Obesity-induced endoplasmic reticulum (ER) stress causes chronic
inflammation in adipose tissue and steatosis in the liver, and eventually leads to
insulin resistance and
type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of
bilirubin, a powerful
antioxidant, reduces
hyperglycemia and ameliorates
obesity in
leptin-receptor-deficient (db/db) and diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with
bilirubin or vehicle ip.
Blood glucose and
body weight were measured. Activation of
insulin-signaling pathways, expression of inflammatory
cytokines, and ER stress markers were measured in skeletal muscle, adipose tissue, and liver of mice.
Bilirubin administration significantly reduced
hyperglycemia and increased
insulin sensitivity in db/db mice.
Bilirubin treatment increased
protein kinase B (PKB/Akt) phosphorylation in skeletal muscle and suppressed expression of ER stress markers, including the 78-kDa
glucose-regulated
protein (
GRP78),
CCAAT/enhancer-binding protein (
C/EBP) homologous protein, X box
binding protein (XBP-1), and
activating transcription factor 4 in db/db mice. In DIO mice,
bilirubin treatment significantly reduced
body weight and increased
insulin sensitivity. Moreover,
bilirubin suppressed macrophage infiltration and proinflammatory
cytokine expression, including TNF-α, IL-1β, and
monocyte chemoattractant protein-1, in adipose tissue. In liver and adipose tissue of DIO mice,
bilirubin ameliorated hepatic steatosis and reduced expression of
GRP78 and
C/EBP homologous protein. These results demonstrate that
bilirubin administration improves
hyperglycemia and
obesity by increasing
insulin sensitivity in both genetically engineered and DIO mice models.
Bilirubin or
bilirubin-increasing drugs might be useful as an
insulin sensitizer for the treatment of
obesity-induced
insulin resistance and
type 2 diabetes based on its profound anti-ER stress and antiinflammatory properties.