title: Perforin is a novel immune regulator of obesity-related insulin resistance.
abstract: Obesity-related insulin resistance is associated with an influx of pathogenic T cells into visceral adipose tissue (VAT), but the mechanisms regulating lymphocyte balance in such tissues are unknown. Here we describe an important role for the immune cytotoxic effector molecule perforin in regulating this process. Perforin-deficient mice (Prf1(null)) show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD). Regulatory effects of perforin on glucose tolerance are mechanistically linked to the control of T-cell proliferation and cytokine production in inflamed VAT. HFD-fed Prf1(null) mice have increased accumulation of proinflammatory IFN-γ-producing CD4(+) and CD8(+) T cells and M1-polarized macrophages in VAT. CD8(+) T cells from the VAT of Prf1(null) mice have increased proliferation and impaired early apoptosis, suggesting a role for perforin in the regulation of T-cell turnover during HFD feeding. Transfer of CD8(+) T cells from Prf1(null) mice into CD8-deficient mice (CD8(null)) resulted in worsening of metabolic parameters compared with wild-type donors. Improved metabolic parameters in HFD natural killer (NK) cell-deficient mice (NK(null)) ruled out a role for NK cells as a single source of perforin in regulating glucose homeostasis. The findings support the importance of T-cell function in insulin resistance and suggest that modulation of lymphocyte homeostasis in inflamed VAT is one possible avenue for therapeutic intervention.
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Xavier S
authors.initials: XS
authors.lastname: Revelo
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Sue
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Helena
authors.initials: H
authors.lastname: Lei
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Luck
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Magar
authors.initials: M
authors.lastname: Ghazarian
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hubert
authors.initials: H
authors.lastname: Tsui
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Sally Y
authors.initials: SY
authors.lastname: Shi
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schroer
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Department of Pathology, University Health Network, Toronto, Ontario, Canada shawn.winer@utoronto.ca dan.winer@uhn.ca.
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Department of Pathology, University Health Network, Toronto, Ontario, Canada shawn.winer@utoronto.ca dan.winer@uhn.ca.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D059305:Diet, High-Fat; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology*; D050152:Intra-Abdominal Fat / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015434:Panniculitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054353:Perforin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D007328:Insulin; C510467:perforin 1, mouse; D054353:Perforin