Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis

Harveen Dhillon; Jeffrey M. Zigman; Chianping Ye; Charlotte E. Lee; Robert A. McGovern; Vinsee Tang; Christopher D. Kenny; Lauryn M. Christiansen; Ryan D. White; Elisabeth A. Edelstein; Roberto Coppari; Nina Balthasar; Michael A. Cowley; Streamson Chua; Joel K. Elmquist; Bradford B. Lowell

doi:10.1016/j.neuron.2005.12.021

Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis

Harveen Dhillon, Jeffrey M. Zigman, Chianping Ye, Charlotte E. Lee, Robert A. McGovern, Vinsee Tang, Christopher D. Kenny, Lauryn M. Christiansen, Ryan D. White, Elisabeth A. Edelstein, Roberto Coppari, Nina Balthasar, Michael A. Cowley, Streamson Chua, Joel K. Elmquist, Bradford B. Lowell

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Abstract

Leptin, an adipocyte-derived hormone, acts directly on the brain to control food intake and energy expenditure. An important question is the identity of first-order neurons initiating leptin's anti-obesity effects. A widely held view is that most, if not all, of leptin's effects are mediated by neurons located in the arcuate nucleus of the hypothalamus. However, leptin receptors (LEPRs) are expressed in other sites as well, including the ventromedial hypothalamus (VMH). The possible role of leptin acting in "nonarcuate" sites has largely been ignored. In the present study, we show that leptin depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-positive neurons in the VMH. We also show, by generating mice that lack LEPRs on SF1-positive neurons, that leptin action at this site plays an important role in reducing body weight and, of note, in resisting diet-induced obesity. These results reveal a critical role for leptin action on VMH neurons.

Original language	English (US)
Pages (from-to)	191-203
Number of pages	13
Journal	Neuron
Volume	49
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2005.12.021
State	Published - Jan 19 2006
Externally published	Yes

Bibliographical note

Funding Information:
The authors acknowledge Amanda R. Waxman, Amy E. Deysher, Brian Choi, Abigail E. Pullen, Lihong Huo, Vaida Glatt, Mary L. Bouxsein, and Christian Bjorbaek for their assistance in performing studies described in this paper. This work was supported by grants from the National Institutes of Health (PO1 DK56116 to B.B.L. and J.K.E., MH61583 and DK53301 to J.K.E., and R01 DK53301-07S2 to B.B.L, J.K.E., and M.A.C.) and by Takeda Pharmaceutical Company, Ltd., Japan. H.D. was supported by an American Heart Association fellowship and a Boston Obesity Nutrition Research Center Pilot Project Award; N.B. was supported by The Wellcome Trust, UK, an EASD-ADA, and a Boston Obesity Nutrition Research Center award. J.M.Z. was supported grants from the National Institutes of Health (1F32DK64564-01 and 5T32DK07516).

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Dhillon, H., Zigman, J. M., Ye, C., Lee, C. E., McGovern, R. A., Tang, V., Kenny, C. D., Christiansen, L. M., White, R. D., Edelstein, E. A., Coppari, R., Balthasar, N., Cowley, M. A., Chua, S., Elmquist, J. K., & Lowell, B. B. (2006). Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron, 49(2), 191-203. https://doi.org/10.1016/j.neuron.2005.12.021

Dhillon, H, Zigman, JM, Ye, C, Lee, CE, McGovern, RA, Tang, V, Kenny, CD, Christiansen, LM, White, RD, Edelstein, EA, Coppari, R, Balthasar, N, Cowley, MA, Chua, S, Elmquist, JK & Lowell, BB 2006, 'Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis', Neuron, vol. 49, no. 2, pp. 191-203. https://doi.org/10.1016/j.neuron.2005.12.021

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AU - Balthasar, Nina

AU - Cowley, Michael A.

AU - Chua, Streamson

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N2 - Leptin, an adipocyte-derived hormone, acts directly on the brain to control food intake and energy expenditure. An important question is the identity of first-order neurons initiating leptin's anti-obesity effects. A widely held view is that most, if not all, of leptin's effects are mediated by neurons located in the arcuate nucleus of the hypothalamus. However, leptin receptors (LEPRs) are expressed in other sites as well, including the ventromedial hypothalamus (VMH). The possible role of leptin acting in "nonarcuate" sites has largely been ignored. In the present study, we show that leptin depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-positive neurons in the VMH. We also show, by generating mice that lack LEPRs on SF1-positive neurons, that leptin action at this site plays an important role in reducing body weight and, of note, in resisting diet-induced obesity. These results reveal a critical role for leptin action on VMH neurons.

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Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis

Abstract

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