The VMH and Molecular Control of Energy Balance The ventral medial hypothalamus (VMH), in concert with other brain regions, regulates energy balance. A group of neurons within the VMH, marked by the expression of the transcription factor, SF1 (Nr5a1), resists the development of obesity. The adipocyte-derived, "catabolic" hormone leptin excites these SF1 neurons, and deletion of leptin receptors (LEPRs) on SF1 neurons results in obesity, and also marked sensitivity to diet-induced obesity. Thus, SF1 neurons in the VMH, like POMC neurons in the actuate nucleus, are direct targets of leptin and promote negative energy balance. While much is known about how POMC neurons cause weight loss, comparatively less is known about how SF1 neurons achieve this effect. This presents the unique opportunity to identify novel mechanisms controlling energy homeostasis. In this grant, we propose to determine the following: 1) the "catabolic" factor released by SF1 neurons (we propose an important role for the neuropeptide, PACAP) (Aim 1), 2) the receptor and neuron immediately downstream of SF1 neurons (we propose that the PAC1-receptor - the high affinity PACAP receptor - on POMC neurons is important) (Aim 2), and 3) on the afferent side of SF1 neurons, we propose that glutamatergic excitatory inputs, which synapse on dendritic spines of SF1 neurons, play a key role in controlling the activity of SF1 neurons, and that glutamate NMDA receptor-mediated plasticity of these inputs, and, importantly, leptin regulation of this plasticity, contributes prominently to the control of energy homeostasis. To accomplish these Aims, we will utilize the following state-of-the-art technologies: 1) neuron- specific gene manipulation to test molecular mechanisms in an in vivo context (in all three Aims), 2) optogenetics to identify functionally relevant, monosynaptic, downstream targets of SF1 neurons (in Aim 2), and 3) functional and morphologic assessments of excitatory synaptic plasticity (in Aim 3).

Public Health Relevance

Complex neurocircuits in the brain work in concert to control body fat stores. In order to intelligently develop anti-obesity therapies, it is first necessary to decipher the "wiring-diagrams" that underpin these circuits. To accomplish this, our group is using the following state-of-the-art technologies: 1) neuron-specific gene manipulations, 2) optogenetics (light-activated neuron stimulation), and 3) functional-morphologic assessments of synaptic organization and plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071051-08
Application #
8233515
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2005-04-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
8
Fiscal Year
2012
Total Cost
$361,316
Indirect Cost
$153,663
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Berglund, Eric D; Liu, Tiemin; Kong, Xingxing et al. (2014) Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat Neurosci 17:911-3
Shah, Bhavik P; Vong, Linh; Olson, David P et al. (2014) MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc Natl Acad Sci U S A 111:13193-8
Krashes, Michael J; Shah, Bhavik P; Madara, Joseph C et al. (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507:238-42
Garfield, Alastair S; Lowell, Bradford B (2013) Was it something I ate? Cell Metab 18:769-70
Krashes, Michael J; Shah, Bhavik P; Koda, Shuichi et al. (2013) Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab 18:588-95
Liu, Tiemin; Kong, Dong; Shah, Bhavik P et al. (2012) Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73:511-22
Klöckener, Tim; Hess, Simon; Belgardt, Bengt F et al. (2011) High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci 14:911-8
Krashes, Michael J; Koda, Shuichi; Ye, ChianPing et al. (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121:1424-8
Xu, Yong; Hill, Jennifer W; Fukuda, Makoto et al. (2010) PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab 12:88-95
Zhang, Ren; Dhillon, Harveen; Yin, Huali et al. (2008) Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight. Endocrinology 149:5654-61

Showing the most recent 10 out of 12 publications