title: Lipocalin 2 regulates brown fat activation via a nonadrenergic activation mechanism.
abstract: In this study, we report that lipocalin 2 (Lcn2), a recently characterized adipokine/cytokine, is a novel regulator of brown adipose tissue (BAT) activation by modulating the adrenergic independent p38 MAPK-PGC-1α-UCP1 pathway. Global Lcn2 knock-out (Lcn2(-/-)) mice have defective BAT thermogenic activation caused by cold stimulation and decreased BAT activity under high fat diet-induced obesity. Nevertheless, Lcn2(-/-) mice maintain normal sympathetic nervous system activation as evidenced by normal catecholamine release and lipolytic activity in response to cold stimulation. Further studies showed that Lcn2 deficiency impairs peroxisomal and mitochondrial oxidation of lipids and attenuates cold-induced Pgc1a and Ucp1 expression and p38 MAPK phosphorylation in BAT. Moreover, in vitro studies showed that Lcn2 deficiency reduces the thermogenic activity of brown adipocytes. Lcn2(-/-) differentiated brown adipocytes have significantly decreased expression levels of brown fat markers, decreased p38 MAPK phosphorylation, and decreased mitochondrial oxidation capacity. However, Lcn2(-/-) brown adipocytes have normal norepinephrine-stimulated p38 MAPK and hormone-sensitive lipase phosphorylation and Pgc1a and Ucp1 expression, suggesting an intact β-adrenergic signaling activation. More intriguingly, recombinant Lcn2 was able to significantly stimulate p38 MAPK phosphorylation in brown adipocytes. Activating peroxisome proliferator-activated receptor γ, a downstream effector of PGC-1α, by thiazolidinedione administration fully reverses the BAT function of Lcn2(-/-) mice. Our findings provide evidence for the novel role Lcn2 plays in oxidative metabolism and BAT activation via an adrenergic independent mechanism.
authors.affiliation: From the Department of Food Science and Nutrition.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Food Science and Nutrition.
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.affiliation: From the Department of Food Science and Nutrition.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Deis
authors.affiliation: From the Department of Food Science and Nutrition.
authors.forename: Mara G
authors.initials: MG
authors.lastname: Mashek
authors.affiliation: From the Department of Food Science and Nutrition.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Minnesota Veterinary Diagnostic Laboratory, Department of Veterinary Population Medicine, and.
authors.forename: DonSanjiv
authors.initials: D
authors.lastname: Ariyakumar
authors.affiliation: Minnesota Veterinary Diagnostic Laboratory, Department of Veterinary Population Medicine, and.
authors.forename: Anibal G
authors.initials: AG
authors.lastname: Armien
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Twin Cities, Minnesota 55108.
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
authors.affiliation: From the Department of Food Science and Nutrition.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mashek
authors.affiliation: From the Department of Food Science and Nutrition, xlchen@umn.edu.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chen
mesh_terms: D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052437:Adipocytes, Brown / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D015870:Gene Expression; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020675:Peroxisomes / Q000378:metabolism; D010766:Phosphorylation; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D002395:Catecholamines; D007473:Ion Channels; D000071068:Lipocalin-2; D054834:Lipocalins; D024101:Mitochondrial Proteins; D015513:Oncogene Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C071332:Lcn2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Adipose Tissue; Brown Adipose Tissue; Gene Knock-out; Lipocalin 2; Mitochondria; Mitochondrial Biogenesis and Oxidation; Peroxisomal Oxidation; Peroxisome; Thermogenesis; p38 MAPK