Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior

G Sheng, G Chang, JY Lin, ZX Yu, ZH Fang, J Rong… - Nature medicine, 2006 - nature.com
G Sheng, G Chang, JY Lin, ZX Yu, ZH Fang, J Rong, SA Lipton, SH Li, G Tong, SF Leibowitz…
Nature medicine, 2006nature.com
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 γ-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 GABAA receptor. Here, we report that fasting upregulates the expression of Hap1 in …
Abstract
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 γ-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 GABAA 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 GABAA 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.
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