Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats

Abstract

We investigated the chronic in vivo effect of resistin on insulin sensitivity and glucose metabolism by overexpressing resistin protein in male Wistar rats using intravenous administration of an adenovirus encoding mouse resistin. After 7 days of elevated resistin levels at a supraphysiological concentration, the animals displayed glucose intolerance and hyperinsulinemia during glucose tolerance tests, and insulin tolerance tests demonstrated an impaired glucose-lowering effect of insulin. The glucose clamp studies were performed at submaximal (4 mU/kg/min) and maximal (25 mU/kg/min) insulin infusion rates and demonstrated the presence of insulin resistance induced by elevated resistin levels. Indeed, the insulin-stimulated glucose infusion rate was decreased by 12-31%; suppression of hepatic glucose output was attenuated by 28-55%; and insulin suppression of circulating FFA levels was inhibited by 7%. Insulin receptor substrate-1 and -2 phosphorylation and Akt activation were impaired in muscle and adipose tissue. Interestingly, activation of AMP-activated protein kinase in skeletal muscle, liver, and adipose tissue was also significantly downregulated. Together, these results indicate that chronic "hyper-resistinemia" leads to whole-body insulin resistance involving impaired insulin signaling in skeletal muscle, liver, and adipose tissue, resulting in glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. Thus elevated resistin levels in normal rats fed a regular chow diet produce many of the features of human syndrome X.

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

“…Considerable debate exists regarding the role of resistin in the pathophysiology of insulin resistance in humans and animals and as to whether resistin acts primarily in muscle, liver or fat [2,3,5,[29][30][31][32]. However, several studies provide convincing evidence for an effect of resistin in skeletal muscle.…”

“…However, several studies provide convincing evidence for an effect of resistin in skeletal muscle. For example, use of adenovirus to overexpress murine resistin at supraphysiological concentrations for 7 days in male Wistar rats caused glucose intolerance, hyperinsulinaemia and an impaired ability of insulin to lower blood glucose [31]. Resistin caused insulin resistance at the level of both skeletal muscle (decreased insulin-stimulated glucose infusion during clamp) and liver (attenuation of suppression of hepatic glucose output) [31].…”

Increased serum resistin in elite endurance athletes with high insulin sensitivity

“…2b). A comparison with the literature for these aspects is difficult because only recently some effects of resistin on lipid metabolism were reported; a hypertriglyceridaemic effect in vivo in animals [3,33] and a lipolytic effect in vitro [34]. It would appear, therefore, that resistin may be associated with increased NEFA availability in the bloodstream and in this regard it is interesting to note the parallelism with the previously reported paradox of the increased intra-myocellular lipid content despite the high insulin sensitivity reported in athletes [35].…”

“…In addition, adenovirusmediated chronic 'hyper-resistinaemia' induced in vivo insulin resistance in normal rats [3] and hepatic insulin resistance in high-fat-fed mice [4]. Based on this research in animal models, it was hypothesised that resistin might represent the link between obesity and insulin resistance.…”

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

“…[6][7][8][9][10][11] In the current studies, we concentrated on the role of resistin in lipid metabolism. We tested the hypothesis that resistin might promote release of FFA from adipocytes by suppressing the re-esterfication of FFA into triglycerides.…”