title: Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice.
abstract: Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoiswohl
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Maja
authors.initials: M
authors.lastname: Stefanovic-Racic
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Marie N
authors.initials: MN
authors.lastname: Menke
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Wills
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Surlow
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Basantani
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Mitch T
authors.initials: MT
authors.lastname: Sitnick
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Cai
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Cynthia F
authors.initials: CF
authors.lastname: Yazbeck
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.affiliation: Division of Endocrinology and Metabolism (G.S., M.S.-R., R.C.W., B.A.S., M.K.B., M.T.S., L.C., C.F.Y., R.M.O., E.E.K.), Department of Medicine, and Department of Cell Biology (D.B.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Obstetrics, Gynecology, and Reproductive Sciences (M.N.M.), Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Biochemistry and Molecular Biology (T.P.), Dalhousie Medicine New Brunswick, Dalhousie University, St John, Canada NB E2L 4L5.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Kershaw
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D015870:Gene Expression; D015151:Immunoblotting; D007249:Inflammation / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood; D008066:Lipolysis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000217:Acyltransferases
chemical_list: D000943:Antigens, Differentiation; D039521:CD11c Antigen; D008049:Lipase; D008055:Lipids; C036763:monocyte-macrophage differentiation antigen; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases