TXNIP in Agrp neurons regulates adiposity, energy expenditure, and central leptin sensitivity.
TXNIP in Agrp neurons regulates adiposity, energy expenditure, and central leptin sensitivity.
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DOI：
10.1523/jneurosci.0353-12.2012
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发表时间：
2012-07-18
期刊：
影响因子：
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通讯作者：
Schwartz GJ
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文献类型：
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作者：
Blouet C;Liu SM;Jo YH;Chua S;Schwartz GJ
硫氧还蛋白相互作用蛋白（TXNIP）最近被描述为通过多效性作用调节能量代谢的关键因子，这些作用包括在中基底下丘脑（MBH）的营养感知。然而，TXNIP在神经化学特异性下丘脑亚群中的作用，以及MBH TXNIP下游参与调节能量稳态的回路仍未被探索。为了评估TXNIP活性在弓状核AgRP神经元内的代谢作用，我们使用AgRP - Ires - cre小鼠、TXNIPflox/flox小鼠以及在Cre重组酶存在条件下表达人TXNIP异构体的慢病毒载体，构建了AgRP特异性TXNIP功能获得和缺失小鼠模型。AgRP神经元中TXNIP的过表达通过降低能量消耗和自发运动，促使饮食诱导的肥胖和脂肪组织储存，但不影响食物摄入。相反，AgRP神经元中TXNIP的缺失通过增加能量消耗和自发运动，防止饮食诱导的肥胖和脂肪组织储存，但不影响食物摄入。AgRP神经元中TXNIP的过表达对血糖控制没有主要影响，而AgRP神经元中TXNIP的缺失改善了空腹血糖水平和葡萄糖耐量，且与它对体重和肥胖的影响无关。TXNIP表达的双向调控引起中枢瘦素敏感性和脂肪分解神经调节的相互变化。总之，这些结果确定了TXNIP在AgRP神经元中通过调节能量消耗和脂肪组织代谢，而非食物摄入，在介导饮食诱导的肥胖中起关键作用。它们还揭示了AgRP神经元在脑 - 脂肪轴中先前未被确定的作用。
Thioredoxin interacting protein (TXNIP) has recently been described as a key regulator of energy metabolism through pleiotropic actions that include nutrient sensing in the mediobasal hypothalamus (MBH). However, the role of TXNIP in neurochemically specific hypothalamic subpopulations, and the circuits downstream from MBH TXNIP engaged to regulate energy homeostasis remain unexplored. To evaluate the metabolic role of TXNIP activity specifically within arcuate Agrp neurons, we generated Agrp-specific TXNIP gain- and loss-of-function mouse models using Agrp-Ires-cre mice, TXNIPflox/flox mice and a lentivector expressing the human TXNIP isoform conditionally in the presence of Cre recombinase. Overexpression of TXNIP in Agrp neurons predisposed to diet-induced obesity and adipose tissue storage by decreasing energy expenditure and spontaneous locomotion, without affecting food intake. Conversely, Agrp neuronal TXNIP deletion protected against diet-induced obesity and adipose tissue storage by increasing energy expenditure and spontaneous locomotion, without affecting food intake. TXNIP overexpression in Agrp neurons did not primarily affect glycemic control, whereas deletion of TXNIP in AgRP neurons improved fasting glucose levels and glucose tolerance independently of its effects on body weight and adiposity. Bidirectional manipulation of TXNIP expression induced reciprocal changes in central leptin sensitivity and the neural regulation of lipolysis. Together these results identify a critical role for TXNIP in Agrp neurons in mediating diet-induced obesity through the regulation of energy expenditure and adipose tissue metabolism, independently of food intake. They also reveal a previously unidentified role for Agrp neurons in the brain-adipose axis.