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

Nature Medicine volume 12, pages 526–533 (2006)Cite this article

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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Figure 1: Fasting and diet regulate expression of Hap1 in the mouse hypothalamus.
Figure 2: Intraperitoneal injection of glucose reduces expression of Hap1 in the hypothalamus.
Figure 3: Insulin reduces expression of Hap1 in the hypothalamus.
Figure 4: Insulin increases ubiquitination and degradation of Hap1.
Figure 5: Altering Hap1 expression in the mouse hypothalamus through adenoviral infection regulates food intake and body weight.
Figure 6: Decreasing Hap1 expression reduces functional GABAA receptors in the hypothalamus.

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Acknowledgements

We thank V. Jaswani for technical assistance and the members of the Li laboratory for comments and critical reading. This work was supported by US National Institutes of Health grants NS36232 and AG19206 (to X.J.L.), NS045016 (to S.H.L.), P01 HD29587 (to S.A.L.), MH43422 to (S.F.L.) and AG00975 (to G.T.).

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Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, 30322, Georgia, USA

    Guoqing Sheng, Zhao-Xue Yu, Zhi-Hui Fang, Juan Rong, Shi-Hua Li & Xiao-Jiang Li

  2. Laboratory of Behavioral Neurobiology, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Guo-qing Chang & Sarah F Leibowitz

  3. Center for Neuroscience and Aging, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    John Y Lin, Stuart A Lipton & Gang Tong

  4. Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Stuart A Lipton & Gang Tong

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Supplementary information

Supplementary Fig. 1

Hap1 transcripts in the hypothalamus. (PDF 166 kb)

Supplementary Fig. 2

Immunostaining of the hypothalamus with Hap1-specific antibody. (PDF 105 kb)

Supplementary Fig. 3

Hypothalamic expression of Hap1 after intracerebroventricular injection of insulin, NPY or leptin. (PDF 229 kb)

Supplementary Fig. 4

Colocalization of Hap1 with GABAA β2/3 subunits. (PDF 173 kb)

Supplementary Fig. 5

Hap1 expression and other peptides in the hypothalamus. (PDF 282 kb)

Supplementary Methods (PDF 46 kb)

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Sheng, G., Chang, Gq., Lin, J. et al. Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior. Nat Med 12, 526–533 (2006). https://doi.org/10.1038/nm1382

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