以小鼠模式探討酮體在米色脂肪細胞分化之作用 與抗肥胖之潛力

Abstract

如何減緩肥胖一直是公共健康的重要課題。隨著肥胖程度的加劇，第二型糖尿病和心血管疾病的風險也大幅提高。近年來，學者開始關注米色脂肪細胞對代謝調節的正面影響，並透過研究遺傳基因、環境、生活方式、飲食和藥物等因素，探索如何增強米色脂肪以抵抗代謝疾病。然而，米色脂肪的起源仍有很多未知。了解米色脂肪的發育起源將有助於發展治療代謝疾病的策略。本論文利用小鼠為實驗模式，從三個方面探討米色脂肪細胞的發育。第一個研究發現 ApoE 基因負向調節米色脂肪生成。ApoE 基因剔除小鼠具有低度的內源性生酮現象，生酮作用所生成的酮體（β-hydroxybutyrate，βHB）促進脂肪前驅細胞分化成米色脂肪細胞。這項發現連結 APOE 基因引發的肥胖易感性和米色脂肪發育之間的關聯性。第二個研究發現哺乳期仔鼠有別於成年鼠，具有自發性的營養性酮症，此生理現象我們定義為「哺乳期酮症（preweaning ketosis）」。生酮基因 Hmgcs2 缺陷或提早斷奶造成的生酮缺失則會損害米色脂肪細胞的分化，觸發肥胖易感性，並於成年後，對代謝表現的調節產生不利影響。此外，哺乳期增強生酮作用（enhanced ketogenesis during lactation）具有促進米色脂肪分化和米色脂肪的產熱功能。這些發現，確認提升哺乳期的血清 βHB 濃度能夠調節小鼠在哺乳期間的米色脂肪發育。第三個研究發現哺乳期以外源性方式增加血清 βHB 濃度，具有促進米色脂肪分化之作用，減緩 PO 子代的肥胖易感性，部分改善 PO 子代在代謝調節方面的表現。綜上所述，本論文發現哺乳階段的 βHB 具有調節米色脂肪發育的新功能。因此，βHB 可能可以作為一種有效的調節劑，有助於肥胖易感性族群抵抗肥胖的發展。

Obesity and metabolic diseases represent significant public health concerns. Recently, beige adipocytes have attracted much attention for their potential positive impact on metabolism. However, the developmental origin of beige adipocytes remains unclear. This study aimed to answer this question through three distinct aspects using mouse models. The first study examined the role of the ApoE gene in obesity. We found that ApoE deficiency induces beiging of white adipose tissue in mice by enhancing the production of the ketone body β-hydroxybutyrate (βHB) from adipose precursor cells. This discovery reinforces the link between APOE gene inheritance, obesity susceptibility, and beige fat development. The second study revealed a novel role of preweaning ketosis in regulating beige fat biogenesis and highlighted its significance in promoting healthy growth in newborns. Deficiency in preweaning ketosis impairs beige fat development and increases susceptibility to obesity, with adverse metabolic consequences in adulthood. The third study demonstrated that enhancing ketogenesis during lactation through exogenous ketone body supplementation can mitigate offspring susceptibility to obesity induced by parental obesity. These results indicate that elevated serum βHB concentration positively regulates beige fat development and improves metabolic outcomes. Overall, this study suggests that augmenting the development of beige adipocytes may offer a novel therapeutic approach for addressing obesity and its associated metabolic diseases.