title: C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes.
abstract: Despite the prevalence of insulin resistance and type 2 diabetes mellitus, their underlying mechanisms remain incompletely understood. Many secreted endocrine factors and the intertissue cross-talk they mediate are known to be dysregulated in type 2 diabetes mellitus. Here, we describe CTRP12, a novel adipokine with anti-diabetic actions. The mRNA and circulating levels of CTRP12 were decreased in a mouse model of obesity, but its expression in adipocytes was increased by the anti-diabetic drug rosiglitazone. A modest rise in circulating levels of CTRP12 by recombinant protein administration was sufficient to lower blood glucose in wild-type, leptin-deficient ob/ob, and diet-induced obese mice. A short term elevation of serum CTRP12 by adenovirus-mediated expression improved glucose tolerance and insulin sensitivity, normalized hyperglycemia and hyperinsulinemia, and lowered postprandial insulin resistance in obese and diabetic mice. CTRP12 improves insulin sensitivity in part by enhancing insulin signaling in the liver and adipose tissue. Further, CTRP12 also acts in an insulin-independent manner; in cultured hepatocytes and adipocytes, CTRP12 directly activated the PI3K-Akt signaling pathway to suppress gluconeogenesis and promote glucose uptake, respectively. Collectively, these data establish CTRP12 as a novel metabolic regulator linking adipose tissue to whole body glucose homeostasis through insulin-dependent and independent mechanisms.
authors.affiliation: Departments of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Zhikui
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Departments of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Peterson
authors.affiliation: Departments of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.affiliation: Departments of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Cebotaru
authors.affiliation: Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wolfgang
authors.affiliation: Departments of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: G Christian
authors.initials: GC
authors.lastname: Baldeviano
authors.affiliation: Departments of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. Electronic address: gwwong@jhmi.edu.
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
mesh_terms: D000256:Adenoviridae; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D054392:Adipokines / Q000097:blood* / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005943:Gluconeogenesis / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008820:Mice, Obese; D009765:Obesity / Q000097:blood* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D054392:Adipokines; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C568466:C1qtnf12 protein, mouse