title: Heme oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity in obesity-induced diabetic rats.
abstract: Obesity-associated inflammation causes insulin resistance. Obese adipose tissue displays hypertrophied adipocytes and increased expression of the cannabinoid-1 receptor. Cobalt protoporphyrin (CoPP) increases heme oxygenase-1 (HO-1) activity, increasing adiponectin and reducing inflammatory cytokines. We hypothesize that CoPP administration to Zucker diabetic fat (ZDF) rats would improve insulin sensitivity and remodel adipose tissue. Twelve-week-old Zucker lean and ZDF rats were divided into 4 groups: Zucker lean, Zucker lean-CoPP, ZDF, and ZDF-CoPP. Control groups received vehicle and treatment groups received CoPP (2 mg/kg body weight) once weekly for 6 weeks. Serum insulin levels and glucose response to insulin injection were measured. At 18 weeks of age, rats were euthanized, and aorta, kidney, and subcutaneous and visceral adipose tissues were harvested. HO-1 expression was measured by Western blot analysis and HO-1 activity by serum carbon monoxide content. Adipocyte size and cannabinoid-1 expression were measured. Adipose tissue volumes were determined using MRI. CoPP significantly increased HO-1 activity, phosphorylated AKT and phosphorylated AMP kinase, and serum adiponectin in ZDF rats. HO-1 induction improved hyperinsulinemia and insulin sensitivity in ZDF rats. Subcutaneous and visceral adipose tissue volumes were significantly decreased in ZDF rats. Adipocyte size and cannabinoid-1 expression were both significantly reduced in ZDF-CoPP rats in subcutaneous and visceral adipose tissues. This study demonstrates that HO-1 induction improves insulin sensitivity, downregulates the peripheral endocannabinoid system, reduces adipose tissue volume, and causes adipose tissue remodeling in a model of obesity-induced insulin resistance. These findings suggest HO-1 as a potential therapeutic target for obesity and its associated health risks.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Nicolai
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Peterson
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Positano
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.forename: Rita
authors.initials: R
authors.lastname: Rezzani
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Rodella
authors.forename: George
authors.initials: G
authors.lastname: Drummond
authors.forename: Claudia
authors.initials: C
authors.lastname: Kusmic
authors.forename: Antonio
authors.initials: A
authors.lastname: L'Abbate
authors.forename: Attallah
authors.initials: A
authors.lastname: Kappas
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D052242:Adiponectin; D011524:Protoporphyrins; D043882:Receptors, Cannabinoid; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase