Regulation of Resistin Expression and Circulating Levels in Obesity, Diabetes, and Fasting

Abstract

Resistin was originally reported as an adipose tissuespecific 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 wildtype 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.

Brain Adipocytokine Action and Metabolic Regulation

“…As with leptin, resistin falls during fasting and increases during refeeding (32). These changes are controlled, at least in part, by insulin and glucose (32).…”

“…Resistin circulates as hexamers and trimers. There appears to be a discrepancy between resistin mRNA expression and protein levels in the circulation, such that plasma levels are increased in obesity while mRNA levels in WAT are reduced (32). As with leptin, resistin falls during fasting and increases during refeeding (32).…”

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

“…Plasma resistin levels are increased in ob/ob, db/db and diet-induced obese mice [6], although, concomitantly, resistin mRNA levels in obese rodents are often found to be decreased [7][8][9]. It is now appreciated that there is often a discrepancy between the circulating protein levels of resistin and the mRNA content in adipocytes [10,11].…”

Regulation of human resistin gene expression in cell systems: an important role of stimulatory protein 1 interaction with a common promoter polymorphic site

“…Many studies show that various hormones and drugs influencing insulin sensitivity regulate resistin mRNA expression in cell culture and animal models [14][15][16][17]. Glucose and dexamethasone increase resistin mRNA levels, but insulin, TNF-α and thiazolidinediones suppress the expression of resistin.…”