Leptin Impairs Metabolic Actions of Insulin in Isolated Rat Adipocytes

Abstract

Leptin is an adipocyte hormone involved in the regulation of energy homeostasis. Generally accepted biological effects of leptin are inhibition of food intake and stimulation of metabolic rate in ob/ob mice that are defective in the leptin gene. In contrast to these centrally mediated effects of leptin, we are reporting here on leptin effects on isolated rat adipocytes. Leptin impairs several metabolic actions of insulin, i.e. stimulation of glucose transport, glycogen synthase, lipogenesis, inhibition of isoproterenol-induced lipolysis, and protein kinase A activation, as well as stimulation of protein synthesis. Insulin effects were reduced by leptin (2 nM) with a half-life of about 8 h. At low leptin concentrations (<1 nM), the insulin sensitivity was reduced leading to a shift to the right in the dose-response curve. At higher concentrations the responsiveness was diminished, resulting in nearly complete inhibition of insulin effects at >30 nM leptin. The IC 50 value of leptin was 3.1 ؎ 1 nM after 15 h of preincubation of adipocytes in primary culture. The natural splice variant des-Gln 49 -leptin exhibited a significantly lower potency. Adipocytes regained full insulin sensitivity within a few hours after leptin removal. The stimulation of glucose transport by vanadate was not affected by leptin. These data show specific and potent impairment of insulin action by leptin in the physiological concentration range of both leptin and insulin, which may be related to the pathophysiology of insulin resistance in both non-insulin-dependent diabetes mellitus and obesity.

Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’

“…In nondiabetic, but not in type 2 diabetic subjects a strong relationship between leptin levels and insulin action on glucose uptake in subcutaneous fat cells was also found. Previous studies have shown a relationship between in vivo insulin resistance and leptin levels [28,29], and leptin has been shown to cause insulin resistance in rat fat cells in vitro [30]. Since leptin was associated with subcutaneous fat cell size as well as insulin resistance in vitro in this study, leptin may serve as a marker and possibly be a link between fat cell size and insulin resistance.…”

Association of a missense mutation in the bovine leptin gene with carcass fat content and leptin mRNA levels

“…Systemic or central administration of leptin reduces feed intake in rodents, chickens, pigs, and sheep [1,13,15,24] and while data from livestock species remains sparse, leptin appears to be an important component of a feedback loop involving key metabolic regulators including insulin, glucocorticoids and the sympathetic nervous system [16]. Finally, in vitro studies suggest that leptin can directly modulate energy metabolism in peripheral tissues and may antagonize insulin activities in adipose [21] and muscle [22]. These physiological properties support leptin as a strong candidate gene for evaluation of genetic polymorphisms that could affect carcass fat content in cattle.…”

Pivotal role of leptin in insulin effects

“…At higher leptin concentrations the responsiveness to insulin was progressively diminished, resulting in nearly complete inhibition of insulin effects at >30 nM leptin. It was also reported that leptin inhibits glycogen synthase activity, protein synthesis and lipogenesis while increasing lipolysis and protein kinase A activation (38). In contrast to these dramatic inhibitory actions of leptin on insulin-stimulated effects, leptin did not reduce glucose uptake or lipogenesis in the absence of insulin, but slightly increased them (1.3-fold at 100 nM).…”

“…However, very few data are available regarding this issue. Recently, it was demonstrated that in isolated rat adipocytes, leptin impairs the metabolic actions of insulin (38).…”