delayed intervention, failed to induce MHO. Since serum concentrations of ketone bodies were elevated during weight loss, we examined the effects of hyperketonemia on obesity-induced adipose tissue remodeling. Transient treatment with 1,3-butanediol (BD), which increased serum ketone body concentrations to levels similar to those observed during weight loss, induced healthy adipose tissue expansion and reduced hepatic steatosis even during continuous high-fat diet (HFD) feeding. Ketone bodies effectively suppressed activation of adipose tissue fibroblasts in vivo and in vitro. This study provides evidence that an appropriate dietary intervention can promote healthy adipose tissue expansion in mice, even after the regaining of weight, thereby leading to MHO. As the underlying mechanism, our data revealed a key role for ketone bodies in suppressing activation of adipose tissue fibroblasts. This study paves the way for nutritional approaches to induce MHO.
随着肥胖的进展，脂肪组织会随时间发生动态组织重塑，即脂肪细胞肥大、慢性炎症和间质纤维化。一些肥胖个体表现出健康的脂肪组织扩张，其特征是尽管存在脂肪细胞肥大，但炎症和纤维化程度较轻，从而导致“代谢健康肥胖（MHO）”。在本研究中，我们调查了短期体重减轻对肥胖发展过程中脂肪组织重塑的影响。雄性C57BL6/J小鼠在饮食诱导肥胖期间接受了各种类型的短期体重减轻治疗。在炎症阶段进行为期2周的体重减轻干预可促进健康的脂肪组织扩张，减少异位脂质积累，并改善葡萄糖代谢。相比之下，持续时间较短和干预延迟的方案未能诱导出MHO。由于体重减轻期间血清酮体浓度升高，我们研究了高酮血症对肥胖诱导的脂肪组织重塑的影响。用1,3 - 丁二醇（BD）进行短期治疗，可使血清酮体浓度升高至与体重减轻期间观察到的水平相似，即使在持续高脂饮食（HFD）喂养期间，也能诱导健康的脂肪组织扩张并减少肝脏脂肪变性。酮体在体内和体外均有效抑制脂肪组织成纤维细胞的活化。本研究提供了证据表明，适当的饮食干预即使在体重恢复后也能促进小鼠健康的脂肪组织扩张，从而导致MHO。作为潜在机制，我们的数据揭示了酮体在抑制脂肪组织成纤维细胞活化中的关键作用。本研究为诱导MHO的营养方法铺平了道路。
