Poursharifi Pegah, Attané Camille, Mugabo Yves, Al-Mass Anfal, Ghosh Anindya, Schmitt Clémence, Zhao Shangang, Guida Julian, Lussier Roxane, Erb Heidi, Chenier Isabelle, Peyot Marie-Line, Joly Erik, Noll Christophe, Carpentier André C, Madiraju S R Murthy, Prentki Marc
Departments of Nutrition, Biochemistry, and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France.
JCI Insight. 2020 Dec 17;5(24):140294. doi: 10.1172/jci.insight.140294.
Enhanced energy expenditure in brown (BAT) and white adipose tissues (WAT) can be therapeutic against metabolic diseases. We examined the thermogenic role of adipose α/β-hydrolase domain 6 (ABHD6), which hydrolyzes monoacylglycerol (MAG), by employing adipose-specific ABHD6-KO mice. Control and KO mice showed similar phenotypes at room temperature and thermoneutral conditions. However, KO mice were resistant to hypothermia, which can be accounted for by the simultaneously increased lipolysis and lipogenesis of the thermogenic glycerolipid/free fatty acid (GL/FFA) cycle in visceral fat, despite unaltered uncoupling protein 1 expression. Upon cold stress, nuclear 2-MAG levels increased in visceral WAT of the KO mice. Evidence is provided that 2-MAG causes activation of PPARα in white adipocytes, leading to elevated expression and activity of GL/FFA cycle enzymes. In the ABHD6-ablated BAT, glucose and oxidative metabolism were elevated upon cold induction, without changes in GL/FFA cycle and lipid turnover. Moreover, response to in vivo β3-adrenergic stimulation was comparable between KO and control mice. Our data reveal a MAG/PPARα/GL/FFA cycling metabolic signaling network in visceral adipose tissue, which contributes to cold tolerance, and that adipose ABHD6 is a negative modulator of adaptive thermogenesis.
棕色脂肪组织（BAT）和白色脂肪组织（WAT）中增强的能量消耗对代谢性疾病具有治疗作用。我们通过使用脂肪特异性ABHD6基因敲除小鼠，研究了脂肪α/β水解酶结构域6（ABHD6）的产热作用，该酶可水解单酰甘油（MAG）。对照小鼠和基因敲除小鼠在室温及热中性条件下表现出相似的表型。然而，基因敲除小鼠对体温过低具有抗性，这可以通过内脏脂肪中产热甘油olipid/游离脂肪酸（GL/FFA）循环的脂解作用和脂肪生成同时增加来解释，尽管解偶联蛋白1的表达未改变。在冷应激下，基因敲除小鼠内脏WAT中的核2-MAG水平升高。有证据表明，2-MAG可导致白色脂肪细胞中PPARα的激活，从而导致GL/FFA循环酶的表达和活性升高。在ABHD6缺失的BAT中，冷诱导后葡萄糖和氧化代谢升高，而GL/FFA循环和脂质周转没有变化。此外，基因敲除小鼠和对照小鼠对体内β3-肾上腺素能刺激的反应相当。我们的数据揭示了内脏脂肪组织中一个MAG/PPARα/GL/FFA循环代谢信号网络，该网络有助于耐寒性，并且脂肪ABHD6是适应性产热的负调节因子。
