Rapid, reversible activation of AgRP neurons drives feeding behavior in mice
Michael J. Krashes, … , Bryan L. Roth, Bradford B. Lowell
Michael J. Krashes, … , Bryan L. Roth, Bradford B. Lowell
Published March 1, 2011
Citation Information: J Clin Invest. 2011;121(4):1424-1428. https://doi.org/10.1172/JCI46229.
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Brief Report Neuroscience

Rapid, reversible activation of AgRP neurons drives feeding behavior in mice

Abstract

Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.

Authors

Michael J. Krashes, Shuichi Koda, ChianPing Ye, Sarah C. Rogan, Andrew C. Adams, Daniel S. Cusher, Eleftheria Maratos-Flier, Bryan L. Roth, Bradford B. Lowell

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Figure 2

Manipulation of AgRP neuron activity alters energy balance.

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Manipulation of AgRP neuron activity alters energy balance. (A) Food int...
(A) Food intake. CNO (0.3 mg/kg of body weight, i.p.) or saline was injected 3 hours after the start of the 12-hour light cycle, and food intake was assessed between 30 minutes and 4 hours after injection (PI). Data are from male mice (mean ± SEM, n = 12; *P < 0.01). AgRP-i-Cre, AgRP-Ires-cre mice. (B) Oxygen consumption. Mice were acclimated in metabolic cages and injected with either saline (blunted arrow) or CNO (arrow) at 8:30 am. Black bars along the x axis indicate the 12-hour dark cycle. Data are from male mice (mean ± SEM, n = 6; *P < 0.01). (C–E) Chronic stimulation of AgRP neurons. (C) Body weight, (D) fat mass, and (E) food intake. AgRP-Ires-cre and wild-type control mice were injected twice daily (at 9:00 am and 5:00 pm) with saline from days 1–5, CNO (0.3 mg/kg of body weight, i.p.) from days 6–10 (arrow), and saline from days 11–15 (blunted arrow). Data are from female mice (mean ± SEM, n = 12; *P < 0.01). (F and G) Inhibitory DREADD (hM4Di). (F) Whole cell, current clamp recording from an AgRP neuron marked by mCherry fluorescence from a AgRP-Ires-cre mouse injected with AAV-hM4Di-mCherry. CNO (10 μM) hyperpolarized the membrane potential and decreased the firing rate. This example trace is representative of 5 similar recordings. (G) Inhibition of AgRP neurons decreases food intake. CNO (0.3 mg/kg of body weight, i.p.) or saline was injected at the start of the 12-hour dark cycle, and food intake was assessed between 30 minutes and 4 hours PI. Data are from male mice (mean ± SEM, n = 6; *P < 0.05).