The overall objective is to define the Ca2+-dependent signaling pathway in hypothalamic neurons that regulates appetite and body weight to provide novel insights to human obesity. AMPK, originally discovered to protect cells against stresses that deplete ATP, is a key enzyme in the pathways by which ghrelin and leptin act on arcuate nucleus (ARM) hypothalamic neurons to control production of NPY and, thus, appetite, energy homeostasis and body weight. Ca2+ is a ubiquitous 2nd messenger that mediates signaling cascades initiated by hormones and growth factors, in which calmodulin (CaM) is the Ca2+ receptor and Ca2+/CaM- dependent protein kinases (CaMK) transduce the Ca2+/CaM signal resulting in many cell responses. A """"""""CaMK cascade"""""""" has been identified composed of Ca2+/CaM, a CaMKK (a or P) and a CaMK (I or IV). Recently the CaMKKs have also been shown to function as AMPKKs and are required to activate AMPK in some human cells. CaMKKp, a brain-specific enzyme, is expressed in the ARM and CaMKKp""""""""'"""""""" mice show decreased hypothalamic AMPK phosphorylation/activity as well as NPY/AgRP mRNAs. Indeed, CaMKKp""""""""'"""""""" mice share many phenotypes with mice null for NPY or an NPY receptor. Infusion of the only selective CaMKK antagonist, STO-609, into the 3rd ventricle of adult wild-type mice results in acute decreases in food intake and body weight as well as hypothalamic content of NPY/AgRP mRNAs. We hypothesize that CaMKKp serves as a primary AMPKK in NPY/AgRP neurons and that acute inhibition of this enzyme leads to decreased production of NPY which causes decreased food intake, altered energy homeostasis and weight loss. To evaluate this hypothesis we will: 1) utilize genetically altered mice to investigate the physiologically relevant role(s) of the CaMKKs, p and a as AMPKKs in mouse hypothalamus and cultured cells to clarify pathways that regulate NPY gene expression and malonyl CoA level;and 2) define the physical interaction between the CaMKKs and AMPK by employing molecular and biochemical technology to understand the nature of the CaMKK/AMPK signaling complex and how this complex can be inhibited. Our results should validate CaMKKp as a target for drug discovery, which could eventually lead to identification of new therapeutics to treat obesity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Gerratana, Barbara
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Duke University
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York, Brian; Li, Feng; Lin, Fumin et al. (2017) Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD. Sci Rep 7:11793
Marcelo, Kathrina L; Ribar, Thomas; Means, Christopher R et al. (2016) Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism. Mol Endocrinol 30:557-72
Marcelo, Kathrina L; Means, Anthony R; York, Brian (2016) The Ca(2+)/Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft. Trends Endocrinol Metab 27:706-718
Fleet, Tiffany; Stashi, Erin; Zhu, Bokai et al. (2016) Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology. J Biol Rhythms 31:443-60
Koh, Eun Hee; Chen, Yong; Bader, David A et al. (2016) Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis. J Biol Chem 291:24747-24755
Scott, John W; Park, Elizabeth; Rodriguiz, Ramona M et al. (2015) Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Sci Rep 5:14436
Fleet, Tiffany; Zhang, Bin; Lin, Fumin et al. (2015) SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis. Proc Natl Acad Sci U S A 112:E6068-77
Hartig, Sean M; Bader, David A; Abadie, Kathleen V et al. (2015) Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes. Mol Endocrinol 29:1320-33
Zhu, Bokai; Gates, Leah A; Stashi, Erin et al. (2015) Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude via REV-ERB Loading. Mol Cell 60:769-783
Marcelo, Kathrina L; Lin, Fumin; Rajapakshe, Kimal et al. (2015) Deciphering hepatocellular responses to metabolic and oncogenic stress. J Biol Methods 2:

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