Appetite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Pungnap-dong, Songpa-ku, Seoul 138-736, Korea.
Endocrinology. 2011 Dec;152(12):4672-82. doi: 10.1210/en.2011-1221. Epub 2011 Sep 20.
Progranulin (PGRN) is a secreted glycoprotein with multiple biological functions, including modulation of wound healing and inflammation. Hypothalamic PGRN has been implicated in the development of sexual dimorphism. In the present study, a potential role for PGRN in the hypothalamic regulation of appetite and body weight was investigated. In adult rodents, PGRN was highly expressed in periventricular tanycytes and in hypothalamic neurons, which are known to contain glucose-sensing machinery. Hypothalamic PGRN expression levels were decreased under low-energy conditions (starvation and 2-deoxy-D-glucose administration) but increased under high-energy condition (postprandially). Intracerebrovetricular administration of PGRN significantly suppressed nocturnal feeding as well as hyperphagia induced by 2-deoxyglucose, neuropeptide Y, and Agouti-related peptide. Moreover, the inhibition of hypothalamic PGRN expression or action increased food intake and promoted weight gain, suggesting that endogenous PGRN functions as an appetite suppressor in the hypothalamus. Investigation of the mechanism of action revealed that PGRN diminished orexigenic neuropeptide Y and Agouti-related peptide production but stimulated anorexigenic proopiomelanocortin production, at least in part through the regulation of hypothalamic AMP-activated protein kinase. Notably, PGRN was also expressed in hypothalamic microglia. In diet-induced obese mice, microglial PGRN expression was increased, and the anorectic response to PGRN was blunted. These findings highlight a physiological role for PGRN in hypothalamic glucose-sensing and appetite regulation. Alterations in hypothalamic PGRN production or action may be linked to appetite dysregulation in obesity.
颗粒体蛋白聚糖（PGRN）是一种具有多种生物学功能的分泌性糖蛋白，包括调节伤口愈合和炎症。下丘脑 PGRN 被认为与性二态性的发展有关。在本研究中，研究了 PGRN 在下丘脑调节食欲和体重中的潜在作用。在成年啮齿动物中，PGRN 在室周小胶质细胞和已知含有葡萄糖感应机制的下丘脑神经元中高度表达。在低能量条件下（饥饿和 2-脱氧-D-葡萄糖给药），下丘脑 PGRN 表达水平降低，但在高能量条件下（餐后）增加。脑室注射 PGRN 可显著抑制夜间摄食以及 2-脱氧葡萄糖、神经肽 Y 和 Agouti 相关肽诱导的过度摄食。此外，抑制下丘脑 PGRN 的表达或作用会增加食物摄入并促进体重增加，表明内源性 PGRN 作为下丘脑的食欲抑制剂发挥作用。作用机制的研究表明，PGRN 减少了食欲刺激神经肽 Y 和 Agouti 相关肽的产生，但刺激了食欲抑制性 proopiomelanocortin 的产生，至少部分是通过调节下丘脑 AMP 激活蛋白激酶。值得注意的是，PGRN 也在下丘脑小胶质细胞中表达。在饮食诱导的肥胖小鼠中，小胶质细胞 PGRN 的表达增加，而 PGRN 的厌食反应减弱。这些发现强调了 PGRN 在下丘脑葡萄糖感应和食欲调节中的生理作用。下丘脑 PGRN 产生或作用的改变可能与肥胖症中的食欲失调有关。
