Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior.
The hypothalamus responds to circulating leptin and insulin in the control of food intake and body weight. A number of neurotransmitters in the hypothalamus, including gamma-aminobutyric acid (GABA), also have key roles in feeding. Huntingtin-associated protein 1 (Hap1) is expressed more abundantly in the hypothalamus than in other brain regions, and lack of Hap1 in mice leads to early postnatal death. Hap1 is also involved in intracellular trafficking of the GABA(A) receptor. Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination. Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA(A) receptors and causes a decrease in food intake and body weight. These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain.
Sheng
Guoqing
G
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
Chang
Guo-qing
GQ
Lin
John Y
JY
Yu
Zhao-Xue
ZX
Fang
Zhi-Hui
ZH
Rong
Juan
J
Lipton
Stuart A
SA
Li
Shi-Hua
SH
Tong
Gang
G
Leibowitz
Sarah F
SF
Li
Xiao-Jiang
XJ
D000818:Animals; D001835:Body Weight; D004435:Eating; D004594:Electrophysiology; D005215:Fasting; D005247:Feeding Behavior / Q000502:physiology*; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
C490758:Hap1 protein, mouse; D007328:Insulin; D020738:Leptin; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; D025801:Ubiquitin