Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
Sci Rep. 2013;3:1254. doi: 10.1038/srep01254. Epub 2013 Feb 13.
Toll-like receptors (TLRs) are traditionally associated with immune-mediated host defense. Here, we ascribe a novel extra-immune, hypothalamic-associated function to TLR2, a TLR-family member known to recognize lipid components, in the protection against obesity. We found that TLR2-deficient mice exhibited mature-onset obesity and susceptibility to high-fat diet (HFD)-induced weight gain, via modulation of food intake. Age-related obesity was still evident in chimeric mice, carrying comparable TLR2(+) immune cells, suggesting a non-hematopoietic-related involvement of this receptor. TLR2 was up-regulated with age or HFD in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, a brain area participating in central-metabolic regulation, possibly modulating the hypothalamic-anorexigenic peptide, α-melanocyte-stimulating hormone (α-MSH). Direct activation of TLR2 in a hypothalamic-neuronal cell-line via its known ligands, further supports its capacity to mediate non-immune related metabolic regulation. Thus, our findings identify TLR2 expressed by hypothalamic neurons as a potential novel regulator of age-related weight gain and energy expenditure.
Toll 样受体（TLRs）通常与免疫介导的宿主防御有关。在这里，我们将 TLR 家族成员 TLR2 的一种新型的、与免疫无关的、下丘脑相关的功能归因于其在肥胖保护中的作用，TLR2 能够识别脂质成分。我们发现 TLR2 缺陷型小鼠表现出成熟肥胖和对高脂肪饮食（HFD）诱导的体重增加的易感性，这是通过调节食物摄入实现的。在携带可比的 TLR2(+)免疫细胞的嵌合小鼠中，仍然存在与年龄相关的肥胖，这表明该受体涉及非造血相关的作用。TLR2 在弓状核的促阿黑皮素原（POMC）神经元中随着年龄的增长或 HFD 而上调，该脑区参与中枢代谢调节，可能调节下丘脑食欲肽 α-促黑素细胞激素（α-MSH）。通过其已知配体直接激活下丘脑神经元中的 TLR2，进一步支持其介导非免疫相关代谢调节的能力。因此，我们的研究结果表明，下丘脑神经元表达的 TLR2 可能是一种潜在的新型与年龄相关的体重增加和能量消耗的调节剂。
