title: Calcium/calmodulin-dependent protein kinase kinase 2 regulates macrophage-mediated inflammatory responses.
abstract: Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) plays a key role in regulating food intake and energy expenditure at least in part by its actions in hypothalamic neurons. Previously, we showed that loss of CaMKK2 protected mice from high-fat diet (HFD)-induced obesity and glucose intolerance. However, although pair feeding HFD to WT mice to match food consumption of CAMKK2-null mice slowed weight gain, it failed to protect from glucose intolerance. Here we show that relative to WT mice, HFD-fed CaMKK2-null mice are protected from inflammation in adipose and remain glucose-tolerant. Moreover, loss of CaMKK2 also protected mice from endotoxin shock and fulminant hepatitis. We explored the expression of CaMKK2 in immune cells and found it to be restricted to those of the monocyte/macrophage lineage. CaMKK2-null macrophages exhibited a remarkable deficiency to spread, phagocytose bacteria, and synthesize cytokines in response to the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS). Mechanistically, loss of CaMKK2 uncoupled the TLR4 cascade from activation of protein tyrosine kinase 2 (PYK2; also known as PTK2B). Our findings uncover an important function for CaMKK2 in mediating mechanisms that control the amplitude of macrophage inflammatory responses to excess nutrients or pathogen derivatives.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Duke University, Durham, North Carolina 27710, USA. luigi.racioppi@duke.edu
authors.forename: Luigi
authors.initials: L
authors.lastname: Racioppi
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Noeldner
authors.forename: Fumin
authors.initials: F
authors.lastname: Lin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Arvai
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Means
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis; D059305:Diet, High-Fat / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055786:Gene Knockout Techniques; D018149:Glucose Intolerance / Q000209:etiology / Q000517:prevention & control; D006505:Hepatitis / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D012772:Shock, Septic / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D018925:Chemokines; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051418:Focal Adhesion Kinase 2; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse