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Role of Agouti-Related Protein-Expressing Neurons in Lactation

Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: R. D. Palmiter, Howard Hughes Medical Institute and Department of Biochemistry, Box 357370, University of Washington, Seattle, Washington 98195. E-mail: palmiter{at}u.washington.edu.

Hypothalamic neurons that express agouti-related protein (AgRP) and neuropeptide Y (NPY) are thought to be important for regulation of feeding, especially under conditions of negative energy balance. The expression of NPY and AgRP increases during lactation and may promote the hyperphagia that ensues. We explored the role of AgRP neurons in reproduction and lactation, using a mouse model in which AgRP-expressing neurons were selectively ablated by the action of diphtheria toxin. We show that ablation of AgRP neurons in neonatal mice does not interfere with pregnancy, parturition, or lactation, suggesting that early ablation allows compensatory mechanisms to become established. However, ablation of AgRP neurons after lactation commences results in rapid starvation, indicating that both basal feeding and lactation-induced hyperphagia become dependent on AgRP neurons in adulthood. We also show that constitutive inactivation of Npy and Agrp genes does not prevent pregnancy or lactation, nor does it protect lactating dams from diphtheria toxin-induced starvation.

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