Resistin was originally reported as an adipose tissue-specific
hormone that provided a link between
obesity and diabetes.
Resistin protein level was elevated in obese mice and decreased by
insulin-sensitizing
thiazolidinediones. Immunoneutralization of
resistin improved
insulin sensitivity in diet-induced obese mice, while the administration of exogenous
resistin induced
insulin resistance. More recently, we have shown that ablation of the
resistin gene in mice decreased fasting
glucose through impairment of gluconeogenesis, while
resistin treatment in these knockout mice increased hepatic
glucose production. However, the link between
resistin and
glucose homeostasis has been questioned by studies demonstrating reduced, rather than increased,
resistin mRNA expression in obese and diabetic mice. To better understand the regulation of
resistin, we developed a sensitive and specific RIA
resistin that could accurately measure serum
resistin levels in several mouse models. We show that while
resistin mRNA is indeed suppressed in obese mice, the circulating
resistin level is significantly elevated and positively correlated with
insulin,
glucose, and
lipids. Both
resistin mRNA expression and
protein levels in Lep(ob/ob) mice are suppressed by
leptin treatment in parallel with reductions in
glucose and
insulin. In wild-type mice, serum
resistin increases after nocturnal feeding, concordant with rising levels of
insulin.
Resistin mRNA and
protein levels decline in parallel with
glucose and
insulin during fasting and are restored after refeeding. We performed clamp studies to determine whether
resistin is causally related to
insulin and
glucose. Adipose
resistin expression and serum
resistin increased in response to
hyperinsulinemia and further in response to
hyperglycemia. Taken together, these findings suggest that the nutritional regulation of
resistin and changes in
resistin gene expression and circulating levels in
obesity are mediated, at least in part, through
insulin and
glucose.