title: Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity.
abstract: We investigated GH action on macrophage (MΦ) by creating a MΦ-specific GH receptor-null mouse model (MacGHR KO). On a normal diet (10% fat), MacGHR KO and littermate controls exhibited similar growth profiles and glucose excursions on intraperitoneal glucose (ipGTT) and insulin tolerance (ITT) tests. However, when challenged with high fat diet (HFD, 45% fat) for 18 weeks, MacGHR KO mice exhibited impaired ipGTT and ITT compared with controls. In MacGHR KO, adipose-tissue (AT) MΦ abundance was increased with skewing toward M1 polarization. Expression of pro-inflammatory cytokines (IL1β, TNF-α, IL6, and osteopontin (OPN)) were increased in MacGHR KO AT stromal vascular fraction (SVF). In MacGHR KO AT, crown-like-structures were increased with decreased insulin-dependent Akt phosphorylation. The abundance of phosphorylated NF-κB and of OPN was increased in SVF and bone-marrow-derived MΦ in MacGHR KO. GH, acting via an NF-κB site in the distal OPN promoter, inhibited the OPN promoter. Thus in diet-induced obesity (DIO), lack of GH action on the MΦ exerts an unexpected deleterious effect on glucose homeostasis by accentuating AT inflammation and NF-κB-dependent activation of OPN expression. These novel results in mice support the possibility that administration of GH could have salutary effects on DIO-associated chronic inflammation and insulin resistance in humans.
authors.affiliation: Department of Pediatrics & Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Lu
authors.forename: P Anil
authors.initials: PA
authors.lastname: Kumar
authors.forename: Jinhong
authors.initials: J
authors.lastname: Sun
authors.forename: Anjali
authors.initials: A
authors.lastname: Aggarwal
authors.forename: Yong
authors.initials: Y
authors.lastname: Fan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sperling
authors.forename: Carey N
authors.initials: CN
authors.lastname: Lumeng
authors.forename: Ram K
authors.initials: RK
authors.lastname: Menon
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004032:Diet / Q000009:adverse effects*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D016328:NF-kappa B; C506896:Spp1 protein, mouse; D053495:Osteopontin; D013006:Growth Hormone; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; C051815:somatotropin-binding protein
keywords: Adipose Tissue; Growth Hormone; Inflammation; Macrophages; Obesity