PDF(Pubmed)
Abstract：
The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.
摘要：
肥胖症的患病率上升已成为全球健康问题。肥胖通常发生在能量摄入和能量消耗之间不平衡时。然而,能量消耗由几个部分组成，包括新陈代谢，身体活动,和产热。Toll样受体4(TLR4)是一种跨膜模式识别受体,在脑中大量表达。这里,我们表明，TLR4的pro-opiomelanocortin（POMC）特异性缺乏以性别依赖的方式直接调节BAT产热和脂质稳态。在POMC神经元中删除TLR4足以增加能量消耗和产热,从而导致雄性小鼠的体重减轻。POMC神经元是酪氨酸羟化酶（TH）神经元的亚群，并投射到BAT，在POMC-TLR4-KO雄性小鼠中调节交感神经系统的活动并有助于产热。相比之下,在POMC神经元中删除TLR4会降低雌性小鼠的能量消耗并增加体重，影响白色脂肪组织（WAT）的脂解。机械上,TLR4敲除降低WAT雌性小鼠脂肪甘油三酯脂肪酶和脂解酶激素敏感脂肪酶的表达。此外，肥胖导致WAT免疫相关信号通路的功能受到抑制,这反过来加剧了肥胖的发展。一起,这些结果表明，POMC神经元中的TLR4以性别依赖的方式调节产热和脂质平衡。
