Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance.
OBJECTIVE
We hypothesized that the induction of heme oxygenase (HO)-1 and increased HO activity, which induces arterial antioxidative enzymes and vasoprotection in a mouse and a rat model of diabetes, would ameliorate insulin resistance, obesity, and diabetes in the ob mouse model of type 2 diabetes.


METHODS
Lean and ob mice were intraperitoneally administered the HO-1 inducer cobalt protoporphyrin (3 mg/kg CoPP) with and without the HO inhibitor stannous mesoporphyrin (2 mg/100 g SnMP) once a week for 6 weeks. Body weight, blood glucose, and serum cytokines and adiponectin were measured. Aorta, adipose tissue, bone marrow, and mesenchymal stem cells (MSCs) were isolated and assessed for HO expression and adipogenesis.


RESULTS
HO activity was reduced in ob mice compared with age-matched lean mice. Administration of CoPP caused a sustained increase in HO-1 protein, prevented weight gain, decreased visceral and subcutaneous fat content (P < 0.03 and 0.01, respectively, compared with vehicle animals), increased serum adiponectin, and decreased plasma tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1beta levels (P < 0.05). HO-1 induction improved insulin sensitivity and glucose tolerance and decreased insulin levels. Upregulation of HO-1 decreased adipogenesis in bone marrow in vivo and in cultured MSCs and increased adiponectin levels in the culture media. Inhibition of HO activity decreased adiponectin and increased secretion of TNF-alpha, IL-6, and IL-1beta levels in ob mice.


CONCLUSIONS
This study provides strong evidence for the existence of an HO-1-adiponectin regulatory axis that can be manipulated to ameliorate the deleterious effects of obesity and the metabolic syndrome associated with cardiovascular disease and diabetes.
Li
Ming
M
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA.
Kim
Dong Hyun
DH
Tsenovoy
Peter L
PL
Peterson
Stephen J
SJ
Rezzani
Rita
R
Rodella
Luigi F
LF
Aronow
Wilbert S
WS
Ikehara
Susumu
S
Abraham
Nader G
NG
D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000097:blood*; D000273:Adipose Tissue / Q000033:anatomy & histology* / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000187:drug effects; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology*; D012867:Skin; D013234:Stem Cells / Q000378:metabolism; D013851:Thinness; D014781:Viscera
D052242:Adiponectin; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)