VGF is Required for Obesity Induced by Diet, Gold Thioglucose Treatment, and Agouti and is Differentially Regulated in Pro-Opiomelanocortin- and Neuropeptide Y-Containing Arcuate Neurons in Response to Fasting
VGF is Required for Obesity Induced by Diet, Gold Thioglucose Treatment, and Agouti and is Differentially Regulated in Pro-Opiomelanocortin- and Neuropeptide Y-Containing Arcuate Neurons in Response to Fasting
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VGF 是饮食、金硫葡萄糖治疗和刺豚鼠诱发的肥胖所必需的，并且在禁食反应中在含有阿皮黑皮质素原和神经肽 Y 的弓状神经元中受到差异性调节
作者：
Seung Hahm;C. Fekete;T. Mizuno;Joan Windsor;Hai;C. Boozer;Charlotte E. Lee;J. Elmquist;R. Lechan;C. Mobbs;S. Salton
有针对性地删除编码神经元和神经内分泌多肽VGF（非首字母缩写）的基因，产生瘦的高代谢小鼠。与这种表型一致，VGF mRNA水平在下丘脑弓状核中响应于禁食而受到调节。为了深入了解VGF的作用部位和机制，我们进一步表征了下丘脑中VGF的表达。双标记研究表明，VGF和pro-opiomelanocortin在进食状态下在外侧弓状神经元中共表达，并且在合成神经肽Y（NPY）的内侧弓状神经元中禁食后诱导VGF表达。与NPY一样，禁食小鼠下丘脑这一区域的VGF mRNA诱导也被外源性瘦素抑制。在瘦素缺乏的ob/ob和受体突变的db/db小鼠中，内侧弓状核中的VGF mRNA水平升高。为了鉴定Vgf消融在功能上受损的神经通路，将VGF突变小鼠与obeseAy/a（agglutinase）和dob/ob小鼠杂交。VGF缺乏完全阻断了Ay/a小鼠肥胖的发展，而在ob/ob小鼠中Vgf缺失减弱了体重增加，但对肥胖没有影响。下丘脑水平的NPY和刺豚鼠相关的多肽mRNA在这两个双突变系显着升高10至15倍以上的野生型小鼠。研究还发现，缺乏VEGF的小鼠能够抵抗饮食和金硫代葡萄糖诱导的肥胖。这些数据和VGF突变小鼠对谷氨酸盐诱导的肥胖的易感性与VGF在流出途径中的作用一致，下丘脑和/或脑干黑皮质素4受体的下游，其通过自主神经系统投射到外周代谢组织并调节能量稳态。
Targeted deletion of the gene encoding the neuronal and neuroendocrine secreted polypeptide VGF (nonacronymic) produces a lean, hypermetabolic mouse. Consistent with this phenotype, VGF mRNA levels are regulated in the hypothalamic arcuate nucleus in response to fasting. To gain insight into the site(s) and mechanism(s) of action of VGF, we further characterized VGF expression in the hypothalamus. Double-label studies indicated that VGF and pro-opiomelanocortin were coexpressed in lateral arcuate neurons in the fed state, and that VGF expression was induced after fasting in medial arcuate neurons that synthesize neuropeptide Y (NPY). Like NPY, VGF mRNA induction in this region of the hypothalamus in fasted mice was inhibited by exogenous leptin. In leptin-deficient ob/ob and receptor-mutant db/db mice, VGF mRNA levels in the medial arcuate were elevated. To identify neural pathways that are functionally compromised by Vgf ablation, VGF mutant mice were crossed with obeseAy/a (agouti) andob/ob mice. VGF deficiency completely blocked the development of obesity inAy/a mice, whereas deletion of Vgf in ob/ob mice attenuated weight gain but had no impact on adiposity. Hypothalamic levels of NPY and agouti-related polypeptide mRNAs in both double-mutant lines were dramatically elevated 10- to 15-fold above those of wild-type mice. VGF-deficient mice were also found to resist diet- and gold thioglucose-induced obesity. These data and the susceptibility of VGF mutant mice to monosodium glutamate-induced obesity are consistent with a role for VGF in outflow pathways, downstream of hypothalamic and/or brainstem melanocortin 4 receptors, that project via the autonomic nervous system to peripheral metabolic tissues and regulate energy homeostasis.
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DOI：
10.1016/s0169-328x(98)00291-5
发表时间：
1999-01
期刊：
Brain research. Molecular brain research
影响因子：
--
作者：
Manou van der Kraan;J. B. Tatro;M. L. Entwistle;J. Brakkee;J. Peter H. Burbach;R. Adan;W. H. Gispen
通讯作者：
Manou van der Kraan;J. B. Tatro;M. L. Entwistle;J. Brakkee;J. Peter H. Burbach;R. Adan;W. H. Gispen
影响因子：
4.8
作者：
Mizuno, TM;Makimura, H;Mobbs, CV
通讯作者：
Mobbs, CV
影响因子：
4.8
作者：
T. Mizuno;C. Mobbs
通讯作者：
T. Mizuno;C. Mobbs
影响因子：
7.7
作者：
Mizuno, TM;Kleopoulos, SP;Mobbs, CV
通讯作者：
Mobbs, CV
DOI：
10.1073/pnas.93.8.3434
发表时间：
1996-04
影响因子：
11.1
作者：
T. M. Mizuno;H. Bergen;Toshiya Funabashi;S. Kleopoulos;Y. Zhong;W. Bauman;C. Mobbs
通讯作者：
T. M. Mizuno;H. Bergen;Toshiya Funabashi;S. Kleopoulos;Y. Zhong;W. Bauman;C. Mobbs