Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus.
Leptin plays a major role in coordinating the integrated response of the CNS to changes in nutritional state. Neurons within the paraventricular nucleus (PVN) of the hypothalamus express leptin receptors and receive dense innervation from leptin receptor-expressing neurons in the arcuate nucleus. To obtain new insights into the effects of circulating leptin on PVN function, we compared global transcriptional profiles of laser-captured PVN from ad libitum fed mice versus 48 h fasted mice receiving either sham or leptin treatment intraperitoneally. Five hundred twenty-seven PVN-expressed genes were altered by fasting in a manner that was at least partially reversible by leptin. Consistent with previous reports, thyrotrophin releasing hormone mRNA levels were decreased by fasting but restored to fed levels with leptin treatment. mRNA levels of oxytocin, vasopressin, and somatostatin were also reduced by fasting and restored by leptin. Given the known effects of leptin on synaptic remodeling, it is notable that, among the top 15 genes that were positively regulated by leptin, five have been implicated in synaptic function and/or plasticity (basigin, apolipoprotein E, Gap43, GABA(A) receptor-associated protein, and synuclein-gamma). Pathway analysis identified oxidative phosphorylation, in particular, genes encoding complex 1 proteins that play a role in ubiquinone biosynthesis, to be the predominant gene set that was significantly regulated in a leptin-dependent manner. Thus, in addition to its effects on the expression of a broad range of neuropeptides, leptin may also exert more general influences on synaptic function in, and the bioenergetic state of, the PVN.
Tung
Yi-Chun Loraine
YC
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Ma
Marcella
M
Piper
Sarah
S
Coll
Anthony
A
O'Rahilly
Stephen
S
Yeo
Giles S H
GS
D000465:Algorithms; D000818:Animals; D005508:Food Deprivation / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D020738:Leptin / Q000008:administration & dosage*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D042282:Microdissection / Q000379:methods; D009473:Neuronal Plasticity / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010085:Oxidative Phosphorylation; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013569:Synapses / Q000235:genetics; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism
D020738:Leptin; D012333:RNA, Messenger; D013973:Thyrotropin-Releasing Hormone