目的:游离脂肪酸受体-1(FFAR1)是一种中链和长链脂肪酸敏感G蛋白偶联受体,在下丘脑中高表达。这里,我们研究了FFAR1对能量平衡的核心作用。
方法:在小鼠中进行中央FFAR1激动和病毒基因敲低。能量平衡研究,BAT的红外热像分析和下丘脑的分子分析,棕色脂肪组织(BAT),进行白色脂肪组织(WAT)和肝脏。
结果:FFAR1的药理学刺激,在饮食诱导的肥胖小鼠中使用其激动剂TUG-905的中心给药,减轻体重,并与增加的能量消耗有关,BAT产热和皮下WAT(sWAT)褐变,以及降低AMP激活的蛋白激酶(AMPK)水平,炎症,下丘脑内质网(ER)应激。由于FFAR1在不同的下丘脑神经元亚群中表达,我们使用表达shRNA的AAV载体特异性敲除肥胖小鼠下丘脑弓状核(ARC)的proopiomelanocortin(POMC)神经元中的Ffar1。我们的数据表明,POMC神经元中Ffar1的敲低促进了饮食过多和体重增加。并行,这些小鼠出现肝脏胰岛素抵抗和脂肪变性。
结论:FFAR1作为一种新的调节全身能量平衡的下丘脑营养传感器出现。此外,药物激活FFAR1可以为肥胖和相关代谢紊乱的治疗提供治疗进展.
OBJECTIVE: Free fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance.
METHODS: Central FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermographic analysis of brown adipose tissue (BAT) and molecular analysis of the hypothalamus, BAT, white adipose tissue (WAT) and liver were carried out.
RESULTS: Pharmacological stimulation of FFAR1, using central administration of its agonist TUG-905 in diet-induced obese mice, decreases body weight and is associated with increased energy expenditure, BAT thermogenesis and browning of subcutaneous WAT (sWAT), as well as reduced AMP-activated protein kinase (AMPK) levels, reduced inflammation, and decreased endoplasmic reticulum (ER) stress in the hypothalamus. As FFAR1 is expressed in distinct hypothalamic neuronal subpopulations, we used an AAV vector expressing a shRNA to specifically knockdown Ffar1 in proopiomelanocortin (
POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) of obese mice. Our data showed that knockdown of Ffar1 in
POMC neurons promoted hyperphagia and body weight gain. In parallel, these mice developed hepatic insulin resistance and steatosis.
CONCLUSIONS: FFAR1 emerges as a new hypothalamic nutrient sensor regulating whole body energy balance. Moreover, pharmacological activation of FFAR1 could provide a therapeutic advance in the management of obesity and its associated metabolic disorders.