title: Involvement of progranulin in hypothalamic glucose sensing and feeding regulation.
abstract: 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.
authors.affiliation: Appetite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Pungnap-dong, Songpa-ku, Seoul 138-736, Korea.
authors.forename: Hyun-Kyong
authors.initials: HK
authors.lastname: Kim
authors.forename: Mi-Seon
authors.initials: MS
authors.lastname: Shin
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Youn
authors.forename: Churl
authors.initials: C
authors.lastname: Namkoong
authors.forename: So Young
authors.initials: SY
authors.lastname: Gil
authors.forename: Gil Myoung
authors.initials: GM
authors.lastname: Kang
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Yu
authors.forename: Min-Seon
authors.initials: MS
authors.lastname: Kim
mesh_terms: D054369:Agouti-Related Protein / Q000502:physiology; D000818:Animals; D001069:Appetite Regulation; D001835:Body Weight; D004435:Eating; D005947:Glucose / Q000378:metabolism*; D000077155:Granulins; D007031:Hypothalamus / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism / Q000502:physiology; D009765:Obesity; D000077153:Progranulins
chemical_list: D054369:Agouti-Related Protein; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D000077153:Progranulins; D005947:Glucose