The brain detects alterations in diet and energy balance, and through various neural circuits, regulates energy intake and energy expenditure. Dysfunction of these homeostatic mechanisms results in obesity, an epidemic problem in affluent societies. Identification of the neural circuits, as well as the molecular effectors operating within these circuits, is a major focus of obesity research. Based upon brain lesion studies, the ventromedial hypothalamus (VMH) has been proposed to play an important role in preventing obesity. Over time, this view fell out of favor, in part because of uncertainty regarding the anatomic specificity of crude, obesity-inducing lesions. More recently, interest in the VMH, as a site of body weight control, has increased. These recent developments, which point to a significant role for the VMH, include: 1) high-level expression of functionally active leptin receptors on VMH neurons, 2) abnormal VMH development and obesity in steroidogenic factor-1 (SF1) gene knockout mice, including mice with brain-specific SF1 gene knockout, 3) nutritional regulation of brain-derived neurotrophic factor (BDNF) in the VMH, 4) obesity in mice with genetic deficiency of BDNF, or its receptor, TrkB, and 5) development of obesity in mice lacking leptin receptors in the VMH (this application). Thus, substantial evidence makes a compelling argument that the VMH plays an important role in preventing obesity. This provides a unique opportunity for novel discoveries as the VMH, in the current """"""""molecular age"""""""", has been underappreciated as a controller of energy homeostasis. With this in mind, the goal of the present application is to use genetic tools (cre/lox neuron-specific gene knockouts) to test the hypotheses that leptin signaling (Aim #1), BDNF expression (Aim #2), melanocortin receptor-4 (MC4R) signaling (Aim #3), and glutamatergic signaling (Aim #4) within the VMH, play important roles in preventing obesity. Novel discoveries of molecular pathways within the VMH that restrict body weight gain could identify new causes of obesity, as well as new therapies for this epidemic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071051-04
Application #
7340749
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Sato, Sheryl M
Project Start
2005-04-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$347,528
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Campbell, John N; Macosko, Evan Z; Fenselau, Henning et al. (2017) A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20:484-496
Garfield, Alastair S; Shah, Bhavik P; Burgess, Christian R et al. (2016) Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci 19:1628-1635
Crowley, Nicole A; Bloodgood, Daniel W; Hardaway, J Andrew et al. (2016) Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit. Cell Rep 14:2774-83
Krashes, Michael J; Lowell, Bradford B; Garfield, Alastair S (2016) Melanocortin-4 receptor-regulated energy homeostasis. Nat Neurosci 19:206-19
Vetrivelan, Ramalingam; Kong, Dong; Ferrari, Loris L et al. (2016) Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 336:102-113
Kong, Dong; Dagon, Yossi; Campbell, John N et al. (2016) A Postsynaptic AMPK?p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons. Neuron 91:25-33
Al-Hasani, Ream; McCall, Jordan G; Shin, Gunchul et al. (2015) Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward. Neuron 87:1063-77
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
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
Garfield, Alastair S; Shah, Bhavik P; Madara, Joseph C et al. (2014) A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab 20:1030-7

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