One of the overall goals of this proposal is to understand the role of PKA signaling in the neuronal pathways that regulate feeding and energy expenditure. Mouse genetic techniques allow us to investigate this problem in a physiological setting and also provide us with novel tools for defining regulation at the molecular level. We propose to use a mouse genetic approach to detect and quantities neuron-specific mRNA regulation in regions of the hypothalamus known to be involved in body weight regulation and the response to the adipose derived hormone, leptin. In addition to detecting changes in transcription we will examine the potential role of translational control of pre-existing mRNAs. Recent work has continued to challenge and expand our views on the neural control of body weight. Leptin receptors have been shown to engage multiple signaling pathways in a neuron specific pattern and the crosstalk between these signaling systems, including the cAMP/PKA pathway, is a new avenue that needs to be explored more comprehensively. The RII2 KO mouse line is lean and resistant to diet-induced obesity and our recent results indicate that this is because of an increase in leptin sensitivity in the brain.
The specific aims of this proposal are: (1) Identify the hypothalamic neurons in which PKA activity plays a role in leptin sensitivity and body weight regulation (2) Assay changes in polysome-associated mRNAs in specific hypothalamic neurons in response to diet and leptin (3) Determine the mechanism of increased leptin sensitivity in RII2 KO mice. The sensitivity of the hypothalamic response network to leptin is one of the ultimate determinants of how much energy is stored as fat and leptin resistance is one of the defining features of obesity.

Public Health Relevance

The regulation of feeding and energy balance is coordinated by neurons in the hypothalamic region of the brain. We have demonstrated that intracellular signaling through the cAMP/Protein Kinase A system can regulate this neuronal pathway and prevent diet-induced obesity in mice. In this project, we will study this mechanism for regulating energy balance and hope to reveal novel therapeutic targets for future clinical applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032875-28
Application #
8487414
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Gerratana, Barbara
Project Start
1997-09-30
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
28
Fiscal Year
2013
Total Cost
$385,336
Indirect Cost
$136,501
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yang, Linghai; McKnight, G Stanley (2015) Hypothalamic PKA regulates leptin sensitivity and adiposity. Nat Commun 6:8237
Gilbert, Merle L; Yang, Linghai; Su, Thomas et al. (2015) Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype. Am J Physiol Renal Physiol 308:F627-38
Sanz, Elisenda; Quintana, Albert; Deem, Jennifer D et al. (2015) Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. J Neurosci 35:5549-56
Vulto-van Silfhout, Anneke T; Rajamanickam, Shivakumar; Jensik, Philip J et al. (2014) Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. Am J Hum Genet 94:649-61
Yang, Linghai; Gilbert, Merle L; Zheng, Ruimao et al. (2014) Selective expression of a dominant-negative type Iα PKA regulatory subunit in striatal medium spiny neurons impairs gene expression and leads to reduced feeding and locomotor activity. J Neurosci 34:4896-904
Wu, Qi; Zheng, Ruimao; Srisai, Dollada et al. (2013) NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus. Proc Natl Acad Sci U S A 110:14765-70
Zheng, Ruimao; Yang, Linghai; Sikorski, Maria A et al. (2013) Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations. Proc Natl Acad Sci U S A 110:E1631-40
Quintana, Albert; Sanz, Elisenda; Wang, Wengang et al. (2012) Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors. Nat Neurosci 15:1547-55
Jones, Brian W; Brunet, Sylvain; Gilbert, Merle L et al. (2012) Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation. Proc Natl Acad Sci U S A 109:17099-104
Lu, Yuan; Zha, Xiang-ming; Kim, Eun Young et al. (2011) A kinase anchor protein 150 (AKAP150)-associated protein kinase A limits dendritic spine density. J Biol Chem 286:26496-506

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